3-位环庚烷(酰)基取代的焦脱镁叶绿酸-a甲酯的合成

以焦脱镁叶绿酸-a甲酯(MPP-a)为起始原料, 在对其E-环羰基进行保护的前提下, 经焦脱镁叶绿酸-d甲酯与环庚基溴化镁进行Grignard反应; 所生成新的卟吩仲醇再经脱保护、脱水和氧化等诸多反应, 将3-位仲羟基转化成碳碳双键和羰基, 其碳氧双键再行Grignard反应并脱水成烯, 完成一系列未见报道的3-位环庚基取代的焦脱镁叶绿酸-a甲酯衍生物的合成. 其化学结构均经UV, IR, ¹H NMR及元素分析予以证实.     

焦脱镁叶绿酸-a甲酯20-meso-1-位的亲电取代反应

利用焦脱镁叶绿酸-a甲酯与亲电试剂发生的取代反应, 在焦脱镁叶绿酸-a甲酯的20-meso-位上分别引进硝基和卤原子, 得到了20-meso位取代的焦脱镁叶绿酸衍生物. 所合成的新叶绿素-a衍生物均经UV, IR, ¹H NMR及元素分析证明其结构. 另外, 对叶绿素-a卟吩环上的芳香性和相应的化学反应活性也进行了讨论, 提出了可能的亲电取代反应机理.     

脱镁叶绿酸-a甲酯的1,3-偶极环加成及其叶绿素衍生物的合成

以脱镁叶绿酸-a甲酯(1)为起始原料, 利用其3-位乙烯基与重氮甲烷的1,3-偶极环加成反应, 得到3-位氢化吡唑取代的脱镁叶绿酸-a衍生物2, 通过热裂解使得3-位吡唑基开环并重排成环丙基. 碱性条件下, 所生成的3-环丙基取代的卟吩3脱甲氧甲酰基后转化成焦脱镁叶绿酸衍生物4. 选用重氮乙烷为另一偶极体与1进行1,3-偶极环加成反应, 则给出2-甲基环丙基取代的立体异构体卟吩5, 同样经过脱甲氧甲酰基处理, 得到焦脱镁叶绿酸衍生物6. 所合成新叶绿素衍生物2～6均经UV, IR, ¹H NMR及元素分析证明其结构.     

具有叶绿素-a碳架的(细菌)卟吩衍生物的合成及其共轭区域变化对光谱性能的影响

以脱镁叶绿酸-a甲酯(MP-a) (1)为起始原料, 通过四氧化锇和高碘酸钠的氧化给出3-位乙烯基和13²-位α-氢的氧化产物2和3, 再用四氧化锇继续氧化卟吩醛2则得到细菌卟吩醛4. 经脱甲酸甲酯和硝酸铊氧化, MP-a (1)转化为焦脱镁叶绿酸衍生物5, 将其进一步用四氧化锇氧化则形成细菌卟吩缩醛6. 卟吩醛2在碱性条件下转化为卟吩e₆三甲酯7, 2与烷基溴化镁的格氏反应给出脱镁叶绿酸醇9, 选择高钌酸四丙基铵(TPAP)和N-甲基吗啉N-氧化物将3-位羟基氧化成羰基, 所生成的卟吩二酮10在酸性条件下脱去甲酸甲酯生成焦脱镁叶绿酸衍生物11, 用四氧化锇对7和11实施氧化, 则分别转化为细菌卟吩衍生物8和12. 同时, 讨论了叶绿素衍生物的共轭区域变化对其光谱性能的影响. 所合成的新卟吩和细菌卟吩衍生物均经UV, IR, ¹H NMR及元素分析证明其结构.     

红紫素-18酰亚胺衍生物的合成

以脱镁叶绿酸甲酯为原料, 通过对其3-位乙烯基的氧化, 得到3-(2,2-二甲氧基乙基)-3-去乙烯基脱镁叶绿酸甲酯, 经过甲酸处理得到3-(2-氧代乙基)-3-去乙烯基脱镁叶绿酸甲酯, 选择适当的条件, 通过Grignard 反应合成了对应的3-(2-羟基烷基)-3-去乙烯基脱镁叶绿酸甲酯. 实验结果表明: 3-(2-氧代乙基)-3-去乙烯基脱美叶绿酸甲酯和Grignard试剂的反应, 只要反应条件控制得当, 13²-位的甲氧甲酰基不会脱去. 结合E环的改造, 将其转变成酸酐环进而转变成N-取代的酰亚胺环. 目标化合物的合成也可以将3-(2,2-二甲氧基乙基)-去乙烯基脱镁叶绿酸甲酯转变成N-取代的酰亚胺后, 再和Grignard试剂反应, 完成目标化合物的合成. 合成的一系列化合物具有长波长的紫外吸收. 化合物的结构变化对紫外吸收的影响作了相应的讨论. 合成的新化合物均由核磁共振、红外光谱、元素分析予以证实.     

3-位长链烷基双(单)取代焦脱镁叶绿酸-a甲酯的合成

以焦脱镁叶绿酸-a甲酯(1)为起始原料, 通过E环保护和3-位乙烯基的氧化反应得到卟吩醛2, 与长链烷基溴化镁的Grignard反应将3-位甲酰基转化为1-羟长链烷基, 选用TPAP和N-甲基吗啉N-氧化物混合氧化剂对卟吩仲醇3的羟基进行氧化, 生成3-位烷酰基焦脱镁叶绿酸-a衍生物4, 再与长链烷基溴化镁进行Grignard反应, 得到亲核加成产物卟吩叔醇5和还原产物3; 以对甲苯磺酸催化, 卟吩醇3和5在干燥苯中回流脱水, 分别给出反式结构的3-位长链烷基单或者双取代的焦脱镁叶绿酸-a甲酯衍生物6和7. 所合成的叶绿酸衍生物均经UV, IR, ¹H NMR及元素分析证明其结构.     

新型环烷烯并嘧啶并噻唑-3-酮类化合物的合成

以环戊酮、环庚酮为起始原料合成的环烷烯并[1,2-d]嘧啶-2-硫酮(2)与氯乙酸、芳香醛反应, 合成具有潜在抗癌活性的稠合杂环化合物5-芳基-2,8-二芳亚甲基-2,3,6,7-四氢-5H,8H-环戊烯并[1,2-d]噻唑并[3,2-a]嘧啶-3-酮(3)以及5-芳基-2,10-二芳亚甲基-2,3,6,7,8,9-六氢-5H,10H-环庚烯并[1,2-d]噻唑并[3,2-a]嘧啶-3-酮(4). 3和4的结构经¹H NMR, IR, MS分析确认.     

3-位苯并含氮杂环取代的焦脱镁叶绿酸-α甲酯的合成

以焦脱镁叶绿酸-a甲酯(MPP-a)(1)为起始原料,在二氯甲烷中与醋酸锌共回流得锌配合物2,在四氯钯锂催化下,通过与苯基氯化汞的偶联反应生成3b-苯基焦脱镁叶绿酸-a甲酯(3).分别选用四氧化锇、高钌酸四丙基铵(TPAP)和N-甲基吗啉N-氧化物将环外烯键氧化成邻二酮(4).在酸性条件下,4与邻苯二胺的缩合形成了3-位喹喔啉取代的焦脱镁叶绿酸-a甲酯(5).用四氧化锇和高碘酸钠将l的3-位碳碳双键氧化,则生成焦脱镁叶绿酸-d甲酯(6).所得卟吩醛与环己二酮和萘胺进行一锅法反应,得到3-位苯并吖啶取代的焦脱镁叶绿酸-a甲酯(7).所合成的新卟吩化合物均经UV,IR,1H NMB及元素分析证明其结构.     

焦脱镁叶绿酸-a甲酯衍生物的合成及其结构与光谱性能关系研究

以焦脱镁叶绿酸-a甲酯(MPP-a, 1)为起始原料,通过乙二醇对E-环羰基进行保护,选用四氧化锇和高碘酸钠将3-位碳碳双键氧化,生成131-二氧环戊基-131-去氧焦脱镁叶绿酸-d甲酯(2),经Grignard反应将3-甲酰基转换成羟烷基得仲醇3,再通过高钌酸四乙基胺和N-甲基吗啡啉N-氧化物将其氧化成酮4,脱去保护基生成3-烷酰基3-去乙烯基焦脱镁叶绿酸-a甲酯(6).焦脱镁叶绿酸-d (MPP-d)7与过量重氮甲烷发生加成和重排反应,生成6a及3-烷酰甲基3-去乙烯焦脱镁叶绿酸甲酯衍生物8和9,7的3-位醛基经过Wittig和氧化反应得到3-苯乙二酰基焦脱镁叶绿酸甲酯11.所合成的新卟吩衍生物均经UV,IR,¹H NMR及元素分析证明其结构,并且讨论了周边取代羰基对核磁共振光谱和最大可见光吸收的影响.     

氢氧化锂存在下(焦)脱镁叶绿酸-a甲酯的空气重排反应

在氢氧化锂存在下, 脱镁叶绿酸-a甲酯(1a)发生空气氧化和重排反应, 经盐酸酸化和重氮甲烷甲基化, 得到由紫红素-7三甲酯(2)、紫红素-18甲酯(3)、卟吩-p₆三甲酯(4)、地质卟啉衍生物(5)和3-环氧乙基-3-去乙烯基紫红素-18甲酯(6)所组成的混合物. 用相同的方法处理焦脱镁叶绿酸-a甲酯(1b), 则分离出13²-氧代焦脱镁叶绿酸-a甲酯(7)、15-甲酰基紫红素-5二甲酯(8)、紫红素-18甲酯(3)和3-环氧乙基-3-去乙烯基紫红素-18甲酯(6). 所得新叶绿素衍生物5, 6和8的化学结构均经UV, IR, ¹H NMR及元素分析得以证实, 并对相应的反应提出可能的反应机理.     

Alkyl Ether Analogs of Chlorophyll-a Derivatives: Part 1. Synthesis, Photophysical Properties and Photodynamic Efficacy

The synthesis, preliminary in vivo biological activity, singlet oxygen and fluorescence yields of a series of alkyl ether derivatives of chlorophyll-a analogs are described. For short-chain carbon ethers (1–7carbon units), it was observed that the biological activity increased by increasing the length of the carbon chain, being maximum in compounds with n-hexyl and n-heptyl chains. Related sensitizers prepared by reacting 2-(1-bromoethyl)-2-devinylpyropheophorbide-a with (sec)alcohols were found to be less effective. Under similar treatment conditions, photosensitizers containing cis- and trans- 3-hexenyl side chains were ineffective. Thus, both stereochemical and steric factors caused differences in sensitizing activity. In general, pyropheophorbide-a analogs were found to be more active than related chlorin e₆ derivatives, in which the isocyclic ring (ring “E”) was cleaved. Related photosensitizers in the 9-deoxy- series were found to be as effective as the corresponding pyropheophorbide-a analogs. The photosensitizers prepared from pyropheophorbide-a methyl ester and chlorin e₆ trimethyl ester have long wavelength absorption at 660 nm (ε 45000 to 50000). Reduction of the carbonyl group in the pyropheophorbide-a to methylene (ring E) resulted in a blue shift to 648 nm (ε 38000).     

Synthesis of 3-nitro-chlorophyll-a derivatives and their electronic absorption/emission data

The formyl group at the 3-position of methyl pyropheophorbide-d, one of chlorophyll-a derivatives, was efficiently transformed to the 3²-cis-unsubstituted/methyl- or 3²-cis-phenyl-3²-trans-nitro-vinyl groups by Henry (nitro-aldol) or nitro-Mannich (aza-Henry) reactions with nitromethane/ethane or nitrophenylmethane, respectively. The introduction of a nitro group at the terminal of the 3-ethenyl moieties directly connected with the chlorin π-system red-shifted and broadened their Qy electronic absorption and fluorescence emission bands in a solution. The fluorescence intensities were largely suppressed by the substitution with the nitro group.     

Stereoselective reduction,methylation, and phenylation of the 13-carbonyl group in chlorophyll derivatives

Regioselective reduction of the 13-carbonyl group on the five-membered exo-ring of methyl pyropheophorbide-a, one of the chlorophyll-a derivatives, with sodium borohydride gave an epimeric mixture of (13¹R/S)-hydroxy-chlorins. The stereoselectivity was controlled by the steric effect of the (17S)-methoxycarbonylethyl group to afford the (13¹S)-rich secondary alcohol (25% de). The use of sterically large lithium tri(sec-butyl)borohydride as the reductant enhanced the stereoselectivity to 55% de. The regio- and stereoselective methylation and phenylation of the 13-CO of pyropheophorbide-a were observed using methyl and phenyl lithium, respectively. The major diastereomer of the tertiary alcohols obtained had the same configuration at the 13¹-stereogenic center as in the reduced product. All of the anion species (H^?, CH₃^?, and C₆H₅^?) favorably attacked the 13¹-carbon atom from the reverse side of the 17-propionate residue, that is, the less sterically crowded face of the 13-CO plane.     

Synthesis of chlorophyll-a derivatives possessing the 3-(2-acylethenyl) group by cross-aldol condensation and their optical properties

Chlorophyll-a derivatives possessing a trans-2-acylethenyl group at the C3-position were prepared by cross-aldol (Claisen-Schmidt) condensation of methyl pyropheophorbide-d having the C3-formyl group with ketones bearing α-hydrogen atoms including (un)substituted acetophenones, acetylarenes, and alkanones under basic conditions. The Qy absorption and fluorescence emission bands of the synthetic chalcone analogs in dichloromethane were largely dependent on the C3³-substituents. Especially, the introduction of electron-donating and withdrawing groups to the C3³-phenyl ring resulted in bathochromic and hypsochromic shifts of the maxima, respectively. Furthermore, fluorescence quantum yields and lifetimes were largely suppressed by the substitution with a nitro group on the C3³-phenyl ring.     

Stereoselective reduction,methylation, and phenylation of the 13-carbonyl group in chlorophyll derivatives

Regioselective reduction of the 13-carbonyl group on the five-membered exo-ring of methyl pyropheophorbide-a, one of the chlorophyll-a derivatives, with sodium borohydride gave an epimeric mixture of (13¹R/S)-hydroxy-chlorins. The stereoselectivity was controlled by the steric effect of the (17S)-methoxycarbonylethyl group to afford the (13¹S)-rich secondary alcohol (25% de). The use of sterically large lithium tri(sec-butyl)borohydride as the reductant enhanced the stereoselectivity to 55% de. The regio- and stereoselective methylation and phenylation of the 13-CO of pyropheophorbide-a were observed using methyl and phenyl lithium, respectively. The major diastereomer of the tertiary alcohols obtained had the same configuration at the 13¹-stereogenic center as in the reduced product. All of the anion species (H^?, CH₃^?, and C₆H₅^?) favorably attacked the 13¹-carbon atom from the reverse side of the 17-propionate residue, that is, the less sterically crowded face of the 13-CO plane.     

Synthesis and photophysical properties of phenyl-sulfanylated chlororophyll derivatives

Chlorophyll derivatives that possessed a phenylsulfanyl group at the C3¹- or C3²-position were synthesized and their optical properties were investigated. Methyl 3¹-phenylsulfanyl-mesopyropheophorbide-a was prepared by substitutions of the corresponding C3¹-hydroxy-chlorin, methyl bacteriopheophorbide-d, with thiophenol in the presence of zinc iodide or of the corresponding C3¹-bromo-chlorin with thiophenol. The regioisomeric C3²-phenylsulfanyl-chlorin was obtained by addition of thiophenol to the C3-vinyl group of methyl pyropheophorbide-a in the presence of AIBN. Both the synthetic compounds gave similar electronic absorption and emission spectra in chloroform, but fluorescence quantum yield of the C3¹-sulfanyl-chlorin (0.18) was ca. 30% smaller than those of the C3²-sulfanyl-chlorin (0.25) and the C3-ethyl-chlorin (0.24). These observations were consistent with their fluorescence lifetime data. It is suggested that the heavy atom effect of a sulfur atom at the C3¹-position can tune photophysical properties of the chlorophyll derivatives.     

Study of Interactions Between Eu(thenoyltrifluoroacetonate)<Subscript>3</Subscript> and a Photosynthetic Chlorophyllous Pigment

Eu(thenoyltrifluoroacetonate)₃(Eu(TTA)₃), an ideal model lanthanide complex which harvests ultraviolet light in high yield and emits visible light efficiently, was coordinated with a chlorophyll derivative, methyl pyropheophorbide-a (MPA). A distinct color change, from blue to deep green, in solution gives evidence for a supramolecular interaction within the binary system. Ultraviolet-visible absorption and luminescence excitation/emission spectra, as well as luminescence lifetimes and quantum yield measurements, further show that molecular interactions occur between the two components.     

Dependence of the Regioselectivity of Photo-oxidative Ring Opening of the Chlorophyll Macrocycle on the Complexed Metal Ion

On irradiation with visible light in the presence of air, the zinc complex 1b of pyropheophorbide-a methyl ester ( 1a ) is photo-oxidized at the C(20) methine bridge yielding the corresponding 19-formyl-21H-bilin-1(23H)-one derivative 2 . Surprisingly, the cadmium complex Ic is cleaved, under the same conditions, at the C(5) methine bridge affording the same type of bilinone which has been recently characterized as an early product of chlorophyll catabolism in plants.     

Synthesis of 3/8-carbonylated chlorophyll derivatives and regiodependent reductivity of their carbonyl substituents

Methyl pyropheophorbide-d possessing a formyl group at the 3-position and its regioisomer having 8-CHO were prepared and their reactivities with a reductant were determined by the ¹H NMR technique: 3-CHO>8-CHO. The regioselective reduction of a synthetic 3,8-diformyl-chlorin also supported the higher reactivity in 3-CHO than in 8-CHO. Regiodependent reduction of the corresponding acetyl-chlorins confirmed that carbonyl groups at the 3-position in chlorophyllous pigments were reduced more rapidly than those at the 8-position. From the reports that reactions of 3-CHO with amines were preferable to those of 7-CHO, the CO functional groups on the pyrrole A-ring of chlorophylls are more reactive than those on the B-ring.     

Synthesis and optical properties of C3-ethynylated chlorin and π-extended chlorophyll dyads

A C3-ethynylated chlorophyll derivative was prepared from methyl pyropheophorbide-d possessing a 3-formyl group by treatment of Bestmann-Ohira reagent. The mono-substituted acetylene was subjected to coupling reactions at the terminal acetylenic carbon atom to form a series of π-extended chlorophyll derivatives. Replacement of the terminal hydrogen to phenyl, phenylethynyl and C3-chlorin-ethynyl caused red-shifts of their Q_y (0,0) maxima from 675 to 679, 686, and 696 nm, respectively. Optical properties of C3²-substituted 3-ethynyl-chlorophyll derivatives including chlorophyll dyads were investigated in comparison with those of their related compounds. Partial quenching of the fluorescence emission (Φ_flu=0.14) was observed for ortho-substituted dyad, compared to meta- (Φ=0.27) and para-dyads (Φ=0.29), suggesting a through-space interaction between the two chlorin macrocycles in a molecule.