Synthesis, Reactivity and Structure of Chlorophylls

Chapter 2 Synthesis, Reactivity and Structure of Chlorophylls Mathias O. Senge,*a Arno Wieheb and Claudia Ryppaa a

Institut für Chemie, Universität Potsdam, Karl-Liebknecht-Str. 24-25, D-14476 Golm, Germany; b Biolitec AG, Winzerlaer Str. 2a, D-07745 Jena, Germany

Summary ................................................................................................................................................................. 27 I. Basic Structure and Reactivity of Chlorophylls................................................................................................. 28 II. Conformational Flexibility of Hydroporphyrins .................................................................................................. 28 A. The Concept of Macrocycle Flexibility ................................................................................................ 28 B. Structural Studies ............................................................................................................................... 28 III. Chemical Synthesis of Chlorophylls and Bacteriochlorophylls ......................................................................... 29 A. Total Syntheses.................................................................................................................................. 29 B. Partial Syntheses ............................................................................................................................... 29 IV. Chemical Modifications .................................................................................................................................... 30 A. Manipulation of the Tetrapyrrole Macrocycle ..................................................................................... 30 B. Functional Group Transformations of the Side Chains ...................................................................... 32 C. Chemical Manipulations of Ring E ..................................................................................................... 33 Acknowledgments ................................................................................................................................................... 35 References .............................................................................................................................................................. 35

Summary Chlorophylls (Chls) and bacteriochlorophylls (BChls) are complex tetrapyrroles that continue to attract the attention of synthetic chemists. While Chl reactivity is similar to that of porphyrins, the reduced pyrrole rings which lower their stability and the complex substituent pattern which is observed in nature, makes their syntheses challenging. This chapter reviews the literature from 1990 to 2001 and highlights selected new developments in the organic and structural chemistry of Chl and BChl derivatives with the basic five-ring phytochlorin macrocycle. Structural studies have concentrated on elucidating the influence of different metals and peripheral substituents on the conformational flexibility of the underlying macrocycle. In synthetic chemistry, no significant efforts were made with respect to novel total syntheses of Chls; however, significant advances were made with partial syntheses of numerous BChls with phytochlorin structure, the preparation of divinyl-pheophorbides (Pheides), and the modification of the 3-vinyl group and ring E in Pheides.

*Author for correspondence, email: [email protected]

Bernhard Grimm, Robert J. Porra, Wolfhart Rüdiger and Hugo Scheer (eds): Chlorophylls and Bacteriochlorophylls: Biochemistry, Biophysics, Functions and Applications, pp. 27–37. © 2006 Springer. Printed in The Netherlands.

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I. Basic Structure and Reactivity of Chlorophylls The chemistry of Chls is governed by the aromatic character of the underlying tetrapyrrole moiety and the reactivity of the functional groups in the side chains. As a cyclic tetrapyrrole with a fused five-membered ring, the overall reactivity of Chls is that of a standard heteroaromatic compound. The extended aromatic system, however, which is capable of coordinating almost any known metal with its core nitrogen atoms, together with the variability of its conformation and its side chains, is responsible for its unique role in photosynthesis. The aromatic system of Pheide a 1, as outlined in Fig. 1, is susceptible mainly to electrophilic reactions, e.g., halogenations, with a preference for reaction at C20, the meso position closest to the reduced pyrrole ring. Note that the C7-C8 double bond in phytochlorin is not part of the aromatic delocalization pathway and thus offers a convenient point for modification of the Chl macrocycle via addition and oxidation reactions. The side chain substituents undergo standard transformations, e.g., the C3 vinyl group undergoes addition and oxidation reactions, the ester groups at C173 and C132 can be saponified or transesterified, and the reactivity of ring E is generally governed by enolization and follow-up chemistry of the β-keto ester system. The latter includes the so-called allomerization reactions, i.e. oxidative degradation reactions involving oxidations, hydroxylation, ring-opening or decarboxylations of the isocyclic pentanone ring. The most comprehensive treatise on Chl chemistry remains the article by Hynninen (1991). Only a few developments have been made in the last decade, which will be the focus of this review. II. Conformational Flexibility of Hydroporphyrins A. The Concept of Macrocycle Flexibility One aspect of Chls that received more attention in recent years concerned the conformation of the underlying macrocycle. While it is obvious that an Abbreviations: BChl – bacteriochlorophyll; Chl – chlorophyll; DBU– diazabicycloundecene; DMAP– dimethylaminopyridine; PDT– photodynamic therapy; Pheide – pheophorbide; PPTs– pyridinium p-toluenesulfonate; TMS– trimethylsilyl

Fig. 1. Reactivity profile of pheophorbides also showing ability to incorporate a central metal atom.

extended aromatic system like that of Chl or BChl must be conformationally flexible, the advent of the routine application of X-ray and vibrational spectroscopy to structural studies has enabled more understanding of the importance of this phenomenon for the functional properties of porphyrins. Numerous synthetic, structural and spectroscopic studies have established that macrocycle conformation can control the physicochemical properties of the tetrapyrrole to a significant extent. Increasing nonplanarity with its destabilization of the π-system leads to bathochromically shifted absorption bands, easier oxidation, lower fluorescence yields, larger Stokes shifts, shorter lifetimes of the lowest excited states, faster intersystem crossing and internal conversion. Thus, manipulation of the macrocycle conformation via steric interactions with the surrounding protein side chain in pigment-protein complexes and/or via axial coordination of the central metal can be used to fine-tune the physicochemical properties of the macrocycle. This presents an intriguing rationale for explaining the often diverse (physico)chemical reactivity of the same chromophore in different protein environments. The presence of the reduced pyrrole rings in chlorins and bacteriochlorins leads to even more conformational flexibility than is observed in porphyrins. A complete discussion of this concept and related studies has been presented (Senge, 2000). B. Structural Studies Most studies on isolated (B)Chl derivatives have been aimed at providing high-resolution singlecrystal X-ray data for theoretical calculations and

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conformational studies (Senge, 1992). As before, no small molecule structure of a Chl or BChl has been reported as the highly amphiphilic character prevents the formation of highly-ordered single crystals. Nevertheless, the more-easily crystallized methyl (B)Pheides and phytochlorins allowed a significant expansion of the structural database. Studies from my own group included a methyl 12-acetyl-BPheide d derivative (Senge et al., 1991), methyl phytochlorin, rhodochlorins, Ni(II) bacteriopetroporphyrins and various methyl metalloPheide a derivatives (Senge and Runge, 1998). A new crystalline modification of methyl BPheide a was described by Barkigia and Gottfried (1994). These studies have also prompted the investigation of atypical metal complexes of Chls; for example, FeII and FeIII complexes of methyl Pheide a derivatives (Kadono et al., 1992; Senge et al., 1995). Several studies on methyl Ni(II) Pheide a derivatives, including that of a 20-chloro derivative, allowed comparative analyses of the influence exercised by the central metal, by substituents at C132, by the degree of reduction (i.e. porphyrin vs. chlorin) and by meso substituents (e.g., BChl c vs. BChl d) on conformation (Senge and Smith, 1994). III. Chemical Synthesis of Chlorophylls and Bacteriochlorophylls A. Total Syntheses Woodward’s classic synthesis of Chl a and subsequent modifications thereof still remain the only total syntheses of natural (B)Chls (Woodward et al., 1990; Smith, 1991). In the last decade, many strides have been made towards the development of more general chlorin syntheses (Montforts and Glasenapp-Breiling, 1998). However, these were exclusively aimed at the synthesis of hydroporphyrins containing geminally dialkylated saturated pyrrole rings as they are found in compounds like bonellin, factors I-III, heme d1, siroheme, factor F430, and others. Total syntheses of hydroporphyrins are very laborious and much attention has focused on the development of syntheses using porphyrin-to-hydroporphyrin transformations. These include the typical standard transformations such as SEAr and SNAr reactions of the macrocycle and oxidation or reduction reactions. Modern developments include cycloadditions, intramolecular cyclizations, rearrangements and dimerizations (Vicente and

29 Smith, 2000). Nevertheless, the substituent patterns obtained by such transformations are unrelated to naturally-occurring Chls. B. Partial Syntheses Two notable synthetic methods were developed in recent years. One involves the synthesis of divinyl derivatives of Chl a which are possible intermediates of Chl biosynthesis and important reference compounds. A facile synthesis of an 8-vinyl derivative (see Gerlach et al 1998) involves the reaction of rhodochlorin-15-acetic acid trimethyl ester 2 with OsO4 to yield the vicinal diol 3 which is dehydrated to the vinyl derivative 4. Then follows a new type of mild anaerobic recyclization of ring E using triphenylphosphine and sodium bis(trimethylsilyl)amide to form methyl 8-deethyl-8-vinyl Pheide a 5 (Scheme 1). Preparation of the 3,8-divinyl derivative (including C13-labeled derivatives) initially involved synthesis of a 3-formyl derivative and then manipulation of the 8-position as shown above. Alternatively, transformation of the 3-vinyl group to an acetal, construction of the 8-vinyl group, followed by reconstruction of the 3-vinyl group gave scaled-up entry to the divinyl chlorin 6. An even simpler method involves conversion of methyl Pheide a to 3-devinyl-3-(1-hexyloxyethyl)rhodochlorin-15 acetic acid trimethyl ester (Zheng et al., 1999). Reaction with OsO4/H2S yielded the respective 7,8-dihydroxy bacteriochlorin derivative and heating in 1,2-dichlorobenzene gave the divinyl compound 6 as the main product. Similar methods were used by the group of Tamiaki, who developed comprehensive partial syntheses for various derivatives of BChls d, e, and f. Transformation of the 3-vinyl group in methyl 31,32-didehydrophytochlorin 7 to an acetyl group followed by synthesis of an 8-vinyl group yielded the central intermediate 8. The vinyl group can then be cleaved by oxidation with OsO4/NaIO4 to the 8-formyl derivative 9, which was alkylated with standard Grignard reagents. Dehydration, hydrogenation and reduction of the 3-acetyl group to a 3-(1-hydroxylethyl) group then resulted in the syntheses of, for example, the methyl 8-propyl-12-methyl BPheide d 10 (Tamiaki et al., 1997). The use of 3-acetyl phytochlorins like 11 (or similar BPheides derived from BChl a) in asymmetric borane reductions using (S)-oxazaborolidines allowed a stereoselective reduction to the (31S)-alcohol 12 (Tamiaki et al., 1998). The use of vicinal diols like 3 also allows an en-

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Mathias O. Senge, Arno Wiehe and Claudia Ryppa

Scheme 1

try into the BChl e and f series. The 7,8-dihydroxybacteriochlorin derived from 12 with OsO4 could be dehydrated under mild conditions to a mixture of the primary 13 and secondary alcohols at C7 and C8. The primary alcohol could then be selectively oxidized with pyridinium dichromate to a formyl group yielding a methyl BPheide f 14 (Tamiaki et al., 1999). A more facile approach utilized a 31,32-didehydro-7-demethyl-7-formylphytochlorin 15 (formerly pyropheophytin b) synthetically prepared from Pheide a (Oba et al., 1997), that was then hydrated with HBr/ AcOH to yield a 31-epimeric mixture of 14. Various synthetic derivatives of BChls e and f suitable for aggregation and spectroscopy studies are accessible via this and related routes (Yagai et al., 1999; Tamiaki et al., 2000). Methyl Pheide d 15 (Fischer et al., 1994; Tamiaki et al., 1996a) provided a convenient entry into various Chl a homologs 16 with modifications at C3 (Tamiaki and Kouraba, 1997).

IV. Chemical Modifications A. Manipulation of the Tetrapyrrole Macrocycle Osmylation of C7-C8 to yield cis-diols has become one of the most widely applied methods in Chl chemistry (Pandey et al., 1992a); formally, this constitutes a chlorin to bacteriochlorin conversion. Compared to the old and cumbersome di-imide reduction, this method has the added benefit of yielding β-substituted (dihydro)pyrrole rings that are more stable against oxidation than unsubstituted ones. Using dihydroxylation for initial modification of the Chl macrocycle, further chemistry then allows the various partial syntheses of BChls described above. In addition, this has led to numerous applications in the syntheses of chlorins, bacteriochlorins, and isobacteriochlorins for applications in PDT (Kozyrev et al. 1996a, Pandey, 2000). The regioselectivity of this reaction is dependent on the central metal and the

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31

Scheme 2

peripheral substituents. The step following dihydroxylation usually involves either dehydratation (to yield 7-methyl-8-vinyl chlorins) or pinacol-pinacolone rearrangements (to yield e.g., 7-oxo-8-methyl-8ethyl bacteriochlorins); however, a thermally induced dimerization yielding C7-C8 linked chlorin dimers that are connected via (–CH=CH–CH2–)-bridges has also been described (Kozyrev et al., 1999). Of more specialized interest are methods to prepare 20-halogenated Chl derivatives like 18 as

models for BChls c and d. While some of the compounds have been known for some time, efficient methods for the fluorination (with CsSO4F or Nfluoropyridinium triflate), chlorination (enzymatic with chloroperoxidase or chemically with HCl/H2O2 or NaClO2/HCl), and bromination (HBr/H2O2) of Pheide and BPheide derivatives have been developed (Senge and Senger, 1989; Kureishi and Tamiaki, 1998; and references cited in both). Several reactions aimed at regioselective ring-opening of the macrocycles

Mathias O. Senge, Arno Wiehe and Claudia Ryppa

32

Scheme 3

either at C5 or C20 have been described and will be treated elsewhere (see Kräutler et al., Chapter 17) on Chl degradation. An interesting BChl to Chl conversion was observed upon treatment of BChl g 19 with weak mineral acids in the dark. Within minutes, the more stable Chl a derivative 20 is formed via an isomerization reaction (Kobayashi et al., 1998). Unrelated to natural Chls, but interesting from a chemical standpoint, are Chl-derived benzochlorins that carry an annelated benzene ring. These compounds are characterized by significantly red-shifted absorption bands and can be prepared by Vilsmeier reaction of (131-deoxo-phytochlorinato methyl ester)nickel(II) with POCl3 and 3-(N,N-dimethylamino)acrolein to yield 21 followed by acid-catalyzed cyclization to 22 (Mettath et al., 1998). B. Functional Group Transformations of the Side Chains Several of the reactions listed in part III.B also serve to yield peripherally altered Chl derivatives (e.g.,

17). A very mild method for the selective reduction of the 7-formyl group in Zn(II) Pheide b was developed by Scheumann et al. (1996). In contrast to older methods, the use of NaBH3CN resulted in sole reduction of the formyl group to the 71-hydroxy methyl derivative 23. Aldehyde functions in Zn(II) Pheide b and d derivatives have also been used to crosslink Chl derivatives to synthetic proteins carrying an aminooxyacetyl-modified Lys residue via oxime formation (Rau et al., 2001). Isotopically labeled BPheide d models were obtained by Grignard reaction of 3-deethyl-3-formylphytochlorins like 16 with 13CH3MgI or CD3MgI in yields of about 80 % (Tamiaki et al., 1996b). A 14Clabeled Chl derivative, [32-14C]Chl a, was prepared via ozonolysis of the vinyl group in methyl Pheide a and subsequent reduction of the 31-formyl group to a -CH2OH derivative 24, followed by transformation to the 3-[CH2P(Ph)3][Br] phosphonium bromide to undergo subsequent Wittig reaction with [14C]paraformaldehyde to yield methyl [32-14C]Pheide a which was then followed by standard transformation to the Chl a derivative (Fischer et al., 1994). The preparation

Chapter 2

Chlorophyll Chemistry

33

Scheme 4

of 3-deethyl-3-formyl-phytochlorins has also been used to covalently link C60 to the Pheide a moiety to yield a phytochlorin-fullerene dyad for electron transfer studies (Helaja et al., 1999) while 3-alkoxy3-deethyl-phytochlorins have been found useful in PDT (Pandey et al., 1996). Several publications have dealt with new esterification reactions for the carboxylic groups. For example, Pheide-quinone adducts were prepared as esters at C17 in yields of 14 – 25 % using a mixed anhydride method with di-t-butyl dicarbonate and a catalytic amount of DMAP (Borovkov et al., 1992). A very convenient method for selective transesterification of the C132 methyl ester in methyl Pheide a was described by Shinoda and Osuka (1996). Treatment of methyl Pheide a with various primary and secondary alcohols (including sterols) in the presence of two equiv. of 2-chloro-1-methylpyridinium iodide and 4 equiv. of DMAP exclusively resulted in transesterification of the keto ester to yield compounds of type 25. Several Zn(II) Chl a derivatives esterified with different alcohols in the C134 position have also been prepared (Furukawa et al., 2000).

A novel approach to perfluorinated hydroporphyrins was reported by Li et al. (1999). TMSCF3 reacted readily with porphyrins containing carbonyl functions and thus could be used for reaction with 7-oxo-8-geminal-dialkyl derivatives 26 (which in turn are derived from vicinal diols like 3 via pinacol-pinacolone rearrangement) to yield trifluoromethylated derivatives 27. C. Chemical Manipulations of Ring E Modification of ring E and the stereochemistry of its substituents plays a major role in controlling the biological function of Chls; e.g., the formation of functional pigment-protein complexes (Storch et al., 1996) or chlorosomal Chl organization (Oba and Tamiaki, 1999). Several analytical studies, mostly employing modern mass spectrometric methods, were aimed at studying the allomerization reaction of Chl (Grese et al., 1990; Rahmani et al., 1993; Brereton et al., 1994; Hyvarinen et al., 1995). A thorough study by Woolley et al. (1998) clearly showed that the 132-CO2Me group is required for allomerization

Mathias O. Senge, Arno Wiehe and Claudia Ryppa

34

Scheme 5

to occur and that a double rather than single bond between C7 and C8 (e.g., Chl vs. BChl) exerts a significant influence on the reactivity of ring E: ring E in Chl a is more susceptible to oxidative ring cleavage and lactone formation than in BChl a. Mass spectrometry also played a crucial role in elucidating ring E biosynthesis for (B)Chls from different organisms (Porra and Scheer, 2000). The isolation of the Ring-E–opened product, 31,32-didehydrorhodochlorin-15-glyoxylic acid, from a shrub has added another compound to the known list of naturally-occurring allomerization products (Cheng et al., 2001). A rather curious derivative, named chlorophyllone 28, was isolated from a clam and involves a formerly unknown cyclization of the C17 side chain to ring E at position 132 (Sakata et al., 1990). Another novel reaction was observed upon attempts to prepare stable enol forms of the β-keto ester system (Ma and Dolphin, 1996). Treatment of methyl Pheide a with trimethylsilyl triflate to yield an activated electrophilic Pheide species followed by an excess

of bases like DBU resulted in a nucleophilic opening of ring E to yield dimethyl 31,32-didehydro-rhodochlorin-15-acetic acid derivatives like 29 in which the formic acid group is amidated with rearranged products from the base. A rather intriguing reaction that allows the synthesis of several ring E modified derivatives involves the LiOH promoted allomerization of phytochlorin (Kozyrev et al., 1998). Treatment of 31,32-didehydrophytochlorin methyl ester with LiOH results in the formation of the stable enolate 30. This can be autooxidized with O2/CH2N2 to the 132-oxophytochlorin 31. Prolonged oxidation can then yield either 15-carboxyrhodochlorin anhydrides, the 12-demethyl-12formyl derivative 32 or the related porphyrins. Basic hydrolysis of 31 yields 31,32-didehydro-15-formylrhodochlorin dimethyl ester. Most synthetic studies in this area were aimed at the preparation of Pheide a analogs for applications in PDT (Pandey et al., 1992b; Pandey, 2000). This often concerns the synthesis of either amphiphilic or more soluble derivatives, preferably with either

Chapter 2

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additional auxochromic groups or an extended aromatic system to yield tetrapyrroles with red-shifted absorption bands. For example, the group of Pandey utilized methyl 31,32-didehydro-132-oxophytochlorin 31 as an entry into Pheides with fused quinoxaline or benzimidazole ring systems (Kozyrev et al., 2000). Purpurins (15-carboxyrhodochlorin anhydrides) or heteroatom derivatives (e.g., 26) thereof have been used prominently both for the synthesis of chlorins and bacteriochlorins with red-shifted absorption bands. These can then be modified further, e.g., by using the Ring B dihydroxylation method described above (Pandey et al., 1994; Kozyrev et al., 1996b). Alternative methods include the use of either the 3vinyl or a synthetic 8-vinyl derivative of Pheides as the diene in Diels-Alder reactions. The instability of ring E requires first transformation into e.g., purpurins to then yield benzopurpurins like 33 (R depends on the ene component used) (Zheng et al., 1996). Acknowledgments The writing of this article was made possible by support from the Deutsche Forschungsgemeinschaft (Heisenberg Fellowship Se543/3-2) and the Fonds der Chemischen Industrie. References Barkigia KM and Gottfried DS (1994) A new crystal form of methyl bacteriopheophorbide a. Acta Cryst C50: 2069–2072 Borovkov VV, Gribkov AA, Kozyrev AN, Brandis AS, Ishida A and Sakata Y (1992) Synthesis and properties of pheophorbidequinone compounds. Bull Chem Soc Japan 65: 1533–1537 Brereton RG, Rahamani A, Liang YZ and Kvalheim OM (1994) Investigation of the allomerization reactions of chlorophyll-a. Use of diode-array HPLC, mass spectrometry and chemometric factor. Analysis for the detection of early products. Photochem Photobiol 59: 99–110. Cheng H-H, Wang, H-K, Ito J, Bastow KF, Tachibana Y, Nakanishi Y, Xu Z, Luo T-Y and Lee K-H (2001) Cytotoxic pheophorbiderelated compounds from Clerodendrum calamitosum and C. cyrtophyllum. J Nat Prod 64: 915–919 Fischer R, Engel N, Henseler A and Gossauer A (1994) Synthesis of chlorophyll a labeled at C(32) from pheophorbide a methyl ester. Helv Chim Acta 77: 1046–1050 Furukawa H, Oba T, Tamiaki H and Watanabe T (2000) Effect of C132-stereochemistry on the molecular properties of chlorophylls. Bull Chem Soc Japan 73: 1341–1351 Gerlach B, Brantley SE and Smith KM (1998) Novel synthetic routes to 8-vinyl chlorophyll derivatives. J Org Chem 63: 2314–2320

35 Grese RP, Cerny RL, Gross ML and Senge M (1990) Determination of structure and properties of modified chlorophylls by using fast atom bombardment combined with tandem mass spectrometry. J Am Soc Mass Spectrom 1: 72–84 Helaja J, Tauber AY, Abel N, Tkachenko NV, Lemmetyinen H, Kilpeläinen I and Hynninen PH (1999) Chlorophylls. IX. The first phytochlorin-fullerene dyads: Synthesis and conformational studies. J Chem Soc, Perkin Trans 1: 2403–2408. Hynninen, PH (1991) Chemistry of chlorophylls: Modifications. In: Scheer H (ed) Chlorophylls, pp 145–209. CRC Press, Boca Raton Hyvarinen K, Helaja J, Kuronen P, Kilpelainen and Hynninen PH (1995) H-1 and C-13-NMR spectra of the methanolic allomerization products of 13(2)(R)-chlorophyll-a. Magn Res Chem 33: 646–656. Kadono K, Hori H, Fukuda K, Inoue H, Shirai T and Fluck E (1992) Spectroscopic characterization of iron complexes of methyl pheophorbide with pyridine and its derivatives. Inorg Chim Acta 201: 213–218 Kobayashi M, Hamano T, Akiyama M, Watanabe T, Inoue K, Oh-oka H, Amesz J, Yamamura M and Kise H (1998) Lightindependent isomerization of bacteriochlorophyll g to chlorophyll a catalyzed by weak acid in vitro. Anal Chim Acta 365: 199–203 Kozyrev AN, Dougherty TJ and Pandey RK (1996a) Effect of substituents in OsO4 reactions of metallochlorins. Regioselective synthesis of isobacteriochlorins and bacteriochlorins. Tetrahedron Lett 37: 3781–3784 Kozyrev AN, Zheng G, Zhu C, Dougherty TJ, Smith KM and Pandey RK (1996b) Syntheses of stable bacteriochlorophylla derivatives as potential photosensitizers for photodynamic therapy. Tetrahedron Lett 37: 6431–6434 Kozyrev AN, Dougherty TJ and Pandey RK (1998) LiOH promoted allomerization of pyropheophorbide a. A convenient synthesis of 132-oxopyropheophorbide a and its unusual enolization. Chem Commun: 481–482 Kozyrev AN, Zheng G, Shibata M, Alderfer JL, Dougherty TJ, Pandey RK (1999) Thermolysis of vic-Dihydroxybacteriochlorins: A new approach for the synthesis of chlorin-chlorin and chlorin-porphyrin dimers. Org Lett 1: 1193–1196 Kozyrev AN, Suresh V, Das D, Senge MO, Shibata M, Dougherty TJ and Pandey RK (2000) Syntheses and spectroscopic studies of novel chlorins with fused quinoxaline or benzimidazole ring systems and the related dimers with extended conjugation. Tetrahedron 56: 3353–3364 Kureishi Y and Tamiaki H (1998) Synthesis and self-aggregation of Zinc 20-halogenochlorins as a model for bacteriochlorophylls c / d. J Porphyrins Phthalocyanines 2: 159–169 Li G, Chen Y, Missert JR, Rungta A, Dougherty TJ, Grossman ZD and Pandey RK (1999) Application of Ruppert’s reagent in preparing novel perfluorinated porphyrins, chlorins and bacteriochlorins. J Chem Soc, Perkin Trans 1: 1785–1787 Ma L and Dolphin D (1996) Nucleophilic reaction of 1,8-diazabicyclo[5.4.0]undec-7-ene and 1,5-diazabicyclo[4.3.0] non5-ene with methyl pheophorbide a. Unexpected products. Tetrahedron 52: 849–860 Mettath S, Shibata M, Alderfer JL, Senge MO, Smith KM, Rein R, Dougherty TJ and Pandey RK (1998) Synthesis and structural properties of novel benzochlorins derived from chlorophyll a. J Org Chem 63: 1646–1656 Montforts F-P and Glasenapp-Breiling M (1998) The synthesis

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Mathias O. Senge, Arno Wiehe and Claudia Ryppa Senge MO and Smith KM (1994) On the conformation of the methyl ester of (20-methyl-phytochlorinato)nickel(II) — A bacteriochlorophyll c model compound. Photochem Photobiol 60: 139–142. Senge MO, Bobe FW and Smith KM (1991) Preparation and crystal structure of methyl [12-acetyl-8-ethyl]-bacteriopheophorbide d.— A new bacteriochlorophyll derivative. Liebigs Ann Chem: 871–874. Senge MO, Ruhlandt-Senge K and Smith KM (1995) Structure and conformation of photosynthetic pigments and related compounds, 8. Molecular structure of an iron(III) chlorophyll derivative — chloro(phytochlorinato methyl ester)iron(III). Z Naturforsch 50b: 139–146 Shinoda S and Osuka A (1996) Transesterification of the aketo ester in methyl pheophorbide-a. Tetrahedron Lett 37: 4945–4948. Smith KM (1991) Chemistry of chlorophylls: Synthesis. In: Scheer H (ed) Chlorophylls, pp 115–143. CRC Press, Boca Raton Storch K-F, Cmiel E, Schäfer W and Scheer H (1996) Stereoselectivity of pigment exchange with 132-hydroxylated tetrapyrroles in reaction centers of Rhodobacter sphaeroides R26. Eur J Biochem 238: 280–286 Tamiaki H and Kouraba M (1997) Synthesis of chlorophyll-a homologs by Wittig and Knoevenagel reactions with methyl pyropheophorbide-d. Tetrahedron 53: 10677–10688 Tamiaki H, Miyata S, Kureishi Y and Tanikaga R (1996a) Aggregation of synthetic zinc chlorins with several esterified alkyl chains as models of bacteriochlorophyll-c homologs. Tetrahedron 52: 12421–12432 Tamiaki H, Shimono Y, Rattray AGM and Tanikaga R (1996b) Synthesis of isotopically labeled zinc methyl bacteriopheophorbided as a model for light harvesting antenna pigments. Bioorg Med Chem Lett 6: 2085–2086 Tamiaki H, Tomida T and Miyatake T (1997) Synthesis of methyl bacteriopheopheophorbide-d with 8-propyl group. Bioorg Med Chem Lett 7: 1415–1418 Tamiaki H, Kouraba M, Takeda K, Kondo S-I and Tanikaga R (1998) Asymmetric synthesis of methyl bacteriopheophorbided and analogues by stereoselective reduction of the 3-acetyl to the 3-(1-hydroxyethyl) group. Tetrahedron: Asymmetry 9: 2101–2112 Tamiaki H, Omoda M and Kubo M (1999) A novel approach toward bacteriochlorophylls-e and f. Bioorg Med Chem Lett 9: 1631–1632 Tamiaki H, Kubo M and Oba T (2000) Synthesis and self assembly of zinc methyl bacteriopheophorbide-f and its homolog. Tetrahedron 56: 6245–6257 Vicente MGH and Smith KM (2000) Porphyrins and derivatives: Synthetic Strategies and reactivity profiles. Curr Org Chem 4: 139–174 Woodward RB, Ayer WA, Breaton JM, Bickelhaupt F, Bonnett R, Buchschacher P, Closs GL, Duffer H, Hannah J, Hauck FP, Ido S, Langemann A, Le Goff E, Leimgruber W, Lwowski W, Sauer J and Valenta Z (1990) The total synthesis of chlorophyll a. Tetrahedron 46, 7599–7659 Woolley PS, Moir AJ, Hester RE and Keely BJ (1998) A comparative study of the allomerization reaction of chlorophyll a and bacteriochlorophyll a. J Chem Soc, Perkin Trans 2: 1833–1839 Yagai S, Miyatake T and Tamiaki H (1999) Self-assembly of

Chapter 2

Chlorophyll Chemistry

synthetic 81-hydroxy-chlorophyll analogues. J Photochem Photobiol B: Biol 52: 74–85 Zheng G, Dougherty TJ and Pandey RK (1999) A simple and

37 short synthesis of divinyl chlorophyll derivatives. J Org Chem 64: 3751–3754