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42 Current Organic Synthesis, 2014, 11, 42-58 : Natural Sources, Synthetic Developments and Main Applications

Kleber T. de Oliveiraa*, Patrícia B. Momoa†, Francisco F. de Assisa†, Marco A.B. Ferreiraa and Timothy J. Brocksoma aDepartamento de Química, Universidade Federal de São Carlos, Rodovia Washington Luís, km 235 - SP-310, 13565-905, São Carlos - SP – Brazil

Abstract: derivatives have attracted considerable attention over the last three decades in different scientific fields. These com- pounds are present in a large number of bacteria, fungi and in all plants found on Earth. Since the discovery of these pigments, chemists, biologists, medical professionals and materials scientists have devoted pronounced efforts in order to develop new synthetic methods and discover useful applications for these compounds. In this review we wish to cover the main natural chlorins, their natural sources, syn- thetic approaches to access these compounds, and the major applications.

Keywords: Chlorin, , porphyrinoid, PDT, solar cells and natural dyes.

1. INTRODUCTION pounds to present a large number of photophysical and electronic Chlorins are by far the most abundant and important porphyri- properties, proving the pronounced ability of Nature to design and noid type compounds, bearing in mind their occurrence in Nature as synthesize ideal molecules for evolution of life. well as the current scope of applications in medicine, and materials Structurally, chlorin derivatives differ from by one science. These compounds are by definition dye-molecules with reduced double bond on the porphyrinoid core structure (Fig. 1), major absorption bands in the UV, and the blue and red visible and from bacterio- and isobacteriochlorins which have a further spectral regions. The low absorption in the green region make them double bond reduced. The absorption spectra of chlorin derivatives mostly exhibit a green colour, justifying the origin of the name are also very different compared to porphyrins, bacterio- and iso- “chlorin”, from the Greek word “chloros” (green). bacteriochlorins (Fig 1). It is no overstatement to say that the evolution of life on Earth Chlorin derivatives are special molecules due to the expressive was mediated by the chlorophylls (normally chlorin derivatives) thermodynamic tendency to oxidize to porphyrinoids, adding an since these molecules are critical in photosynthesis. The extensive additional challenge to their synthesis. A number of efficient syn- double bond conjugation in chlorin derivatives allow these com- thetic methodologies have been developed over the last decades and

1.2 1.0 1.0 0.8 NH N NH N 0.8 0.6 0.6

0.4 0.4 Absorbance N HN Absorbance N HN 0.2 0.2

0.0 0.0 350 400 450 500 550 600 650 700 750 350 400 450 500 550 600 650 700 Chlorin Wavelength (nm) 22 electrons Wavelength (nm) 20 electrons

0.7 0.8

0.6 0.7 NH N 0.5 NH N 0.6 0.4 0.5 0.4 0.3

Absorbance 0.3

N HN 0.2 Absorbance N HN 0.2 0.1 0.1 0.0 0.0 Bacteriochlorin 350 400 450 500 550 600 650 700 750 800 Isobacteriochlorin 350 400 450 500 550 600 650 700 18 electrons Wavelength (nm) 18 electrons Wavelength (nm) Fig. (1). Structures and absorption spectra of the common porphyrinoids.

*Address correspondence to this author at the Departamento de Química, Universidade we intend to cover the most relevant in this review. We also intend Federal de São Carlos, Rodovia Washington Luís, km 235 - SP-310, 13565-905, São Carlos - SP – Brazil; Tel: +55 16-3351-8083; Fax: +5516-3351-8350; to cover the main chlorophylls described in the literature and their E-mail: [email protected] principal natural sources. †These authors contributed equally to this review

1875-6271/14 $58.00+.00 © 2014 Bentham Science Publishers Chlorins: Natural Sources, Synthetic Developments and Main Applications Current Organic Synthesis, 2014, Vol. 11, No. 1 43

H O

3 5 7 2 8 B C N N 1 N N Mg 10 Mg 19 N N N N A 16 D 12 18 14 17 13 132 1 13 MeO C O MeO2C O 2 O O O O

Chlorophyll a (1) b (2)

N N Mg

N N

O H H MeO2C O HO2C O N N N N Chlorophyll c1 (3) Mg Mg

N N N N

MeO2C O MeO2C O

O O O O

Chlorophyll d (4) Chlorophyll f (5)

Fig. (2). Structures of the chlorophylls, Chl a, b, c1, d and f.

2. NATURAL CHLOROPHYLLS, SOURCES AND THE 2.1. (1) UNIQUE TOTAL SYNTHESIS OF A NATURAL CHLORIN Chl a (1) is the most abundant chlorophyll and is found in pho- Chlorophylls comprise the most abundant natural chlorins tosynthetic organisms from plants to cyanobacteria, but absent in found in cyanobacteria and the of algae and plants [1]. oxygenic photosynthetic bacteria [7, 9, 10]. The real importance of The chlorophyll name is derived from the Greek words , this compound has been assigned as the “dye of life” after the com- chloros ("green") and , phyllon ("leaf"). prehension of photosynthetic systems as well as the biosynthetic pathways [4, 9, 11-14]. Chl a (1) represents a dual role in oxygenic The chlorophylls were first isolated by Caventou and Pelletier photosynthesis, specifically in the conversion of absorbed photons in 1817 [2], but, only in 1864, Stokes observed for the first time to chemical energy as well as in light harvesting. This molecule is that this chlorophyll (Chl) extract was made up of two components, crucial in photosynthetic organisms, operating since photosystem II designated as Chl a and Chl b [3]. However, these compounds were (PS II) that leads to water oxidation, until the photosystem I (PS I) only separated by Willstätter’s group after the advent of chromatog- that leads to ferrodoxin reduction [9]. raphy [1, 4]. Currently, there are five structurally confirmed chloro- phylls, termed Chl a, b, c, d, and f (Fig. 2). Chlorophyll e (Chl e) The gross chemical structure of Chl a (1) was completely as- has only two reported occurrences. First in 1943 [5], as a pigment signed with the total synthesis by Woodward’s group in 1960 extracted from Tribonema bombycinum, with maximum absorption (Scheme 1) [15]. Later, the absolute configuration of the Chl a (1) at 415 and 654 nm in methanol [6], and in 1948 from Vaucheria chiral centers was determined by Fleming [16], thus clarifying the hamate [7]. However, no further characterizations have been de- last uncertainties about this compound [17]. The Woodward’s total scribed [8]. synthesis of Chl a (1) involved 46 steps and started from Knorr’s 44 Current Organic Synthesis, 2014, Vol. 11, No. 1 Oliveira et al.

H N NH2 2

A N A H NH 7 CO2Me NH D D OHC N H

8 MeO2C CO2Et 11

EtO2C N H S 6 B CH Cl (NC)2C=HC N 2 H B 9 HN

Me CO2Et HN C C O N H CO2Me 10 12 MeO2C AcHN

A B 11 NH N NH N

+ 1 12 N HN N HN D C

CO2Me CO2Me

CO2Me MeO C MeO C 2 CO2Me 2 13 Chlorin e6 trimethyl ester (14) Scheme 1. Woodward’s total synthesis of chlorophyll a (1). (6) until the chlorin e6 trimethyl ester (14), that is the direct 2.2. (2) precursor of Chl a (1) (Scheme 1). The four bearing the Chl b (2) can be considered as a light absorbing accessory dye rings A, B, C and D were synthesized and condensed to give 11 and in photosynthesis. It is found in all green land plants, and in green 12. These two intermediates were then condensed to give a porphy- algae as well as some cyanobacteria [7, 11]. As mentioned before, rin derivative (13), and after several steps, yielded the chlorin e6 this pigment was first observed by Stokes in 1864, and isolated by trimethyl ester (14) and then Chl a (1). Willstätter’s group [3, 4]. Chl a (1) has four Soret-bands and four Q-bands in the absorp- The chemical structure of Chl b (2) differs from Chl a (1) only tion spectrum, with maximum absorptions (diethyl ether) at 428, by a formyl group at C-7 instead of the methyl group (Fig. 2). The 409, 379 and 326 nm (blue side), and 660, 612, 572 and 519 nm presence of this 7-CHO group results in minor absorbance intensity (red side) [9]. These photophysical properties make Chl a (1) a and a blue-shift of the Q-band from 665 nm in 1 to 652 nm in 2 [11, unique dye sensitizer for the photosynthetic system, and conse- 18]. Thus, organisms that contain both Chl a and b accept the solar quently a key-structure for the existence of a number of organisms spectrum because they extend light absorption into adequate re- and plants. Reviews on Chl a (1) and the photosynthetic system in gions for the photosynthetic system. plants have been published showing the fascinating design of this Chl b is obtained by plants through the same biosynthetic path- molecule by Nature [4, 9, 12]. way as for 1 [12, 19], involving the intermediate chlorophylide a Chlorins: Natural Sources, Synthetic Developments and Main Applications Current Organic Synthesis, 2014, Vol. 11, No. 1 45

CO2Me

N N N N N N Mg Mg Mg

N N N N N N

MeO2C O MeO2C O MeO2C O HO2C HO2C HO2C Chl c1 Chl c2 Chl c3 15 16 17

Fig. (3). Structures of chlorophylls c1, c2, and c3.

(the molecule without the phytyl group). Subsequently, the C7- 2.5. Chlorophyll f (5) methyl group is oxidized into a C7-CH2OH and then to the C7- CHO group by the chlorophylide a oxygenase (CAO) and molecu- Chl f (5) was reported for the first time in 2010 [8]. It was iso- lar oxygen [9, 12, 19, 20]. lated from stromatolites in Western Australia, as the most red- shifted chlorophyll with maximum absorbance at 706 nm [8]. Chl f 2.3. (3) (5) differs from 1 in the C-2 position where there is a formyl group (Fig. 2). The structure of Chl f (5) was completely assigned by UV- Chl c (3) is present in different groups of marine algae such as Vis, 1H-NMR spectroscopy, CD spectroscopy and mass spectrome- Phaeophyta (brown algae), Bacillariophyta (diatoms) and Pyrro- try, [8, 32, 33] as well as molecular modelling studies [34]. phyta (dinoflagellates) [21]. In these organisms, Chl c (3) is found together with Chl a (1), and is described as an accessory dye mole- Recently, the cyanobacteria that contains Chl f (5) was isolated cule in photosynthesis [9, 21]. However, the biosynthesis of c-type from stromatolites, cultured in the laboratory, and named as Ha- chlorophylls is still incompletely resolved [9, 21]. lomicronema hongdechloris after its isolation [35]. It was observed that this cyanobacteria contains both Chl a (1) and Chl f (5). The The three most common types of c chlorophylls are: Chl c1 content of Chl f (5) is controlled and reversibly changed from (15), Chl c2 (16), and Chl c3 (17) [22]. They differ by the variation 12.5% of total chlorophylls under far-red light to an undetectable in their side chains at C-7 and C-8 (Fig. 3) [23]. Unlike other chlo- level under white-light culture conditions. In view of this, Chl f (5) rophylls, Chl c (3) generally does not possess a phytyl group and its has been considered to be a red light dependent chlorophyll [35]. D ring is not reduced, so that Chl c is chemically classified as a Chf f (5) has also been found in a unicellular cyanobacterium iso- porphyrin derivative [9, 21]. However, the term Chl c was retained lated in Lake Biwa (the largest freshwater lake in Japan), and was for these compounds isolated from natural sources, and also due to detected only in small amounts when this organism is cultivated some structural similarities with other chlorophylls [21]. under near-infrared light [36]. The maximum absorption for the series of Chl c in diethyl ether, is observed at 444, 578 and 628 nm for Chl c1 (15), at 447, 3. MAJOR SYNTHETIC COMPOUNDS AND METHODS 579 and 628 nm for Chl c2 (16), and at 451, 585 and 625 nm Chl c3 (17) [24]. The first reports concerning the synthesis of chlorin derivatives appeared in 1936 to 1943, in which these compounds were obtained 2.4. Chlorophyll d (4) by modification of chlorophyll derivatives [37] or as by-products in porphyrin syntheses [38]. In 1955, Eisner and Linstead [39] pub- Chl d (4) is a historically important dye molecule which was lished the first synthesis of a chlorin employing the pyrrole (18) and discovered by Strain and Manning in 1943, as the minor chloro- ethyl- bromide (Scheme 2). However, this methodology phyll component of some red algae (Rhodophyta) [25]. Chl d (4) provides very low yields and no tolerability to functional groups. was proposed as Mg-3-formylchlorophyll a (C54H70O6N4Mg), pre- senting a maximum absorption at 445 and 686 nm in ethyl ether [26]. In 1959 Holt and Morley demonstrated that the oxidation of NH N the 2-vinyl group in Chl a (1) with potassium permanganate in ace- EtMgBr tone resulted in Chl d (4) [26]. In view of this evidence, and due to N the fact that Chl d (4) is not present in all algae, it was initially con- N Xylene N HN sidered an artefact produced during the extraction. However, in H  1996 Chl d (4) was found as the main dye-sensitizing compound in 18 the cyanobacterium Acaryochloris marina [27]. This organism uses 19 (1%) Chl d (4) as its major photosensitizing dye (95%) and Chl a (1) as the minor component [27]. In A. marina, Chl d (4) can replace Scheme 2. Synthesis of a chlorin nucleus 19 from pyrrole 18. nearly all the functions of Chl a (1) in light-harvesting complexes After this period, the importance of chlorins and the challenge and in photosynthesis reactions [28-30]. Recently, Chl d (4) has to synthesize stable derivatives encouraged a number of approaches been detected in filtered light environments in several ecological to these heterocycles. In this section, we will cover the main ap- niches [31]. proaches to obtain chlorins by total synthesis, as well as by porphy- The electron withdrawing formyl group in the A ring of the rin transformations. It is important to mention that a number of macrocycle changes the electron density distribution, causing a red chlorin derivatives have been synthesized by common methodolo- shift in the absorbance spectrum [9, 29]. gies such as the Diels-Alder reaction. 46 Current Organic Synthesis, 2014, Vol. 11, No. 1 Oliveira et al.

Ar Ar

NH N p-CH3C6H4SO2NHNH2 NH N K2CO3 Ar Ar Ar Ar pyridine N HN N HN

Ar = OMe Ar Ar 20 21 (70%)

Ph NO2 Ph NO2

NH N NH N NaBH4 Ph Ph Ph Ph DMSO N HN N HN

Ph Ph 22 23 (100%)

Ph Ph

n-Bu NH N NH N n-BuLi Ph Ph Ph Ph THF N HN N HN

Ph Ph 24 25 (18%)

Scheme 3. Obtention of chlorins by reduction of porphyrins.

3.1. Reductions and Additions at the -positions an oxidant permits the preparation of 1,2-dihydroxychlorins 29 and The most obvious method to synthesize chlorins is by reduc- 30 from the corresponding porphyrins 24 and 26, respectively tion/addition in one of the -positions of porphyrins (Scheme 3). (Scheme 4) [44]. The vicinal diol moiety showed good stability, and also allows further transformations depending on the substitu- In 1993, King and collaborators obtained the chlorin 21 from tion pattern of the starting porphyrin. Bonnett reported that the por- meso-tetra(4-methoxyphenyl)porphyrin (20) in 70% yield by using phyrin 31 can undergo an acid catalysed pinacol rearrangement p-toluenesulfonylhydrazide in pyridine [40]. Arnaut and co-workers giving the ketochlorin 32 in 75% yield (Scheme 4) [45]. A number described basically the same reaction conditions, but under vacuum of other porphyrin derivatives were subsequently studied, demon- [41] reporting some improvements in the experimental results. strating the great versatility of this methodology. The required Gabel and co-workers have also demonstrated that hydrazine is stoichiometric amount of OsO4 is the only restriction in this meth- capable of accomplishing this transformation [42]. odology, due to the difficulty in the use of co-oxidants in the pres- Hydrides or organo lithium compounds have also been em- ence of porphyrins. ployed in the preparation of chlorins. King and co-workers demon- 3.3. Cycloaddition Reactions strated that the -NO2 substituted arylporphyrin 22 can be easily reduced by NaBH4 through a Michael addition, leading to chlorin The formation of carbon-carbon bonds can be considered the 23 in quantitative yield (Scheme 3) [40]. The reaction of meso- most effective way to access chlorin derivatives. In this context, tetraphenylporphyrin 24 with n-butyl lithium allows the reaction to cycloaddition reactions are valuable tools that can be used for car- occur without the presence of an electron withdrawing group at- bon-carbon bond formation, and have been intensely reviewed in tached to the double bond, thus providing the 2-butyl-meso- chlorin synthesis [46, 47]. One of the first publications on the use of tetraphenylchlorin 25 in 18% yield (Scheme 3) [43]. this kind of reaction on a porphyrin system was reported by Dol- phin and co-workers in 1980 [48], when they demonstrated that 3.2. Oxidation at the -position tetracyanoethylene and protoporphyrin di-tert-butyl ester (33) un- Some oxidizing reagents are useful in producing chlorin deriva- dergo a Diels-Alder reaction to generate the pair of regioisomeric tives, especially if the double bond at the -position of the porphy- chlorins 35 and 36 (Scheme 5). It is important to mention that Dol- ® rin is electron-rich. Dolphin demonstrated that the use of OsO4 as phin also prepared the commercial photosensitizer Visudyne by Chlorins: Natural Sources, Synthetic Developments and Main Applications Current Organic Synthesis, 2014, Vol. 11, No. 1 47

N O O Ph Ph O Os Ph OH N O OH

N N N N N N OsO H2S(g) 4 M Ph Ph M Ph Ph M Ph Ph pyridine/CHCl3 N N N N N N

Ph Ph Ph

24: M = 2H 27: M = 2H 29: M = 2H (50%) 26: M = Zn 28: M = Zn 30: M = Zn (50%)

OH OH O NH N NH N Fuming H2SO4

N HN N HN

31 32 (75%)

Scheme 4. Synthesis of bis-hydroxychlorins and ketochlorins.

NC NC CN NC NC NC CN NC NC NH N NC CN NC N HN NH N 34 + CHCl 3 HN N HN  NH N N

t-BuO C CO2t-Bu t-BuO C CO2t-Bu t-BuO C CO2t-Bu 2 33 2 35 2 36

Scheme 5. Reaction of protoporphyrin-IX di-tert-butylester (33) with tetracyanoethylene (34). the same approach, starting from protoporphyrin IX dimethyl ester In 1972 Callot reported the use of diazo compounds as carbene and dimethyl acetylenedicarboxylate [49]. precursors in cyclopropanation reactions of porphyrin 26, furnish- Cavaleiro and co-workers have also explored the reactivity of ing chlorins 47-50 (Scheme 8) [57]. The expansion of this chemis- porphyrins as dienes or dienophiles as demonstrated in (Scheme 6) try was implemented by Cavaleiro and co-workers using meso- [50, 51]. More recently, Serra and de Oliveira expanded the scope tetrakis(pentafluorophenyl)porphyrin (37a), providing better results of these reactions by using functionalized maleimides to produce in terms of yields and selectivity [58]. They also employed this chlorins with low-aggregation in solution [52, 53]. strategy to couple protected sugar moieties to the chlorin core struc- tures 52a-d and 52a-d [59], followed by deprotection in order to 1,3-Dipolar cycloaddition reactions have also been extensively improve the water-soluble character (Scheme 8). used to afford chlorin type compounds. Cavaleiro’s group was the first to explore this approach using azomethine ylides, generated from acetaldehyde and N-methylglycine, yielding the chlorin 44 and bis- 3.4. The Total Synthesis of Chlorins adducts (Scheme 7) [54, 55]. Recently, de Oliveira’s group has The most important total synthesis of a chlorin derivative per- demonstrated the use of bulky dipoles and -poly-functionalized formed is undoubtedly the Woodward synthesis of Chl a (1) [15] as porphyrins such as 45, yielding the sterically hindered chlorin 46, self-prevented from aggregation in solution (Scheme 7) [56]. described in (Scheme 1). 48 Current Organic Synthesis, 2014, Vol. 11, No. 1 Oliveira et al.

SO2 R

NH N R R N HN

R 1,2,4-trichlorobenzene R  38: R = Ph (26%) NH N R R R N HN N HN 1,2,4-trichlorobenzene  R R R NH N 24: R = Ph 37: R = C6F5

R

39: R = Ph (63%) 40: R = C6F5 (60%)

CO2H HO2C ROC

ROC N HN

NH N NH N 1) Maleic anhydride toluene,  NH N +

N HN N HN 2) Nucleophile, 

MeO2C CO2Me 41 CO Me MeO2C 2 MeO2C CO2Me 42a: R = OMe (41%) 43a: R = OMe (29%) 42b: R = O(CH2CH2)2CH2CH2OMe (31%) 43b: R = O(CH2CH2)2CH2CH2OMe (22%) 42c: R = O(CH2CH2)2CH2CH2OH (26%) 43c: R = O(CH2CH2)2CH2CH2OH (19%) 42d: R = NHCH2CH2OH (36%) 43d: R = NHCH2CH2OH (26%)

Scheme 6. Diels-Alder reactions using porphyrins as dienes and dienophiles.

Using a similar strategy, a number of chlorins were synthesized In 1984, aiming at biosynthetic studies of chlorins, Battersby by preparing each one of the rings (A, B, C and D) in a convergent developed a convergent route to these C-dimethylated derivatives. approach. Montforts [60] developed the first synthesis of the non- In this methodology, the pyrrolic rings are incorporated into the natural chlorin 64 (Scheme 9). In this approach, the gem-dimethyl system one by one, and as the key step a thermal Cu-mediated cy- precursor 61 was synthesized in order to obtain a stable -reduced clization was employed, leading to the chlorin 72 (Scheme 10A) ring of the chlorin system. Despite being a multi-step route, this [61]. In another approach, Battersby employed a very efficient route flexible approach permits placing different groups on each ring of to build the chlorin 77. An acid-catalysed condensation of 74 and the chlorin system, leading to stable compounds with regard to 75, and a mild photochemical cyclization resulted in the chlorin 77 possible back-oxidation. Chlorins: Natural Sources, Synthetic Developments and Main Applications Current Organic Synthesis, 2014, Vol. 11, No. 1 49

O H + N CO2H H H C F C6F5 6 5 H N

N NH N NH N H C F C F bisadducts C6F5 6 5 C6F5 6 5 + toluene N HN N HN 

C6F5 C6F5 O 37 44 (61%) H.HCl + Ph N CO H OO 2

Ph EtO2C N EtO2C CO2Et Ph EtO2C

CO Et EtO2C EtO2C 2 N NH CO Et NH N N 2 + bisadducts chlorobenzene N HN N HN 130 ˚C, 4h EtO2C CO2Et EtO2C CO2Et

EtO2C CO2Et EtO2C CO2Et 45 46 (18%)

Scheme 7. 1,3-Dipolar cycloaddition reactions on porphyrin.

R2 Ph Ph H R1 1 2 1) N2CR R H 1 2 N N PhH, rt or reflux NH N 47: R = R = H (28%) 1 2 48: R = CO2Me, R = H (3%) Zn Ph 2) HCl, CH Cl Ph Ph 1 2 Ph 2 2 49: R = H, R = CO2Me (20%) 1 2 N N N HN 50: R = R = CO2Me (30%)

Ph 26 Ph F C H CO2R F C H H 5 6 C6F5 5 6 H CO2R H H N N N N N N N2CHCO2R, CuI Zn C F + C6F5 6 5 C F C F Zn C6F5 C6F5 Zn 6 5 6 5 CH Cl , 40 °C N N N N 2 2 N N deprotection

Water-soluble C6F5 C F C6F5 Compounds 6 5 52a-d 37a 51a- d

O O O O O O O O R = O O

O O O BnO O O O O O a b cd

Scheme 8. Cyclopropanation reactions on ZnTPP. 50 Current Organic Synthesis, 2014, Vol. 11, No. 1 Oliveira et al.

+ DBU, MS 3Å P2S5, NaHCO3 OHC CO Et NH HN NH HN O N N 2 H THF, reflux THF, rt H O CO2Et S CO2Et 53 54 55: (67%) 56: (85%)

1) CH3CN, 0 °C 1) NBS, CH2Cl2, rt O (C H CO ) , K CO CN 6 5 2 2 2 3 t-BuO C CN 2) DBU, CH CN, rt Si CO2t-Bu + 2 3 S N 2) P(OEt)3, 80 °C N 3) P(CH CH CN) O H H 2 2 3 3) TBAF, THF, reflux CF CO H/CHCl 57 58 3 2 3 59 (47%) reflux

1) THF, KOH NH N N HN N N Zn(OAc)2.2H2O MeOH/H2O, reflux M CO2Et t-BuOK/t-BuOH 2) PTSA NH N N HN 70°C N CHCl3, reflux

CN Br CN

CHO 64 (57%) 63 (63%) Br N H 60: M= 2H (41%) Ni(OAc)2.4H2O 62 NaOAc, MeOH/THF, rt 61: M= Ni (86%)

Scheme 9. Montforts’s synthetic approach. in 54% yield for two steps (Scheme 10B) [62]. In 2000, Lindsey BPD-MA (85), also known as Verteporfin or Visudyne®, is expanded the scope of the Battersby approach for the preparation of manufactured by Novartis Pharmaceuticals. This compound pre- -1 -1 meso substituted chlorins 84a-d through the thermal pathway [63, sents a Q-band in 689 nm with max 34,000 M cm allowing irra- 64] (Scheme 11). The dihydrodipyrin 82 was synthesized according diation with red light. It also presents a high singlet oxygen quan- ® to the Battersby route, [61] and the dipyrromethanecarbinols deriva- tum yield ( = 0.84) [70]. Visudyne is mostly used for the treat- tives 80a-d were prepared from the less elaborated dipyrromethanes ment of subfoveal choroidal neovascularization due to age-related 78a-d [65, 66]. After the preparation of these two fragments, a cy- macular degeneration (AMD) [74], pathologic myopia or presumed clization/oxidation reaction was performed using procedures devel- ocular histoplasmosis syndrome [75]. oped by Lindsey’s group [67, 68]. m-THPC 86 is commercialized as or Foscan® by Biolitec Pharma and is activated by light at 652 nm with max 35,000 M-1cm-1. This compound presents a high ability to produce 4. APPLICATIONS OF CHLORINS IN PHOTODYNAMIC ® THERAPY, CATALYSIS, MEDICAL DIAGNOSTICS AND singlet oxygen ( = 0.87) [70]. Foscan is widely utilized for PDT MATERIALS SCIENCE and in photodiagnostics (PD) [76], and it has been extensively stud- ied by several research groups. Recent reviews on Foscan® discuss 4.1. its development, clinical use, nano derivatives, and also advances in chemical modifications to the basic m-THPC framework for 3rd Chlorins have been applied in photodynamic therapy (PDT) ® treatments as photosensitizers (PS) [69] due to their remarkable generation photosensitizers [77, 78]. PDT treatment with Foscan photophysical and photochemical properties. These compounds was reported for prostate, breast, head, neck and pancreatic cancers [69-71]. present strong absorption around 650-670 nm, the ability to gener- ate reactive oxygen species, and low phototoxicity. A considerable Purlytin™ is the trademark name of tin ethyl etiopurpurin number of photosensitizers have been developed for PDT, but only (SnEt2) (87). The chelated tin atom leads to a red shift absorbance -1 -1 a few have been approved for effective use [70]. Examples of chlo- at 664 nm and gives max 30,000 M cm [70]. Purlytin™ has rins approved for use in PDT treatments are: benzoporphyrin de- shown significant potential in Phase I/II trials for the treatment of rivative monoacid ring A (BPD-MA) (85), m-tetra(hydroxy- basal cell carcinoma (BCC), metastatic breast adenocarcinoma, and phenyl)chlorin (m-THPC) (86), tin ethyl etiopurpurin (SnEt2) (87), Kaposi’s sarcoma, and in Phase III for subfoveal choroidal neovas- 2-(1-hexyloxyethyl)-2-devinyl pyropheophorbide (HPPH) (88) and cularization [69-71]. Purlytin™ has not yet been approved by the N-aspartyl chlorin e6 (NPe6) (89) (Fig. 4) [70, 71]. It is important FDA. to mention that, since the first time it was reported in the literature [72], NPe6 was believed to be a mixture of regioisomers, or the N-Aspartyl chlorin e6 (NPe6) (88) is known by numerous 3 commercial names such as sodium, Ls11, MACE, Laser- aspartyl amide at C-17 position. Recently, Vicente’s group has phyrin, Litx™, Photolon or Apoptosin™ and is produced by several proven by NMR and X-Ray analysis, that the correct structure for manufacturers [69]. NPe6 is activated by light at 664 nm with NPe6 is the one with the amide group at C-152 position (Fig. 4) max 40,000 M-1cm-1 and gives singlet oxygen quantum yield = 0.77 [73].  Chlorins: Natural Sources, Synthetic Developments and Main Applications Current Organic Synthesis, 2014, Vol. 11, No. 1 51

O

A) 1) NaOAc, CH3NH2.HCl, CH3NO2, MeOH, 20 °C, 3h. t-BuO C NH NO2 2 NO2 N (n-Bu)4NF.3H2O, O CHO H t-BuO C t-BuO2C N 2) NaBH4, MS 3Å, DMF, 2 67 (88%) H DMF/MeOH 66 (56%) 20 °C, 2h 65

NH NH 1) Basic allumina 1) AcOH, Zn, 30 min t-BuO2C 67 O 2) NH OAc, TiCl , 15h 2) CHCl3, TFA, 20 °C, 6 min 4 3 NH N 3) Picric acid, MeOH O2N NO2 69

68 (88%) NO2

Br Br N N HN N HN CH2Cl2, 40 min Cu(OAc)2.xH2O Cu 69 + CH CN, reflux, 9.5 h Br 3 N N HN NH HN Br

CO2Me CO2Me CO2Me 72 (6.9%) 70 71

B)

N

R1 1 R R R 1 1 NH MeO R R2 2 CO2H OMe 1 R R CO t-Bu R2 2 2 N N N NH R N h, TFA, DIPEA NH 2 75 THF N HN TFA(cat) NH NH NH N R1 R1 1 R R1 R R1 1 CO2t-Bu CHO R2 R2 R2 R 76 R2 R2 2 77 (54%) 73 74

R1 = R2 = CO2Me CO2Me

Scheme 10. Battersby’s synthetic approaches.

[70]. At present, this photosensitizer is clinically used only in Japan Roswell Park Cancer Institute (RPCI) [83]. Photochlor® has been for early-stage endobronchial cancer, and has been used in preclini- used in Phase I/II trials for esophageal cancer and Barrett’s esopha- cal trials for superficial malignancies, glioma, refractory late-stage gus, in Phase II trials for lung cancer, and in Phase I trials for head bulky tumors, symptomatic benign prostatic hyperplasia, hepatocel- and neck cancer, basal cell skin cancer, and also, for treating dys- lular carcinoma, and metastatic colorectal cancer [79]. Recent stud- plasia, carcinoma of the oral cavity, and carcinoma of the orophar- ies show that NPe6 (88) may be a potential treatment for gastric ynx [70]. cancer [80], esophageal cancer [81] and bile duct carcinoma [82]. Some chlorins derivatives have also been applied as photosensi- HPPH (89), also known as Photochlor®, absorbs light at 665 nm tizers for photodynamic inactivation (PDI) of microorganisms -1 -1 with max 47,000 M cm [70]. This compound is being evaluated at (Fig. 5). 52 Current Organic Synthesis, 2014, Vol. 11, No. 1 Oliveira et al.

O 1 1 O Ar1 Ar Ar or 2 Ar Cl N S Ar2 NBS, THF, -78°C NH HN NH HN EtMgBr, THF, rt NH HN Br 2 Ar2 Ar 78a-d 79a-d (37-92%) 80a-d (65-80%) O O Br

Ar1 NH N N HN N N AgIO3, piperidine Ar1 Zn Ar1 NaBH4 82 Zn(OAc)2 80a-d NH HN N N THF/MeOH NH HN PhCH3, 80 °C, 2h TFA, CH3CN rt Br Ar2 0 °C or rt HO Ar2 Ar2 81a-d (quantitative) 83a-d 84a-d

F F

1 2 a: Ar1 = , Ar2 = b: Ar = Ar = F

F F

1 , 2 c: Ar1 = I, Ar2 = d: Ar = TMS Ar =

Scheme 11. Lindsey’s synthesis.

OH

MeO2C

MeO C HO 2 N HN NH N N Cl N

NH N N HN Sn OH N Cl N EtO2C

CO H CO2Me 2 SnET2 HO 87 BPD-MA m-THPC 85 86

O

NH N

NH N N HN

N HN

O CO2H 152 HO2C HN 3 O 17 CO2H HO2C CO2H HPPH NPe6 88 89

Fig. (4). Structures of some commercial chlorins. Chlorins: Natural Sources, Synthetic Developments and Main Applications Current Organic Synthesis, 2014, Vol. 11, No. 1 53

H N NH2

N 6 HN H O

Ar N I HO2C N HO2C I NH N NH HN N Ar Ar F F N N HN Ar= S

Ar F F PEI-ce6 lin 90 91

Fig. (5). Chlorin derivatives used as photosensitizers for PDI studies.

HO2C HO2C

HO2C

NH N NH N NH N NH N

N HN N HN N HN N HN

CO2H CO2H O O HO2C MeO C O 2 MeO2C H C(H C) O C Chlorin e6 92 93 3 2 11 2  94 = 0.2% = 3.8%  95 = 6.5% = 8.0%

Fig. (6). Examples of chlorophylls derivatives tested for use in DSSCs.

Compound 90 was prepared by the coupling of a polyethyle- tives in materials science. This technology has been inspired in neimine chain, and chlorin e6 (92). The purpose of such a chain is natural photosynthesis that involves light-harvesting by chloro- to increase the permeability of the photosensitizer through the cell phylls and energy conversion [94]. Chlorin derivatives have also membrane. This compound demonstrated to be an efficient PDI attracted interest for their use in DSSCs because they absorb solar agent against the gram-positive bacteria Staphylococcus aureus and energy over a wide range of the solar spectrum [95]. Streptococcus pyogenes, and also against the fungi Candida albi- cans [84]. The cationic chlorin 91 proved to be effective not only Studies have shown that photosensitizers prepared by modified against the same gram-positive bacteria, but also against the gram- natural pigments, such as chlorin e6 (92) (Fig. 6), presented low  negative Pseudomonas aeruginosa, [85] which proves that posi- conversion efficiency ( ) due to the weak interaction with TiO2 tively charged chlorins represent a good choice for potential PDI films. However, compounds 93-95 exhibited moderate to excellent photosensitizers. light conversion. Wang and Tamiaki have shown that the best com- bination between chlorophyll sensitizer and a TiO2 semiconductor To conclude this section, it is important to note that researchers occurs when the carboxyl group is disposed along the y-axis (C-3 around the world are actively involved in the development of new position) (Fig. 6) [95]. chlorin derivatives, showing adequate structural and spectroscopic characteristics, to become more efficient photosensitizers in PDT The use of chlorophyll a (1) and b (2) derivatives as sensitizers treatments. For example, chemical modifications of chlorins have in DSSCs has been explored due to their availability in Nature [95, been performed by insertion of sugar units to increase the hydro- 96]. Studies on short-circuit photocurrent (Jsc), open-circuit voltage philicity and the targeted activities [86-89], as well as by the inser- (Voc) and energy-to-electricity conversion efficiency (), have tion of bulky groups targeting compounds with low-aggregation been performed in order to compare their performance in DSSCs properties [51-53, 56, 90]. Currently, research is being developed [97, 98]. using formulations of chlorins with nanoparticles [91], nano- Recently, some artificial chlorins were synthesized by the reac- carriers [92] and lyotropic liquid crystals [93]. tion between an A3B-porphyrin and a nitrile oxide dipole in order to obtain new dye-sensitizers for use in DSSC. These compounds 4.2. Materials Science Applications presented efficiencies between 2-4% [99]. However, there are many The construction of new organic dye-sensitized solar cells challenges to improve the semiconductor devices and obtain better (DSSCs) is the main perspective of application of chlorin deriva- efficiency. For example, chlorins have been immobilized in silica- 54 Current Organic Synthesis, 2014, Vol. 11, No. 1 Oliveira et al.

Silica surface

Ar Ar N N

Cl Cl N N N N o-Cl-Ph, reflux Ar Mn Ar + Br Silica surface Ar Mn Ar Cl N N N N Ar =

97 (0.2-1.4mol%) Ar O Ar Cl NH OAc, CH CN 96 4 3 97 H2O2 or t-BuOOH 98 99

Scheme 12. Epoxidation of cis-cyclooctene using the silica supported catalyst 97.

Ar Ar N N Cl OH O Cl Cl 103 or 104 (0.01mol%) N N N N + Ar Mn Ar Ar Mn Ar imidazole N N CH2Cl2/CH3CN N N 100 102 PhIO or H2O2 101

Ar Ar

103 104 F F

Ar = F

F F Scheme 13. Oxy-functionalization of hydrocarbons using catalysts 103 or 104. surfactant nano-composite films with a C60-based donor-acceptor presence of oxidants PhIO or H2O2, and imidazole as co-catalyst, [100]. This combination provides an efficient antenna effect for yielded up to 60% of the alcohol 101 exclusively, or as the main visible light capture [101]. Many other photo-functional nanomate- product in several conditions. rials have been developed to improve the efficiency of DSSC de- vices by using the combination between porphyrinoids and new Sulfides can also be oxidized by using chlorins as catalysts materials [102-104]. [111]. Khavasi and collaborators explored the use of different chlo- rins as catalysts for sulfoxidation (Scheme 14). The chlorins 105a-b Other applications for chlorins have been described such as and the oxachlorins 106a-b were tested toward a wide range of immobilization on the electrode surface of electrochemical sensors substrates. In most of the cases, 100% conversion was found and [105], as chemosensor for alcohols and amines in the form of a the selectivity of sulfoxide formation remained between 82 and trifluoroacetyl-chlorin derivative [106], as organized assemblies for 100%. supramolecular electronics based on biological systems [107], and as dyes immobilized onto a silica gel based thin layer substrate for 4.4. Medical Diagnostics photoinduced hydrogen production [108]. It is known that chlorins exhibit enhanced fluorescence emis- sion in the red/NIR region. This property, associated with preferred 4.3. Catalysis tumor location, low toxicity in the body and photostability, has Just like porphyrins, chlorins have found applications as cata- brought some of these compounds into the field of medical diagnos- lysts in oxidation reactions, such as epoxidation [109], dye- tics for optical imaging creation techniques. The coupling of such a discoloration [110], sulfoxidation [111], and hydrocarbon oxy- technique with PDT allows a more oriented and efficient medical functionalization [112], by mimicking the enzymatic system cyto- treatment, besides providing information about the distribution of chrome P450. Cavaleiro and coworkers [109] have published the use photosensitizer and cellular death. of the manganese chlorin 97 covalently immobilized on silica, for The fluorophore character of these compounds can be used to the oxidation of cis-cyclooctene (98) (Scheme 12). The substrate track the photosensitizer inside the patient’s organism. Viriot and conversion rates range from 78 to 100% on the first run, and the collaborators [113] used fluorescence microscopy analysis to trace catalytic activity was maintained for four cycles. the path of Foscan® (86) (Fig. 4) inside human breast cells. Chen The same group also reported the use of another kind of man- and co-workers demonstrated the use of chlorin e6 (92) (Fig. 6) in ganese chlorin in the conversion of hydrocarbons to alcohols and/or the preparation of silica-coated gold nanoclusters for photodynamic ketones (Scheme 13) [112]. The use of chlorins 103 or 104 in the therapy [114]. Chlorins: Natural Sources, Synthetic Developments and Main Applications Current Organic Synthesis, 2014, Vol. 11, No. 1 55

Ph OH Ph O

OH O N N N N

Ph M Ph Ph M Ph N N N N

Ph Ph

105a: M = Fe-Cl 106a: M = Fe-Cl 105b: M = Mn-OAc 106b: M = Mn-OAc

a: R1 = Ph, R2 = Me O b: R1 = R2 = Ph 105a-b or 106a-b (0.05mol%) O O S S + S c: R1 = R2 = Pr R1 R2 R1 R2 R1 R2 MeOH, H2O2 d: R1 = R2 = Allyl 1 2 107a-e 108a-e 109a-e e: R = Et, R = CH2CH2OH

Scheme 14. Oxidation of sulfides to sulfoxides and sulfones using chlorin derivatives.

N OHexyl Linker

N S H NH N O3S N H O N Et

N O

Cyanine portion Pheophorbide portion

NaO3S 110

N N N HN M OMe N N NH N

111 M = H2 112 M = Zn

Fig. (7). Structure of the dyads built by the union of chlorin/cyanine and chlorin/bacteriochlorin units. 56 Current Organic Synthesis, 2014, Vol. 11, No. 1 Oliveira et al.

Pandey et al. [115], investigated the properties of a pheophor- lenta, Z.; Volz H. The total synthesis of chlorophyll. J. Am. Chem. Soc., bide hexyl ether cyanine conjugate 110 (Fig. 7), which presented 1960, 82, 3800-3802; (b) Woodward, R.B. The total synthesis of chlorophyll. Pure Appl. Chem., 1961, 2, 383-404. characteristics of a bifunctional agent, acting as a fluorophore for [16] Fleming, I. Absolute configuration and the structure of chlorophyll. Nature, optical imaging detection and photosensitizer for photodynamic 1967, 216,151-152. therapy. Bacteriochlorins have also been coupled with chlorins [17] Woodward, R.B.; Ayer, W.A.; Beaton, J.M.; Bickelhaupt, F.; Bonnett, R.; (compounds 111 and 112) for use as optical probes (Fig. 7) [116]. Buchschacher, P.; Closs, G.L.; Dutler, H.; Hannah, J.; Hauck, F.P.; Itô, S.; Langemann, A.; Le Goff, E.; Leimgruber, W.; Lwowski, W.; Sauer, J.; Va- These compounds show narrow and appropriately located absorp- lenta, Z.; Volz, H. The total synthesis of chlorophyll a. Tetrahedron, 1990, tion and emission bands at the red/NIR region, with a Stokes shift 46, 7599-7659. which can be considered very good for this application (>85 nm). [18] Hoober, J.K.; Eggink, L.L.; Chen, M. Chlorophylls, ligands and assembly of light-harvesting complexes in chloroplasts. Photosynth. Res., 2007, 94, 387- In general, chlorin derivatives present great potential for use in 400. PDT treatments, as well as fluorescent markers for tumour detection. [19] Rüdiger, W. Biosynthesis of chlorophyll b and the chlorophyll cycle. Photo- synth. Res., 2002, 74, 187-193. [20] Schneegurt, M.A.; Beale, S.I. Origin of the chlorophyll b formyl oxygen in CONCLUSION AND PERSPECTIVES Chlorella vulgaris. Biochemistry, 1992, 31, 11677-11683. As demonstrated in this review, chlorin derivatives present a [21] Dougherty, R.C.; Strain, H.H.; Svec, W.A.; Uphaus, R.A.; Katz, J.J. The structure, properties, and distribution of chlorophyll c. J. Am. Chem. 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[29] Chen, M.; Blankenship, R.E. Expanding the solar spectrum used by photo- The authors would like to thank the São Paulo Research Foun- synthesis. Trends Plant Sci., 2011, 16, 427-431. dation (FAPESP) for the PhD fellowship of Assis, F.F. [30] Larkum, A.W.D.; Kuhl, M. Chlorophyll d: the puzzle resolved. Trends Plant (2012/04964-1) and financial supports (Broksom, T.J. 2011/13993- Sci., 2005, 10, 355-357. 2, Ferreira, M.A.B. 2013/02311-3 and de Oliveira, K.T. [31] Kashiyama, Y.; Miyashita, H.; Ohkubo, S.; Ogawa, N.O.; Chikaraishi, Y.; Takano, Y.; Suga, H.; Toyofuku, T.; Nomaki, H.; Kitazato, H.; Nagata, T.; 2013/06532-4). Thanks are also due to CNPq and CAPES for fi- Ohkouchi, N. Evidence of global chlorophyll d. Science, 2008, 321, 658-658. nancial supports and fellowships. [32] Li, Y.; Scales, N.; Blankenship, R.E.; Willows, R.D.; Chen, M. Extinction coefficient for re-shifted chlorophylls: chlorophyll d and chlorophyll f. Bio- REFERENCES chim. Biophys. Acta, 2012, 1817, 1292-1298. 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Received: August 09, 2013 Revised: September 26, 2013 Accepted: September 29, 2013