Tigliane Diterpenoids from the - American Chemical Society

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Tigliane Diterpenoids from the Euphorbiaceae and Thymelaeaceae Families Hong-Bing Wang,*,† Xiao-Yang Wang,†,‡ Li-Ping Liu,† Guo-Wei Qin,§ and Ting-Guo Kang‡ †

Research Center for Translational Medicine, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai 200092, People’s Republic of China ‡ School of Pharmacy, Liaoning University of Traditional Chinese Medicine, Dalian 116600, People’s Republic of China § Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, People’s Republic of China 4.3. Intramolecular [3+2] Cycloaddition Approach 4.4. Oxyallyl [4+3] Cycloaddition Approach 5. The 1H NMR Data of Tigliane Diterpenoids 6. The 13C NMR Data of Tigliane Diterpenoids 7. Conclusions Author Information Corresponding Author Notes Biographies Acknowledgments References

CONTENTS 1. Introduction 2. Tigliane Diterpenoids Isolated from the Euphorbiaceae and Thymelaeaceae Families 2.1. Phorbol Esters 2.2. Esters of 12-Deoxyphorbol 2.3. Esters of 4-Deoxyphorbol and 4-Deoxy(4α)phorbol 2.4. Esters of 4,12-Dideoxyphorbol and 4,12Dideoxy(4α)phorbol 2.5. Esters of 4,20-Dideoxyphorbol and 4,20Dideoxy(4α)phorbol 2.6. Esters of 12,20-Dideoxyphorbol 2.7. Esters of 20-Deoxyphorbol 2.8. Esters of 4,12,20-Trideoxyphorbol 2.9. 16- or 17-Substituted Derivatives 3. Biological Activity 3.1. Proinflammatory Activity 3.1.1. Phorbol 3.1.2. 12-Deoxyphorbol 3.1.3. 4-Deoxyphorbol 3.1.4. 12,20-Dideoxyphorbol 3.1.5. 4,20-Dideoxyphorbol 3.2. Cocarcinogenic and Tumorigenic Activities 3.3. Anticancer Activity 3.4. Antiviral Activity 3.5. Other Activities 3.5.1. Epstein−Barr Virus Inducing Activity 3.5.2. Inducing Platelet Aggregation Activity 3.5.3. Growth-Inhibitory and Insecticidal Effects 3.5.4. Analgesic and Sedative Activities 3.5.5. Antimycobacterial Activity 3.5.6. Inhibition of NADH Oxidase Activity 3.5.7. Activation of the TRPV4 Channel 3.5.8. IFN γ-Inducing Activity 3.5.9. Anti-inflammatory Activity 4. Synthesis 4.1. Intramolecular Diels−Alder Approach 4.2. Intramolecular Oxidopyrilium [5+2] Cycloaddition Approach © XXXX American Chemical Society

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1. INTRODUCTION For thousands of years, natural products have played an important role throughout the world in the treatment and prevention of human diseases. Natural products serve as a vast source of compounds with a broad range of chemical and functional diversity, as well as providing a rich source of new drugs and therapeutic agents.1−6 Plants belonging to the Euphorbiaceae family, which consists of about 229 genera and 6974 species,7,8 and the Thymelaeaceae family, which consists of about 52 genera and 859 species,9 are universally known for the chemical diversity of their isoprenoid constituents.10 In particular, the diterpenoids derived from these two families are the major chemical components and exist as a variety of different core frameworks such as tiglianes, ingenanes, daphnanes, jatrophanes, lathyranes, and myrsinols.11 Tigliane diterpenoids are one of the main chemical components present in these two families, and significant research efforts have been focused on isolating natural products from various Euphorbiaceae and Thymelaeaceae species including their roots, seeds, latex, lactiferous tubes, stem wood, stem barks, leaves, and whole plants. The diterpene compounds isolated from Euphorbiaceae and Thymelaeaceae species possess a broad range of biological activities, including anti-HIV, tumor promotional, cytotoxic, skin irritant, and proinflammatory properties. Among the diterpene compounds, the tigliane diterpenoids in particular have been reported to show a diverse range of interesting biological activities. Tigliane derivatives, especially 12-Otetradecanoylphorbol 13-acetate (TPA), have been used as pharmacological and biochemical tools to provoke inflamma-

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Received: October 16, 2011

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DOI: 10.1021/cr200397n Chem. Rev. XXXX, XXX, XXX−XXX

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tion and investigate tumor promotion mechanisms in both in vivo and in vitro systems (see section 3). Certain tigliane diterpene esters have been shown to possess antitumor and anti-HIV activities and have consequently been recommended for use as therapeutic agents in these disease areas.12−20 Among them, prostratin (12-deoxy-phorbol-13-acetate) and DPP (12deoxy-phorbol-13-phenylacetate) are nontumor-promoting tigliane diterpenoids that exhibit potent in vitro activity toward the induction of HIV expression in latently infected cell lines and primary cells (see section 3).17−20 On the basis of its activity in this context, prostratin has recently progressed into preclinical development. Although several reviews have been published pertaining to the active principles of plants belonging to the Euphorbiaceae and Thymelaeaceae families, some of the earlier reviews did not focus specifically on the tigliane diterpenes derived from these two families. In 1978, Evans reviewed the tigliane, daphnane, and ingenane diterpenes isolated from Euphorbiaceae and Thymelaeaceae, in terms of their chemistry, distribution, and biological activities.21 Appendino et al.22 published a minireview in 1997 that briefly reviewed the history of Euphorbium isolated from the dried latex of Euphorbia resinifera, with particular emphasis on the enormous contribution of resiniferatoxin to our current understanding of the anatomical localization, function, and pharmacology of vanilloid receptors. In 2007, Goel et al.23 reviewed phorbol esters, in terms of their structure, mode of action, biological activity, and toxic effects in animals, as well as providing some discussion of approaches aimed at detoxifying feeds containing phorbol esters from Jatropha sp. In 2008, Shi et al.11 reviewed research that had been focused on the chemical and pharmacological properties of plants belonging to the genus Euphorbia. Judit Hohmann’s group recently published a review of the diterpenes derived from European Euphorbia species in terms of their application as prototypes for natural-product-based drug discovery.24 This Review focuses on naturally occurring tigliane diterpenes isolated from plant species belonging to the Euphorbiaceae and Thymelaeaceae families from 1965 to the end of August 2013, with particular emphasis on the occurrence, biological activity, structure activity relationship (SAR), synthesis, and 1H and 13C NMR data of these compounds.

Figure 1. Main structure skeletons of diterpenoids from the Euphorbiaceae and Thymelaeaceae families.

these tigliane derivatives possess polydroxy groups at their C12, C-13, and C-20 positions that can be readily esterified. Tigliane derivatives occur naturally as 13-monoesters, 12,13-, 13,16-, or 12,20-diesters, and 12,13,20- or 13,16,20-triesters that have been esterified with acetic, isobutyric, tiglic, 2methylbutyric, benzoic, 2-methylaminobenzoic, or saturated and unsaturated long-chain aliphatic fatty acids. Almost all of the reported tigliane diterpenoids exist in the form of aglycons, and only three tigliane glycosides (50, 114, 115) have been isolated, to date, from plant species belonging to the Euphorbiaceae and Thymelaeaceae families.26 The occurrence and distribution details of the known tigliane derivatives are summarized in Table 1. 2.1. Phorbol Esters

Plant species belonging to the Euphorbiaceae and Thymelaeaceae families are known to produce “cryptic” phorbol esters. Phorbol (1), the parent diterpene of phorbol esters, contains five hydroxyl groups that possess different levels of reactivity toward acylation.44 Most phorbol esters exist as the 12,13- or 13,20-diesters, although a few phorbol esters also exist in the form of 12,13,20-triesters (54−58). The A ring is on the left and trans linked to the B ring (except for 59, which is cis linked to the B ring in this structural class). The C ring in these compounds is 6-membered and cis linked to the cyclopentane D ring. Two unique phorbol derivatives (69 and 70) bearing a 3-hydroxy group at the C-3 position instead of carbonyl group were isolated from Euphorbia fischeriana.60 The details of several phorbol esters belonging to this structural class are shown in Table 2. Phorbol esters are a large group of natural products that are well-known for their proinflammatory and tumor-promoting activities. Although the tumor-promoting abilities of these compounds could potentially limit their application as therapeutic agents, it is important to note that some phorbol esters have been reported to exert profoundly beneficial biological effects.31,34,51,62

2. TIGLIANE DITERPENOIDS ISOLATED FROM THE EUPHORBIACEAE AND THYMELAEACEAE FAMILIES In contrast to all of the other diterpenes isolated from species belonging to the Euphorbiaceae and Thymelaeaceae families (Figure 1), the tigliane diterpenoids are based on a 5/7/6/3tetracyclic ring system consisting of a five-membered ring A, a seven-membered ring B, a six-membered ring C, and a cyclopropane system D. The skeleton contains 20 carbons, consisting of five methyl, five methylene, and nine methine groups, as well as one quaternary carbon. In general, compounds belonging to this structural class contain a double bond between the C-1 and C-2 positions in their A ring, as well as another double bond in their B ring. The α,β-unsaturated ketol in the A ring of these compounds represents a structural figure that is unique to compounds of this type (except 69 and 70). Phorbol (1), which was initially isolated from Croton tiglium,25 is a common tigliane diterpenoid. There are several tigliane diterpenoid derivates based on phorbol, including 12deoxyphorbol, 4-deoxyphorbol, 4,12-dideoxyphorbol, 4,20dideoxyphorbol, and 4,12,20-trideoxyphorbol, and most of

2.2. Esters of 12-Deoxyphorbol

A new parent alcohol, 12-deoxyphorbol (74), was obtained from a variety of different plants including Excoecaria bicolor,63 Euphorbia triangularis,64 and Euphorbia resinifera.65 12-Deoxyphorbol can be readily esterified at the C-13 and C-20 positions, and 12-deoxyphorbol esters exist predominantly in one of two groups. The first group consists of diesters with an acetate moiety at C-20 and a long-chain fatty acid at C-13, whereas the second group consists of 13-monoesters with a free B


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Table 1. Tigliane Diterpenoids Isolated from the Euphorbiaceae and Thymelaeaceae Familiesa no.

species (familyb)c

name

Phorbol Esters 1 2 3 4 5 6 7 8 9 10 11 12 13

phorbol phorbol phorbol phorbol phorbol phorbol phorbol phorbol phorbol phorbol phorbol phorbol phorbol

12-myristate 12-monoacetate 12,13-diacetate (PDA) 12-acetate-13-tigliate 12-acetate-13-decanoate 12-acetate-13-dodecanoate 12-acetate-13-(2,4,6,8,10-tetradecapentaenoate) 12-tiglate-13-acetate 12-(N-methylaminobenzoate)-13-acetate (sapintoxin D) 12-octanoate-13-acetate 12-[(2Z,4E)-2,4-octadienoate]-13-acetate 12-decanoate-13-acetate

14 15 16 17 18 19

phorbol phorbol phorbol phorbol phorbol phorbol

12-(4Z-deca-4-enoate)-13-acetate 12-(4Z,7Z-deca-4,7-dienoate)-13-acetate 12-(deca-2,4,6-trienoate)-13-acetate 12-[(2Z,4E)-2,4,6-decatrienoate]-13-acetate 12-undecadienoate-13-acetate 12-dodecanoate-13-acetate

20 21 22 23

phorbol phorbol phorbol phorbol

12-tetradecanoate-13-acetate (TPA, PMA) 12-(2,4,6,8-tetradecatetraenoate)-13-acetate 12-(2,4,6,8,10-tetradecapentaenoate)-13-acetate 12-hexadecanoate-13-acetate

24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41

phorbol phorbol phorbol phorbol phorbol phorbol phorbol phorbol phorbol phorbol phorbol phorbol phorbol phorbol phorbol phorbol phorbol phorbol

12-octadecenoate-13-acetate 12,13-dibutyrate (PDB) 12-butyrate-13-dodecanoate 12-tiglate-13-propionate 12-tiglate-13-isobutyrate 12-tiglate-13-butyrate 12-tiglate-13-(2-methylbutyrate) 12-tiglate-13-octenoate 12-tiglate-13-decanoate 12-tiglate-13-dodecanoate 12-(2-methylbutyroate)-13-isobytyrate 12-(2-methylbutyrate)-13-angelate 12-(2-methylbutyrate)-13-tiglate 12-(2-methylbutyrate)-13-octenoate 12-α-methylbutyrate-13-decanoate 12-(2-methylbutyrate)-13-dodecanoate 12,13-dibenzoate 12-benzoate-13-octanoate

42 43

phorbol 12-benzoate-13-nonanoate phorbol 12-benzoate-13-decanoate (stellerarin)

44 45 46 47 48 49 50 51 52 53

phorbol 12-benzoate-13−4Z-decenoate (stelleracin A) phorbol 12-benzoate-13-(3E,5E-decadienoate) phorbol 12-benzoate-13−4Z,7Z-decadienoate (stelleracin B) phorbol 12-decanoate-13-(2-methylbutyrate) phorbol 12,13-didecanoate phorbol-13,20-diacetate fischeroside C phorbol 13-acetate-20-oleate phorbol 13-acetate-20-linoleate phorbol 13-tiglate-20-linoleate C

C. tiglium (E)25,27−29 C. tiglium (E)30 C. tiglium (E)30 C. tiglium (E)30 C. tiglium (E)31 C. tiglium (E)31−34 C. tiglium (E)33−35 E. tirucalli (E)36 C. tiglium (E)32 S. indicum (E)37,38 P. elongata (T)39 E. tirucalli (E)36 C. tiglium (E)32,33 P. elongate (T)39 D* genkwa (T)40 P. elongata (T)39 P. elongata (T)39 S. japonicum (E)41 E. tirucalli (E)36 O. paniculata (E)42 C. tiglium (E)32,33 C. sparciflorus (E)43 C. tiglium (E)30−34,44,45 E. tirucalli (E)36 E. tirucalli (E)36 S. sebiferum (E)46,47 C. tiglium (E)34,44,45 A. fordii (E)48 S. sebiferum (E)46 C. tiglium (E)30 C. tiglium (E)44,45 C. tiglium (E)34 C. tiglium (E)32,34 C. tiglium (E)44,45 C. tiglium (E)31,34 C. tiglium (E)44,45 C. tiglium (E)44,45,49 C. tiglium (E)44,45 C. tiglium (E)34,35 E. franckiana (E)50 C. tiglium (E)34 C. tiglium (E)44,45 C. tiglium (E)32,44,45 C. tiglium (E)31,34,44,45 C. tiglium (E)30 S*** chamaejasme (T)51 D* aurantiaca (T)52 D* aurantiaca (T)52 W. canescens (T)53 S*** chamaejasme (T)51 S*** chamaejasme (T)51 W. canescens (T)53 S*** chamaejasme (T)51 C. tiglium (E)31 C. tiglium (E)30 C. tiglium (E)30 E. fischeriana (E)26 C. tiglium (E)34 C. tiglium (E)31,34 C. tiglium (E)31 DOI: 10.1021/cr200397n Chem. Rev. XXXX, XXX, XXX−XXX

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Table 1. continued no.

species (familyb)c

name

Phorbol Esters 54

phorbol 12,13,20-triacetate (PTA)

55 56 57 58 59 60 61 62 63

phorbol phorbol phorbol phorbol phorbol phorbol phorbol phorbol phorbol

64 65 66 67 68 69 70 71 72 73 12-Deoxyphorbol 74

stelleracin E stelleracin D ostodin phorbol 7β-hydroperoxide-5-ene-12-hexadecanoate-13-acetate phorbol 5β-hydroxy-12-benzoate-13-octanoate (Stelleracin C) 69 70 phorbol 6α,7α-epoxy-12-hexadecanoate-13-acetate phorbol 6α,7α-epoxy-5β-hydroxy-12-(n-deca-2E,4E,6E-trienoate)-13-acetate phorbol 6α,7α-epoxy-5β-hydroxy-12-tiglate-13-(2-mehylbutanoate)

75

12-deoxyphorbol 13-acetate (prostratin)

76

12-deoxyphorbol 13-isobutyrate

77

12-deoxyphorbol 13-(2-methylbutyrate)

78

12-deoxyphorbol 13-tiglate

79

12-deoxyphorbol 20-hydroxy-13-angelate

80 81

12-deoxyphorbol 13-benzoate 12-deoxyphorbol 13-phenylacetate (DPP)

82 83 84 85 86 87

12-deoxyphorbol 12-deoxyphorbol mellerin A 12-deoxyphorbol 12-deoxyphorbol 12-deoxyphorbol

12-(2Z,4E-octadienoyl)-13,20-diacetate 12-tetradecanoate-13,20-diacetate 12-isobutyrate-13-acetate-20-angelate 12-dodecanoate-13-acetate-20-linolenate 4α-12,13-didecanoate 7-oxo-5-ene-12-neodecanoate-13-acetate 7-oxo-5-ene-12-(2E,4E)-decadienoate-13-acetate 7-oxo-5-ene-12-dodecanoate-13-acetate (trigowiin A) 7-oxo-5-ene-12-hexadecanoate-13-acetate

12-deoxyphorbol

13-(4-methoxyphenyl)acetate 13-heptanoate 13-(3E,5E-decadienoate) 20-hydroxy-13-(cis-9,10-methylene)- undecanoate 13-dodecenoate D

C. tiglium (E)30,32,54 S* grantii (E)55 E. broteri (E)56 C. tiglium (E)32 E. franckiana (E)50,57 C. sparciflorus (E)43 C. tiglium (E)30 D* genkwa (T)40 D* genkwa (T)40 T. cherrieri (E)58 S. sebiferum (E)47 A. fordii (E)48 S*** chamaejasme (T)51 S*** chamaejasme (T)51 O. paniculata (E)42 S. sebiferum (E)47 S*** chamaejasme (T)51 E. fischeriana (E)59,60 E. fischeriana (E)60 S. sebiferum (E)46 E* acerifolia (E)61 H** dockrillii (E)62 E* bicolor (E)63 E. triangularis (E)64 E. resinifera (E)65 H. nutans (E)19 E. fischeriana (E)66 P. prostrata (T)67−69 E. triangularis (E)70 E. cornigera (E)71 S** sylvatica (E)72 D. racemosa (T)73 E. ledienii (E)70,74 E. resinifera (E)75 E. triangularis (E)64,70,76 E. poisonii (E)74 S* grantii (E)56 E. poisonii (E)74 E. ledienii (E)70 E. coerulescens (E)70,77 E. ortissimo (E)78 E. triangularis (E)64 E. unispina (E)74 E. fortissima (E)77,78 E. ledienii (E)70 E. triangularis (E)64,70 E. helioscopia (E)77 E. poisonii (E)16,74 E. resinifera (E)75 E. unispina (E)74 S. sebiferum (E)79 E. poisonii (E)80,81 E. resinifera (E)75,82 E. resinifera (E)75 E. coerulescens (E)77 N. melleri (E)83 E. agallocha (E)84 E. poisonii (E)16 E. fortissima (E)77,78 DOI: 10.1021/cr200397n Chem. Rev. XXXX, XXX, XXX−XXX

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species (familyb)c

name

12-Deoxyphorbol 88 12-deoxyphorbol 13-dodecanoate 89

12-deoxyphorbol 13-tetradecanoate

90 91

12-deoxyphorbol 13-(3-tetradecenoate) 12-deoxyphorbol 13-(3,5-tetradecadienoate)

92 93 94

12-deoxyphorbol 13-tetradecatrienoate 12-deoxyphorbol 13-pentadecanoate 12-deoxyphorbol 13-hexadecanoate

95 96 97

12-deoxyphorbol 13-(3,5,7-hexadecatrienoate) 12-deoxyphorbol 13,20-diacetate 12-deoxyphorbol 13-isobutyrate-20-acetate

98

12-deoxyphorbol 13-(2-methylbutyrate)-20-acetate

99

12-deoxyphorbol 13-angelate-20-acetate

100

12-deoxyphorbol 13-tiglate-20-acetate

101

12-deoxyphorbol 13-phenylacetate-20-acetate

102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 121 122 123 124 125

12-deoxyphorbol 12-deoxyphorbol 12-deoxyphorbol 12-deoxyphorbol 12-deoxyphorbol 12-deoxyphorbol 12-deoxyphorbol 12-deoxyphorbol 12-deoxyphorbol 12-deoxyphorbol 12-deoxyphorbol 12-deoxyphorbol fischeroside A fischeroside B 12-deoxyphorbol 12-deoxyphorbol 12-deoxyphorbol 12-deoxyphorbol 12-deoxyphorbol 12-deoxyphorbol 12-deoxyphorbol 12-deoxyphorbol 12-deoxyphorbol 12-deoxyphorbol

13-p-hydroxyphenylacetate-20-acetate 13-(4-methoxyphenyl)acetate-20-acetate 13-p-acetoxyphenylacetate-20-acetate 13-octenoate-20-acetate 13-decdienoate-20-acetate 13-dodecanoate-20-acetate 13-dodecenoate-20-acetate 13-dodecdienoate-20-acetate 13-myristate-20-acetate 13-(9Z)-octadecanoate-20-acetate 13-acetate-20-benzoate 13-acetate-20-p-methoxybenzoate

13-acetate-20-decanoate 13-butanoate-20-decanoate 13-hexanoate-20-decanoate 13-octanoate-20-decanoate 13-decanoate-20-angelate 13-decanoate-20-tiglate 13-decanoate-20-decanoate 13-dodecanoate-20-decanoate 13-hexadecanoate-20-dodecanoate 6α,7α-epoxy-5β-hydroxy-13-decanoate E

E. coerulescens (E)57,77 E. fortissima (E)78 S. sebiferum (E)46 P. prostrata (T)68 S. sebiferum (E)46 E. agallocha (E)85 S. sebiferum (E)46 E* bicolor (E)63 S. sebiferum (E)46 N. macrocalyx (E)86 E. fischeriana (E)59,66 S. sebiferum (E)46 B. montanum (E)87 E. agallocha (E)85 E. fischeriana (E)21,26 E. poisonii (E)74 E. ledienii (E)70 E. fortissima (E)77,78 E. triangularis (E)64,70 E. resinifera (E)75,82,88 E. poisonii (E)74 E. ledienii (E)70 E. fortissima (E)77,78 E. triangularis (E)64,70 E. unispina (E)74 E. coerulescens (E)57,70,77 E. poisonii (E)16,74 E. unispina (E)74 E. resinifera (E)75,88 E. fortissima (E)77,78 E. helioscopia (E)77 E. coerulescens (E)77 E. ledienii (E)70 E. triangularis (E)64,70 E. poisonii (E)16,80,81 E. resinifera (E)75,88 E. poisonii (E)80,89 E. resinifera (E)75,88 E. poisonii (E)80,90 E. polyacantha (E)77 E. polyacantha (E)77 E. coerulescens (E)57,77,91 E. fortissima (E)77,78 E. helioscopia (E)77 A. moluccana (E)92 E. fischeriana (E)59 E. cornigera (E)71 E. cornigera (E)71 E. fischeriana (E)26 E. fischeriana (E)26 E. cornigera (E)71 E. cornigera (E)71 E. cornigera (E)71 E. cornigera (E)71 E. cornigera (E)71 E. cornigera (E)71 E. cornigera (E)71 E. cornigera (E)71 N. macrocalyx (E)86 P. elongata (T)39 DOI: 10.1021/cr200397n Chem. Rev. XXXX, XXX, XXX−XXX

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species (familyb)c

name

12-Deoxyphorbol 126 12-deoxyphorbol 6α,7α-epoxy-5β-hydroxy-13-dodecanoate 127 12-deoxyphorbol 6α,7α-epoxy-5β-hydroxy-13-tetradecanoate

128

12-deoxyphorbol 6α,7α-epoxy-5β-hydroxy-13-tetradeca-2,4-dienoate (subtoxin B)

129

mancinellin

130 12-deoxyphorbol 6α,7α-epoxy-5β-hydroxy-13-hexadecanoate-20-dodecanoate 131 12-deoxyphorbol 5β-hydroxy-13-acetate 132 12-deoxyphorbol 5β-hydroxy-13-myristate 133 12-deoxyphorbol 5β-hydroxy-13-hexadecanoate 134 12-deoxyphorbaldehyde-13-acetate 135 12-deoxyphorbaldehyde-13-hexadecanoate 4-Deoxyphorbol and 4-Deoxy(4α)phorbol 136 4-deoxyphorbol 137 4-deoxyphorbol 12-(N-methylanthraniloate)-13-acetate (sapintoxin A) 138 139 140 141 142 143 144 145 146 147 148 149 150 151 152 153 154

4-deoxyphorbol 4-deoxyphorbol 4-deoxyphorbol 4-deoxyphorbol 4-deoxyphorbol 4-deoxyphorbol 4-deoxyphorbol 4-deoxyphorbol 4-deoxyphorbol 4-deoxyphorbol 4-deoxyphorbol 4-deoxyphorbol 4-deoxyphorbol 4-deoxyphorbol 4-deoxyphorbol 4-deoxyphorbol 4-deoxyphorbol

12-(n-deca-2,4,6-trienoate)-13-acetate (sapatoxin A) 12-acetate-13-(2,4-octadienoate) 12-acetate-13-(1-octenoate) 12-acetate-13-(2,4-decadienoate) 12-acetate-13-[(2Z,4E)-2,4,6-decatrienoate] 12-acetate-13-(2,4,6-dodecatrienoate) 12-acetate-13-(2,4,6,8-dodecatetraenoate) 12-acetate-13-(2,4,6,8-tetradecatetraenoate) 12-acetate-13-(2,4,6,8,10-tetradecapentaenoate) 12,13-bis (isobutyrate) 12-(2,4-decadienoate)-13-isobutyrate 12-(2,4,6-decatrienoate)-13-isobutyrate 12-(2′-methyl-2′-butenoate)-13-(2″-methylbutanoyl) 4-epi-12-(2′-methyl-2′-butenoate)-13-(2″-methylbutanoate) 12-tiglate-13-(phenylacetate) 12-,13-,20-triacetate 12-(2Z,4E-octadienoate)-13,20-diacetate

155 156 157 158 159 160 161 162 163 164 165 166 167 168 169 170 171 172 173 174 175 176 177 178

4-deoxyphorbol 12-benzoate-13-isobutyrate-20-acetate 4-deoxyphorbol 12,13-bis(isobutyrate)-20-acetate 4-deoxyphorbol 12-isobutyrate-13-acetate-20-benzoate 4-deoxy(4α)phorbol 12-tiglate-13-acetate 4-deoxy(4α)phorbol 12-(N-methylanthraniloate)-13-acetate (α-sapinine) 4-deoxy(4α)phorbol 12-hexanoate-13-acetate 4-deoxy(4α)phorbol 12-(2Z,4E-octadienoate)-13-acetate 4-deoxy(4α)phorbol 12-[(2Z,4E)-2,4,6-decatrienoate 13-acetate 4-deoxy(4α)phorbol 12-tiglate-13-isobutyrate 4-deoxyphorbol 4-epi-12,13-bis(isobutyrate) 4-deoxy(4α)phorbol 12-(2,3-dimethyl)butyrate-13-isobutyrate 4-deoxy(4α)phorbol 12-tiglate-13-(2-methyl)butyrate 4-deoxy(4α)phorbol 12-tiglate-13-phenylacetate 4-deoxy(4α)phorbol 12-tiglate-13-decanoate 4-deoxy(4α)phorbol 12-acetate-13-(1,4,6,8-tetradecatetraenoate) 4-deoxy(4α)phorbol 12,13-diisobutyrate-20-acetate 4-deoxy(4α)phorbol 12-benzoate-13-isobutyrate-20-acetate 4-deoxy(4α)phorbol 13-acetate-20-linoleate 4-deoxy(4α)phorbol 13-acetate-20-oleate 4-deoxy(4α)phorbol 5,20-dihydroxy-12-(2′-N-methylaminobenzoyl)-13-acetate 4-deoxyphorbol 5,20-dihydroxy-12-(2′-N-methylaminobenzoyl)-13-acetate (sapintoxin B) 4-deoxyphorbol 5-hydroxy-12-(n-deca-2,4,6-trienoate)-13-acetate (sapatoxin B) 4-deoxy(4α)phorbaldehyde-12-(2-methylaminobenzoyl)-13-acetate 4-deoxyphorbaldehyde 12-(2-methylaminobenzoate)-13-acetate F

B. montanum (E)87 N. macrocalyx (E)86 P. prostrata (T)68,69 P. simplex (T)93 P. elongata (T)39 P. simplex (T)94 H* mancinella (E)95 P. prostrate (T)68 N. macrocalyx (E)86 D. racemosa (T)73 B. montanum (E)87 S** sylvatica (E)72 E. fischeriana (E)59 E. fischeriana (E)59 S. hippomane (E)96 S. indicum (E)38,97−99 S. sebiferum (E)79 S. indicum (E)38,100,101 E. tirucalli (E)102 E. tirucalli (E)102 E. tirucalli (E)102 E. tirucalli (E)103 E. tirucalli (E)102 E. tirucalli (E)102 E. tirucalli (E)103 E. tirucalli (E)103 E. obtusifolia (E)104,105 E. prolifera (E)106 E. prolifera (E)106 S. hippomane (E)96 S. hippomane (E)96 S* grantii (E)107 S. hippomane (E)96 E. broteri (E)56 E. biglandulosa (E)108 E. nubica (E)109 E. obtusifolia (E)104,105 E. nubica (E)109 C. tiglium (E)34,35 S. indicum (E)38,97,110 S. insigne (E)111 P** tithymaloides (E)112 E. tirucalli (E)103 C. tiglium (E)34,35 E. obtusifolia (E)104,105 E. aellenii (E)113 C. tiglium (E)34 C. tiglium (E)34 C. tiglium (E)34 E. tirucalli (E)103 E. nubica (E)109 E. nubica (E)109 C. tiglium (E)34 C. tiglium (E)34 S. indicum (E)97 S. indicum (E)38,97,99 S. indicum (E)38,100 S. indicum (E)38,98 S. indicum (E)38,97,98 DOI: 10.1021/cr200397n Chem. Rev. XXXX, XXX, XXX−XXX

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species (familyb)c

name

4,12-Dideoxyphorbol and 4,12-Dideoxy(4α)phorbol 179 4,12-dideoxyphorbol 180 4,12-dideoxyphorbol 13-(2,3-dimethyl)butyrate 181 4,12-dideoxyphorbol 13-(3,5-tetradecadienoate) 182 4,12-dideoxyphorbol 13,20-diacetate 183 4,12-dideoxyphorbol 13-(2,3-dimethyl)butyrate-20-acetate 184 4,12-dideoxyphorbol 13-isobutyrate-20-benzoate 185 4,12-dideoxyphorbol 13-isovalerianate-20-benzoate 186 4,12-dideoxy(4α)phorbol 187 4,12-dideoxy(4α)phorbol 13-(3,5-tetradecadienoate) 188 4,12-dideoxy(4α)phorbol 13-hexadecanoate 189 4,12-dideoxy(4α)phorbol 13,20-diacetate 4,20-Dideoxyphorbol and 4,20-Dideoxy(4α)phorbol 190 4,20-dideoxyphorbol 12-(2-N-methylaminobenzoate)-13-acetate 191 4,20-dideoxyphorbol 12,13-bis(isobutyrate) 192 4,20-dideoxyphorbol 12-benzoate-13-isobutyrate 193 4,20-dideoxy(4α)phorbol 12-(2-N-methylaminobenzoate)-13-acetate 194 4,20-dideoxy(4α)phorbol 5β-hydroxy-12-(2-N-methylaminobenzoate)-13-acetate 195 4,20-dideoxy(4α)phorbol 5β-hydroxy-12-benzoate-13-isobutyroate (euphodendriane A) 196 4,20-dideoxyphorbol 5β-hydroxy-12-(2-N-methylaminobenzoyl)-13-acetate (sapintoxin C) 197 4,20-dideoxyphorbol 5β-hydroxy-12-(n-deca-2,4,6-trienoate)-13-acetate (sapatoxin C) 198 4,20-dideoxyphorbol 5β-hydroxy-12-(n-tetradecanoate)-13-acetate 199 4,20-dideoxyphorbol 5β-hydroxy-12,13-diisobutyrate 200 4,20-dideoxyphorbol 5β-hydroxy-12-benzoate-13-isobutyrate 201 4,20-dideoxyphorbol 5ξ-acetate-12-benzoate-13-isobutyrate 202 4,20-dideoxyphorbol 5α-hydroxy-12-tiglate-13-isobutyrate 203 4,20-dideoxyphorbol 5ξ-hydroxy-12,13-diisobutyrate 204 4,20-dideoxyphorbol 5ξ-hydroxy-12-benzoate-13-isobutyrate 205 4,20-dideoxyphorbol 5α-hydroxy-12-tiglate-13-phenylacetate 12,20-Dideoxyphorbol 206 12,20-dideoxyphorbol 13-isobutyrate 207

12,20-dideoxyphorbol 13-angelate

20-Deoxyphorbol 208 20-deoxyphorbol 5α-hydroxy-13-phenylacetate-12-tiglate 209 20-deoxyphorbol 5α-hydroxy-13-isobutyrate-12-tiglate 4,12,20-Trideoxyphorbol 210 4,12,20-trideoxyphorbol 13-(2,3-dimethyl)butyrate 16- or 17-Substituted Derivatives 211 12-deoxyphorbol 5-ene-7-oxo-13-isobutyrate-16-angelate 212 phorbol 7-oxo-5-ene-12-hexadecanoate-13-acetate-16-hydroxy 213 12-deoxyphorbol 5-ene-7β-hydroxy-13-isobutyrate-16-angelate 214 jatropha factor C1 215 jatropha factor C2 216 jatropha factor C3 217 jatropha factor C4 218 jatropha factor C5 219 pycnocomolides A 220 pycnocomolides B 221 pycnocomolides C 222 12-deoxyphorbol 16-hydroxy 223 12-deoxyphorbol 13-phenylacetate-16-hydroxy 224 12-deoxyphorbol 13-hexadecanoate-16-hydroxy 225 12-deoxyphorbol l3-angelate-16-isobutyrate

226 227 228

2-deoxyphorbol l3-tiglate-16-isobutyrate 12-deoxyphorbol l3-angelate-16-(2-methylbutyrate) 12-deoxyphorbol 13-phenylacetate-16-(2-methylbutyrate) G

E* bicolor (E)63 E. pityusa (E)114 E* bicolor (E)63 E* bicolor (E)63 E. pityusa (E)114 E. pannonica (E)115 E. pannonica (E)115 E* bicolor (E)63 E* bicolor (E)63 E. guyoniana (E)116 E* bicolor (E)63 S. indicum (E)99 E. obtusifolia (E)104,105 E. prolifera (E)106 S. indicum (E)97 S. indicum (E)97 E. dendroides (E)117 S. indicum (E)38,97,99 S. sebiferum (E)79 S. indicum (E)38,100 S. indicum (E)38 E. tuckeyana (E)118 E. tuckeyana (E)118 E. nubica (E)109 S* grantii (E)107 E. prolifera (E)106 E. prolifera (E)106 S* grantii (E)107 E. E. E. E.

unispina (E)75,119 resinifera (E)119,120 unispina (E)119 resinifera (E)75,119,120

S* grantii (E)107 S* grantii (E)107 E. pityusa (E)114 E. grandicornis (E)121 A. fordii (E)48 E. grandicornis (E)121 J. curcas (E)122−124 J. curcas (E)123,124 J. curcas (E)123,124 J. curcas (E)123,124 J. curcas (E)123,124 P* cornuta (E)125 P* cornuta (E)125 P* cornuta (E)125 E. poisonii (E)126 E. poisonii (E)80 B. montanum (E)87 E. ledienii (E)70 E. cooperi (E)127 E. triangularis (E)70 E. cooperi (E)29 E. coerulescens (E)70 E. poisonii (E)80 DOI: 10.1021/cr200397n Chem. Rev. XXXX, XXX, XXX−XXX

Chemical Reviews

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species (familyb)c

name

16- or 17-Substituted Derivatives 229 12-deoxyphorbol 13-phenylacetate-16-benzoate 230 12-deoxyphorbol l3-angelate-16-isobutyrate-20-acetate

231 232

12-deoxyphorbol l3-tiglate-16-isobutyrate-20-acetate 12-deoxyphorbol l3-angelate-16-(2-methylbutyrate)- 20-acetate

233 234 235 236 237 238 239 240

12-deoxyphorbol 13-phenylacetate-16-(2-methylbutyrate)-20-acetate 12-deoxyphorbol 13-phenylacetate-16-benzoate-20-acetate 12-deoxyphorbol 13-phenylacetate-16-(2-methylbutyrate)- 20-(2-methylbutyrate) 4,20-dideoxyphorbol 12,13-bis(isobutyrate)-17-acetate 4-deoxyphorbol 12,13-bis(isobutyrate)-17-acetate 4-deoxyphorbol 12-(2E,4E-decadienoate)-13-acetate-16-hydroxy 4-deoxyphorbol 16-acetate phorbol 16-hydroxy

241

phorbol 12-palmitate-13-acetate-16-hydroxy

242 243 244 245 246 247 248

phorbol 13-angelate-16-hydroxy phorbol 12-palmitate-13-angelate-16-hydroxy phorbol 16-acetate 4-deoxy(4α)phorbol 12-hexanoate-13-acetate-16-hydroxy 4-deoxy(4α)phorbol 12-dodecanoate-13-acetate-16-hydroxy 4-deoxy(4α)phorbol 12-hexadecanoate-13-acetate-16-hydroxy 4-deoxy(4α)phorbol 12-(2,3-dimethyl)butyrate-13-isobutyrate-17-hydroxy

E. resinifera (E)75 E. ledienii (E)70 E. cooperi (E)127 E. triangularis (E)70 E. cooperi (E)29 E. ledienii (E)70 E. coerulescens (E)70 E. poisonii (E)80,126 E. resinifera (E)75 E. poisonii (E)80 E. obtusifolia (E)104,105 E. obtusifolia (E)104,105 S. insigne (E)111 S. insigne (E)128 J. podagrica (E)129 J. multifida (E)129 V. fordii (E)130 A. fordii (E)48 A. fordii (E)131,132 A. fordii (E)131,132 S. insigne (E)128 S. insigne (E)111 S. insigne (E)111 A. fordii (E)48 E. aellenii (E)113

a A = Aleurites; B = Baliospermum; C = Croton; D = Daphnopsis; D* = Daphne; E = Euphorbia; E* = Excoecaria; H = Homalanthus; H* = Hippomane; H** = Hylandia; J = Jatropha; N = Neoboutonia; O = Ostodes; P = Pimelea; P* = Pycnocoma; P** = Pedilanthus; S = Sapium; S* = Synadenium; S** = Stillingia; S*** = Stellera; T = Trigonostemon; V = Vernicia; W = Wikstroemia. bE, Euphorbiaceae; T, Thymelaeaceae. cReference.

2.4. Esters of 4,12-Dideoxyphorbol and 4,12-Dideoxy(4α)phorbol

hydroxy group at C-20. Although these compounds are more widely distributed than phorbol esters, they are less stable. Two rare 12-deoxyphorbol esters (134 and 135) bearing an aldehyde group at the C-6 position instead of an ethoxy group were isolated from the roots of Euphorbia fischeriana.59 Prostratin (75), which is a particularly promising 12deoxyphorbol ester, has been advanced into phase I human clinical trials for the treatment of HIV/AIDS. The structures of a series of 12-deoxyphorbol esters have been summarized in Table 3.

4,12-Dideoxyphorbols are oxygenated at C-13 and C-20, and have either 4β-H or 4α-H. 4,12-Dideoxy(4α)phorbol (186) and three of its esters (187−189) have been isolated previously only from Excoecaria bicolor and Euphorbia guyoniana (Euphorbiaceae).63,116 To date, there have been no reports in the literature focused on investigating the pharmacological potential of 4,12-dideoxyphorbol esters. The structures of all of the known 4,12-dideoxyphorbol and 4,12-dideoxy(4α)phorbol esters are listed in Table 5.

2.3. Esters of 4-Deoxyphorbol and 4-Deoxy(4α)phorbol

This type of skeleton is similar to that of phorbol except that there is a β-H or an α-H at C-4 instead of a β-OH. Fürstenberger and Hecker103 described the characteristic differences in the NMR spectra of 4-deoxyphorbol and 4deoxy(4α)phorbol with regard to the H-1, H-7, and H-10 protons of the diterpene parent. The differences in the shifts of these protons can be understood in terms of the shielding effects of the 1,2- and 6,7-double bonds and the deshielding effect of the adjacent 9α-OH. These effects can therefore be attributed to the change in the stereochemistry of the diterpene parent following epimerization at C-4. The stereochemistry at C-4 was determined to be crucial to the bioactivity of 4deoxyphorbol, and 4-deoxy-4α-phorbol esters are generally inactive or less potent than 4-deoxyphorbol with 4β-H (see section 3). Two 4-deoxyphorbol esters (177 and 178) bearing an aldehyde group instead of ethoxy group at C-6 were isolated from Sapium indicum.38,97,98 The structures of all of the known 4-deoxyphorbol and 4deoxy(4α)phorbol esters are listed in Table 4.

2.5. Esters of 4,20-Dideoxyphorbol and 4,20-Dideoxy(4α)phorbol

In contrast to 4-deoxyphorbols, 4,20-dideoxyphorbols have a methyl group at C-20 instead of an ethoxy group. 4,20Dideoxyphorbol esters commonly exhibited no or weak bioactivities because they do not possess a free hydroxy at C20.38,79,97,105,117 The structures of all of the known 4,20-dideoxyphorbol and 4,20-dideoxy(4α)phorbol esters are listed in Table 6. 2.6. Esters of 12,20-Dideoxyphorbol

To date, only two 12,20-dideoxyphorbols (206 and 207) have been isolated from plants belonging to the Euphorbiaceae family.75,119,120 2.7. Esters of 20-Deoxyphorbol

Although very few 20-deoxyphorbols have been discovered to date, two 20-deoxyphorbols (208 and 209) bearing a 5αhydroxy moiety have been isolated from Synadenium grantii.107 H


Chemical Reviews

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Table 2. Phorbol Esters

I


Chemical Reviews

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Table 3. Esters of 12-Deoxyphorbol

2.8. Esters of 4,12,20-Trideoxyphorbol

molluscicidal and platelet aggregation activities on compounds 214−218.124

Only one 4,12,20-trideoxyphorbol (210, Figure 2), representing the most deoxygenated form of phorbol, has been reported to date, and was isolated from Euphorbia pityusa.114 It remains unknown whether this compound and the other less oxygenated analogues of phorbol are derived from the parent polyol by the removal of oxygen atoms, or, alternatively, from the transannular cyclization of less oxygenated lathyrane precursors.114

3. BIOLOGICAL ACTIVITY Tigliane diterpenes possess a variety of different biological activities, including anti-HIV, anticancer, tumor promotional, and proinflammatory activities, which have been the subject of considerable attention. Herein, we will focus predominantly on the activities of the tigliane diterpenes in these areas. 3.1. Proinflammatory Activity

2.9. 16- or 17-Substituted Derivatives

Plants belonging to the Euphorbiaceae and Thymeleaceae families cause irritation to the skin and mucous membranes.21 The active principles of these plants have been determined to be tigliane diterpenes, which exhibited irritant effects in a mouse ear test. The irritant dose 50 (ID50) data published in the literature for these compounds are shown in Table 8. 3.1.1. Phorbol. The parent alcohol phorbol did not behave as an irritant in the mouse ear test. 21 Phorbol 12-

These compounds differ from other tiglianes in that they possess an extra primary hydroxy group or ester moiety at C-16 or C-17 of the cyclopropane ring system (Table 7). Compounds 211 and 213121 and compound 21248 also possess an unusual 5-en-7-one or 5-en-7-ol functionality instead of the usual 6,7-olefin group. The unique dicarboxylic acid moiety formed at C-13 and C-16 (214−218,123 219−221125) imparted J


Chemical Reviews

Review

Table 4. Esters of 4-Deoxyphorbol and 4-Deoxy(4α)phorbol

Table 5. Esters of 4,12-Dideoxyphorbol and 4,12Dideoxy(4α)phorbol

Table 6. Esters of 4,20-Dideoxyphorbol and 4,20Dideoxy(4α)phorbol

a

tetradecanoate-13-acetate (TPA) showed the highest irritant activity (ID50 = 0.016 nmol/ear),44 and is therefore the most potent irritant of the phorbol derivatives reported to date from the two families. This compound is commonly used as a standard irritant. Wikstroemia factor C1 (41), which was isolated from Wikstroemia canescens, gave an ID50 value of 0.04 nmol/ear, which was comparable to that of the standard irritant phorbol ester TPA.53 16-Hydroxyphorbol (240), which can be obtained from Jatropha podagrica and Jatropha multifida, exhibited an ID50 value of 0.13 nmol/ear.129 Several phorbol 12,13-diesters (8, 12, 17, 21, 22) isolated from Euphorbia tirucalli showed ID50 values in the range of 0.02−0.10 nmol/

Absolute positions at C-5 not known.

Figure 2. Ester of 4,12,20-trideoxyphorbol.

ear.36 It could be inferred from these data that an increasing number of C atoms or an increasing number of double bonds at K


Chemical Reviews

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Table 7. Tigliane Derivatives Substituted at C-16 or C-17

Table 8. ID50 Data for Tigliane Derivatives from the Literature compd

ID50a

Phorbol TPA 0.016 8 0.03 12 0.10 17 0.07 19 0.10 21 0.03 22 0.02 41 0.04 57 >100 59 11.29 71 0.27 78 0.28 83 1.96 87 0.19 88 0.53 97 1.50 98 1.50 99 0.18 100 1.20 101 0.027 102 2.32 104 0.23 105 7.81 106 6.48 107 4.37 108 3.51 109 1.94 127 0.17 129 0.24−0.33 131 3.00 12-Deoxy-16-hydroxyphorbol 225 0.25 228 0.19 230 0.91 232 2.40 233 0.48 16-Hydroxyphorbol 240 0.13 4,20-Dideoxyphorbol 192 2.60 196 >20 203 >76 204 >48 4-Deoxyphorbol 137 0.04 148/149 0.09 157 1.40 170 3.70 171 3.30 a

ref 44, 36 36 36 43 36 36 51 43 57 46 70, 57, 77 57, 70, 57, 88 70, 80, 80 80 77 77 77 77 77 68, 95 73

72, 77

77 77 77 77, 88 70, 77 77 88

69, 93

70 79 70 70 80 129 106 79 106 106 79 106 109 109 109

In nm/5 μL/ear; 24 h.

a fixed number of C atoms in the acyl moieties of the phorbol esters investigated would lead to an increase in the irritant activity of these compounds. As compared to their saturated analogues, the unsaturated phorbol esters exhibited similar irritant activities.36 The 12,13-diester (19) and corresponding 12,13,20-triester (57) of phorbol were isolated from Croton sparciflorus. The former showed an ID50 value of 0.1 nmol/ear, L


Chemical Reviews

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whereas 57 was much less potent (ID50 > 100 nmol/ear).43 These data highlighted the importance of a free OH group at C-20 for the irritant activity. 3.1.2. 12-Deoxyphorbol. 12-Deoxyphorbol esters are potent toxins that cause severe inflammation to the skin.133 Most of the 13-monoesters and 13,20-diesters of 12deoxyphorbol showed different levels of inflammatory activity in a mouse ear method.46,57,68−70,72,73,75,78,79,85,88,95,129 As shown in Table 8, the parent alcohol of the above compounds, 12-deoxyphorbol (74), was originally isolated from Euphorbia triangularis and exhibited no irritant effects upon mice skin.64 The presence of a 5β-hydroxy group (131) in the tigliane increased the biological activity as compared to the corresponding 5-deoxy compounds (75).73 Analysis of the ID50 data in Table 8 indicated that the monoesters were more potent than the diesters in terms of their irritant effect and that their irritant effects were longer lasting. Furthermore, an increase in the length of the fatty acid located at C-13 produced greater biological activity in both the mono- and the diester groups, and the presence of some degree of unsaturation in the side chain increased the potency even further.65,77 The presence of a free hydroxy group at C-20 together with a trans-fused A/B ring system also led to higher levels of potency and longer lasting effects. The 6,7-oxide phorbol derivatives were less active than the corresponding phorbol esters. 3.1.3. 4-Deoxyphorbol. The 4-deoxyphorbol derivatives (142, 145, 146, 162, and 169) were isolated from Euphorbia tirucalli and showed high levels of irritant activity (no ID50 data available in the literature), whereas the 4-deoxy-4α-phorbol derivatives (162 and 169) were inactive.103 A mixture of the 4deoxyphorbol-12,13-diesters (148 and 149) showed high irritant activity,106 whereas the 12,13,20-triesters of 4deoxyphorbol (157, 170, and 171) exhibited only moderate irritant activities.109 These results were in agreement with the trends observed for the 12-deoxyphorbol esters, in that the presence of a free hydroxy group at C-20 together with a transfused A/B ring system appeared to be important to the irritant effects of these compounds. Furthermore, the 4-OH was not critical to the irritant activity of these compounds. 3.1.4. 12,20-Dideoxyphorbol. The 12,20-dideoxyphorbols (206 and 207) obtained from Euphorbia resinifera and Euphorbia unispina showed no irritant activity,75,120 and indicated that the hydroxy function at C-20 was important to the irritant activity. 3.1.5. 4,20-Dideoxyphorbol. The 12,13-diesters of 4,20dideoxyphorbol (192, 203, and 204), which were isolated from Euphorbia prolifera, showed weak or no irritant activity106 and further highlighted the importance of the free hydroxy group at C-20 to the irritant activity.

between tumor promoters and cocarcinogens is that tumor promoters can function when applied long after the initiating agent, whereas cocarcinogens can only enhance tumor yield if they are applied close to or at the same time as the carcinogen. An important feature of tumor promoters is that, unlike initiating agents, their action is relatively reversible.135 One of the most important experiments on mouse skin for the analysis of the mechanism of carcinogenesis is referred to as the “Berenblum experiment”.33 The “two-stage hypothesis” of skin carcinogenesis, including the first or “initiation” stage and the second or “promotion” stage, was derived from the results of experiments of this type.33,136 Hecker33 reported that phorbol 12-tetradecanoate-13-acetate (TPA), which is the most potent phorbol ester derived from Croton tiglium, was not a carcinogen but a cocarcinogen that was classified as a tumor promoter following a quantitative Berenblum experiment. Zayed et al.65 prepared a series of 13-monoesters derivatives of 12deoxyphorbol and tested their tumor-promoting activities. The results of this particular study indicated that there was an optimum chain length for the acyl residue. Of the 12deoxyphorbol esters tested to date, only 12-deoxyphorbol 13tetradecanoate (89) has been reported to show a level of cocarcinogenic activity similar to that of TPA.21,65 It was suggested that tetradecanoate was the most optimum chain length for the acyl residue of 12-deoxyphorbol. Hecker’s group65,137 reported that 12-deoxyphorbol esters containing intermediate hydrophobicity, such as the isobutyrate, tiglate, and phenylacetate esters, were inflammatory but only weakly promoting or nonpromoting. Esters of 12-deoxy-16-OHphorbol have been shown to be weaker tumor promoters than TPA.33,75,95,127 In contrast to the phorbol ester TPA, the parent diterpene was inactive when applied to mouse skin.33,45 Protein kinase C (PKC), which is a phospholipid- and calcium-dependent kinase, has been demonstrated to be the phorbol ester receptor site,138,139 and a range of phorbol esters have been shown to activate this enzyme.140 For example, Brooks et al.79 reported that 12-deoxyphorbol ester (80) and 4deoxyphorbol (137), which were obtained from Sapium sebiferum, demonstrated pro-inflammatory activity in vivo and significantly activated PKC with Ka (the concentration at which 50% activation of PKC occurs) values of 76 and 176 nM, respectively. In contrast, the 4,20-dideoxyphorbol derivative (196) was inactive up to a concentration of 100 μM. A new type of phorbol ester (214) with a macrocyclic dicarboxylic acid diester structure was isolated from the seed oil of Jatropha curcas. This compound behaved in a manner similar to that of TPA, in that it activated PKC in vitro in a dose−response manner, although its activity was slightly weaker than that of TPA. The Ka values for 214 and TPA were 36.0 and 9.0 nM, respectively.122 Wada et al.141 reported that the PKC agonist activity of these compounds can be converted to antagonist activity by modifying the hydrophobicity of the 12-ester side-chain, which ultimately effected the stability of the phorbol esterPKC-membrane complex required for PKC activation. Krauter et al.142 demonstrated that in addition to the oxygen at C-20, the O-acyl function at C-13 was critical to the skinirritant and tumor-promoting bioactivities of these compounds. The importance of the O-acyl group at C-13 was independently supported by photo-cross-linking experiment using special phorbol ester derivatives in a sample of PKC that had been partially purified from rat brain.143 Furthermore, the carbonyl oxygen at C-3 could be reduced to a hydroxy group without any

3.2. Cocarcinogenic and Tumorigenic Activities

Following their initial isolation and characterization, there was significant interest in tigliane diterpenes because of their cocarcinogen and tumorigenic activities. All of the naturally occurring diterpene cocarcinogens are potent skin blistering and reddening agents. Although an ability to cause skin irritation can be a useful guide to cocarcinogenic activity, it does not necessarily follow that all diterpene skin irritants are cocarcinogenic.134 Tumor promoters are only one type of cocarcinogen and have been classified as incomplete carcinogens because they are only capable of completing a process that was started by an initiator.21 One important distinction M


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the fatty acid ester substituent at C-13 was contributing to this effect.16 Kupchan et al.49 reported the isolation of phorbol 12-tiglate 13-decanoate (32) from Euphorbia esula and that this compound was the active ingredient in the P-388 system in vivo. Nineteen tigliane derivatives, including 12 phorbol esters (6, 7, 14, 20, 23, 27, 28, 36−38, 51, and 53) and seven 4deoxy-4α-phorbol esters (158, 163, 166-168, 172, and 173), were isolated from Croton tiglium.34 All of these isolates were evaluated against the SNU387 hepatic tumor cell line, and the phorbol 13,20-diesters (51 and 53) were the only compounds to exhibit potent activity against this cell line with IC50 values of 0.80 and 2.27 μg/mL, respectively. In contrast, the 4-deoxy-4αphorbol esters (158, 163, 166-168, 172, and 173) showed no cytotoxic activity toward this cell line.34 The two 12,13-diester phorbol derivatives (18 and 66) isolated from Ostodes paniculata exhibited high levels of cytotoxic activity in a P388 lymphocytic leukemia test system with ED50 values of 4.5 × 10−5 and 0.055 μg/mL, respectively.42 The cytotoxic activities of 6α,7α-epoxy-5β-hydroxyphorbol ester (72), which was isolated from Excoecaria acerifolia, were evaluated against five cancer cell lines (HL-60, SMMC-7721, A-549, MCF-7, and SW480) and gave IC50 values in the range of 7.62−10.87 μg/ mL.61 It can be inferred on the basis of these results that the type of long-chain acyl group at C-12 or C-13, a free C-20 hydroxy, a trans-fused A/B ring system, and a 6,7-olefinic group may be important to the anticancer activity of these compounds. It is clear that the main active groups in the tigliane diterpenes having anticancer activity are generally the same are those in the diterpenes exhibiting tumor-promoting activity. The nature of the long-chain acyl group appears to be more important to the anticancer and tumor-promoting activities, as evidenced by compounds where the other groups on the skeleton are the same. The higher activities of these compounds toward the tumor cell lines tested may be attributed to the 3-carbonyl, 6,7-olefinic, and acyl groups attached to the skeleton. Although TPA (20) exhibited significant tumor-promoting activity and was cytotoxic toward SNU387 hepatic tumor cells (IC50 = 6.16 μg/mL),34 a mixture composed of phorbol 12-tetradecanoate-13-acetate (TPA, 20), dexamethasone, and choline magnesium trisalicylate is currently undergoing a phase II clinical trial for the treatment of Hematologic Malignancies. A tigliane derivative known as EBC46 (73), which was isolated from the Australian Bush tree Hylandia dockrilii,62 is currently being studied for the treatment of several different cancers (mainly limited at this stage to nonmetastasized solid tumors) in both animals and humans. Veterinary trials involving this compound started in March 2010, and clinical trials in humans are scheduled to follow.

significant loss in the bioactivity, and the structural features of the hydrophilic−lipophilic moieties in these compounds were found to be essential to their PKC binding as well as providing further insights into the molecular interactions of these compounds with the macromolecular target.142 Irie et al.144 synthesized a series of 4β-deoxyphorbol derivatives to investigate the role of the hydroxy group at C-4 of the phorbol esters on their PKC binding and function. The results of their work suggested that the hydroxy group at C-4 of the phorbol esters was not necessary for their PKC binding or tumorpromoting activity. Furstenberger et al.36 reported a series of phorbol esters containing long unsaturated alkyl chains and compared the irritant activities of these compounds to those of the corresponding saturated compounds. The results of this study revealed that the tumor-promoting activity of the compounds decreased as the number of conjugated double bonds in the acyl moieties of the phorbol esters increased, and suggested that the irritant activity was a necessary but insufficient requirement for promoting the activity of the phorbol esters. 3.3. Anticancer Activity

Although tigliane diterpenes generally exhibit tumor-promoting activity, research published in the last 20 years has also shown that some derivatives show significant anticancer activity. For example, the 12-deoxyphorbol derivatives 94, 126, 132, and 224, which were obtained from Baliospermum montanum, showed antileukemic activity with ED50 values in the range of 0.4−3.4 μg/mL in a P-388 lymphocytic leukemia system in vitro.87 The cytotoxic effects of several 13,20-diesters of 12deoxyphorbol (112, 113, and 116−123) over human KB cells were evaluated, and compounds 119, 122, and 123, bearing long acyl chains at C-13, showed higher levels of toxicity than the other compounds tested, with IC50 values of 0.8, 0.5, and 1.0 μg/mL, respectively.71 The 12-deoxyphorbol esters 75, 94, and 111 isolated from Euphorbia fischeriana were evaluated for their cytotoxicity against Ramos B cells, and compound 94, bearing a long acyl chain at C-13 and a free hydroxy at C-20, showed potent cytotoxic activity against this cell line with an IC50 value of 0.0051 μg/mL. Furthermore, this compound showed greater activity than 75, which had an acetate at C-13 (IC50 = 0.056 μg/mL) and exhibited no tumor-promoting activity.19,59 4,20-Deoxyphorbol (195) obtained from Euphorbia dendroides showed very weak cytotoxicity against four human cancer cell lines (NCI-H460, NCI-H460/R, DLD-1, and U-87MG) with IC50 values in the range of 7.46−31.37 μg/ mL.117 Compounds 134 and 135 with an aldehyde group at C20 showed moderate or no inhibitory activity toward several human cancer cell lines.59 The unique phorbol derivative with a hydroxy group at C-3 (69), which was isolated from Euphorbia fischeriana, showed no cytotoxic activity against two human cancer cell lines (MDA-MB-231 and HepG2) and one human immortalized cell line.60 These results suggested that the presence of a long chain saturated aliphatic acyl group at C-13, as well as a carbonyl at C-3 and the free hydroxy at C-20, was important to the activity of these compounds. When the cytotoxicities of several 12-deoxyphorbol esters (79, 86, 99, 101) were evaluated in a panel of six human solid tumor cell lines, compound 86 showed the highest level of activity and was a million-fold more selective for human kidney carcinoma (A498) than the other isolated 12-deoxyphorbol esters (79, 99, and 101).16 These results indicated that the cyclopropyl ring in

3.4. Antiviral Activity

Six 12,13-diesters of phorbol (6, 5, 20, 30, 37, and 47) isolated from Croton tiglium31 were evaluated for their ability to inhibit an HIV-induced cytopathic effect (CPE) in MT-4 cells, as well as their ability to activate PKC associated with tumorpromoting action. In this experiment, TPA (20) was found to be an equipotent inhibitor of HIV-1-induced CPE and an activator of PKC (IC100 of 0.48 ng/mL for the inhibition of CPE; 100% activation of PKC at 10 ng/mL),31 and these results were in agreement with those previously reported by Chowdhury et al.145 Considerable interest was shown for compound 6, because it exhibited anti-HIV activity as low as 7.6 ng/mL without activating PKC (no activation was seen at N


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This assay demonstrated that the introduction of an O-acetyl or glucopyranosyl moiety at C-20 of the prostratin (75) dramatically reduced the anti-HIV-1 activity. Furthermore, prostratin (75) was more active than 6, likely because of the 12deoxidization of prostratin or the presence of the acetate group at C-13. The most interesting thing about prostratin (75), however, was that it did not exhibit tumor-promoting effects and caused growth inhibition in all of the cell lines in which it was tested.19 These results suggested that a long chain was not necessary for 12-deoxyphorbol to show anti-HIV activity, but that the presence of a long chain was necessary for these compounds to show tumor-promoting effects. The persistence of the latent HIV-infected cellular reservoirs represents the major hurdle to virus eradication with highly active antiretroviral therapy (HAART), because the latently infected cells remain a permanent source of viral reactivation. Gulakowski et al.148 and Kulkosky et al.149 reported that the potency and degree of cytoprotection provided by prostratin (75) were dependent on both the viral strain and the host cell type, and that although this compound activated viral expression in two latently infected cell lines, it had little to no effect on chronically infected cell lines. Furthermore, Gulakowski et al.148 found that prostratin had no effect on reverse transcriptase or HIV-1 protease, and that it inhibited the binding of gp120 to CD4. On the basis of these observations, they concluded that prostratin inhibited HIV cytopathicity and replication through a mechanism involving PKC enzymes.148 Hezareh et al.150 found that prostratin (75) exerted its effects through the activation of conventional and/or novel PKC isoforms, and rapidly reduced the cell surface expression of CD4 and CXCR4, but not CCR5, by inducing their internalization and degradation. Williams et al.151 demonstrated that prostratin was capable of both activating NF-κB and driving NF-κB-dependent gene expression within sorted primary CD4+ CD45RO+ T-lymphocytes, whereas the research of Rullas et al.152 suggested that prostratin induced HIV activation in latently infected cells through the induction of NF-κB and Sp1in peripheral blood mononuclear cells (PBMCs), and that the strong and persistent down regulation of HIV receptors decreased the infection of new targets and delayed HIV propagation. Marquez et al.153 investigated a series of phorbol 13-monoesters in terms of their capacity to reactivate HIV latency using a Jurkat T cell line containing latent HIV proviruses, and demonstrated that prostratin stimulated IKK-dependent phosphorylation and degradation of IκBα, leading to the activation of NF-κB. The AIDS Research Alliance in West Hollywood, CA, is currently in the process of filing an initial new drug (IND) application to facilitate the initiation of a phase I human clinical trial with prostratin (75) for the treatment of HIV/AIDS.154,155 In light of its limited availability from natural sources, a semisynthesis of prostratin from phorbol or crotophorbolone has been developed; both compounds are readily available from a renewable source.20 It can be inferred that 12-deoxyphorbol derivatives that possess anti-HIV-1 activity without tumor-promoting effects do so because of the type of 13-acyl group. For example, the 13acetate of prostratin (75) was critical to its nontumorpromoting effects. These findings suggested that the antiHIV-1 and tumor-promoting activities of tigliane derivatives were related to the type of 13-acyl group, and that short chain acyl groups were generally good for anti-HIV-1 activity, whereas long chain acyl groups effectively enhanced the tumor-promoting activity.

concentrations in the range of 10−100 ng/mL). Furthermore, this compound did not influence the cell growth or viability of MT-4 cells at a concentration exhibiting anti-HIV-1 activity, and therefore demonstrated that HIV inhibition without PKC activation was worthy of further investigation.31 Seven 12,13diesters of phorbol (42, 45, 46, 49, 64, 65, and 68), which were isolated from Stellera chamaejasme, showed potent anti-HIV activity in MT4 cells with EC90 values in the range of 0.00050− 1.52 μM, and relatively low levels of cytotoxicity, with IC50 values in the range of 3.5−17.2 μM.51 As compared to the antiHIV-1 activity of the 12,13-diesters of phorbol, compound 6 (IC100 = 7.6 ng/mL;31 EC50 = 1.7 ng/mL146 equivalent to 0.0027 μM) and the 12-benzoyl derivative of 6 (45) exhibited higher levels of anti-HIV activity (EC90 = 0.00050 μM).51 Taken together, these results indicated that the anti-HIV-1 activities of compounds belonging to this class of phorbol were affected by the type of 12-acyl and/or 13-acyl group. ElMekkawy et al.147 evaluated the structure−activity relationships of compounds 6 and 20 in terms of their inhibition of HIV-1induced CPE on MT-4 cells and their activation of PKC by preparing a series of derivatives. The results of this study showed that phorbol derivatives with trans-fused A/B configuration possessed higher levels of activity in both cases, and that the acetylation of the hydroxy group at C-20, as well as methylation of 4-OH or reduction of the carbonyl group at C-3 in the phorbol derivatives, significantly reduced their inhibition of CPE and activation of PKC. In contrast, the positional isomer (phorbol 12-acetate-13-tetradecanoate) of TPA 20 showed no activities, and the loss of activity in both cases was attributed to the removal of the long acyl group in 20. An increase or decrease in the size of the carbon chain of the fatty acid resulted in a significant reduction in the inhibition of CPE relative to compound 6, which provided the highest inhibition of CPE of all of the derivatives tested.147 Matsuya et al.146 synthesized and evaluated a series of 12-O-alkyl derivatives of 6 and found that the 12-O-(methoxymethyl) phorbol 13decanoate derivative exhibited high potency and low cytotoxicity. Furthermore, this compound was demonstrated to keep its anti-HIV-1 activity, even after preincubation with mouse plasma, implying that, in contrast to the corresponding 12acetate (6), it possessed sufficient stability under physiological conditions. 12-Deoxyphorbol-13-(3E,5E-decadienoate) (85), which was isolated from Excoecaria agallocha, was reported to be a potent in vitro inhibitor of HIV-1 replication, in terms of its inhibition of supernatant reverse transcriptase and p24 levels (IC50 0.006 μM), and nontoxic to the host cells at concentrations up to the highest dose tested (2 μM).84 12-Deoxyphorbol, otherwise known as prostratin (75), which was initially isolated from Pimelea prostrata,67−69 was found to be capable of preventing HIV-1 reproduction at noncytotoxic concentrations (≥0.1 μM) in lymphocytic and monocytoid target cells.19 The anti-HIV-1 activities of compounds 52, 75, 96, 114, and 115 were evaluated using an inhibition assay for the CPE of HIV-1, and the results revealed that 52 exhibited weak activity toward the CPE of HIV-1 with an EC50 value of 0.02 μM.26 12Deoxyphorbol-13,20-diacetate (96) displayed significant antiHIV-1 activity with an EC50 value of 0.003 μM, whereas prostratin (75) showed the strongest anti-HIV-1 activity of all of the compounds tested with an EC50 value of 0.00006 μM (equivalent to 0.0234 ng/mL),26 representing a therapeutic index (TI) of more than 8500, although this was less than that of zidovudine (1 017 500), which was used as a positive control. O


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As well as its anti-HIV-1 activity, Bourjot et al.58 reported that the phorbol derivative trigowiin A (18) exhibited moderate antiviral activity in a virus-cell-based assay for Chikungunya virus (CHIKV). Prostratin (75) and TPA (20) were also reported to exhibit potent and selective anti-CHIKV activity.

noteworthy that the 4β-isomers showed higher activity than the 4α-isomers. 3.5.6. Inhibition of NADH Oxidase Activity. Six tigliane diterpenes (147, 156, 164, 191, 236, and 237) isolated from the latex of Euphorbia obtusifolia were evaluated for their inhibition of the NADH oxidase activity in submitochondrial particles from beef heart. 4,20-Dideoxyphorbol-12,13-bis(isobutyrate) (191) was the found to be the most potent inhibitor of all of the compounds tested with an IC50 value of 2.6 ± 0.3 mM. In contrast to other phorbol esters possessing tumor-promoting or irritant activities, compounds 156, 236, and 237, which were oxygenated at C-17 and C-20, were found to be much less active.105 3.5.7. Activation of the TRPV4 Channel. The transient receptor potential vanilloid 4 (TRPV4) channel is widely expressed in epithelial cells and has also been found in the brain, endothelium, liver, and trachea. Several lines of evidence have pointed to the involvement of TRPV4 in important pathological conditions such as hypotonic hyperalgesia, thermal hyperalgesia, asthma, and neuropathic pain.156 Klausen et al.157 investigated the structure−activity relationship of the semisynthetic nontumor-promoting phorbol ester 4α-phorbol12,13-didecanoate, and described it as one of the best small molecule TRPV4 ligands currently available. The results of their study showed that the decoration of the C ring with an ester and the A, B ring junction of the 4α-phorbol were critical to the activity of this compound. 3.5.8. IFN γ-Inducing Activity. Five tigliane diterpene esters (49, 63, 65, 68, 241) were obtained from the leaves of Aleurites fordii and evaluated for their ability to induce IFN-γ in NK92 cells. Compounds 49 and 241 exhibited the most potent responses in IFN-γ induction that were comparable to that of the positive control, phorbol 12-myristate 13-acetate (PMA).48 3.5.9. Anti-inflammatory Activity. Two phorbol esters (42 and 44) isolated from Daphne aurantiaca were tested for their inhibitory activity against LPS-induced NO production in RAW 264.7 macrophages, and gave an IC50 value of 0.01 μM.53

3.5. Other Activities

3.5.1. Epstein−Barr Virus Inducing Activity. The Epstein−Barr virus (EBV) is a ubiquitous viral agent known to be distributed among humans, and EBV-activating agents in our environment have come to be recognized as a serious health problem. Three tigliane type diterpene esters (23, 63, and 67) isolated from Sapium sebiferum have been shown to exhibit EBV-inducing activity, and the 12,13-diester (23) showed higher EBV-inducing activity than the 12,13-diester autoxidation derivatives (63 and 67).47 3.5.2. Inducing Platelet Aggregation Activity. The tigliane esters (10, 137, 138, 159, 175−178, 196−198), which were isolated from Sapium indicum, were tested for their ability to induce human and rabbit platelet aggregation in vitro. The authors reported that the flatter shape of the trans-fused ABring compounds was necessary for the interaction of the phorbol esters at their receptor because the cis analogues were inactive. The tertiary C-4 hydroxy group of phorbol was not necessary for the observed activity, although the 4-deoxy derivatives were less potent than the 4-hydroxy diterpenes. A primary hydroxy group at C-20 was essential for the biological activity, and the 5-hydroxy-analogues possessed much lower levels of activity.38 Several 12-deoxy-16-hydroxyphorbol diesters containing a unique dicarboxylic acid motif (214−218), which were isolated from Jatropha curcas, exhibited platelet aggregation activity, although these compounds were less effective than TPA (20) in this regard.124 3.5.3. Growth-Inhibitory and Insecticidal Effects. The phorbol esters (9, 13, 19, 20, 25, 28, 55, 56), which were isolated from Croton tiglium, were screened for their growthinhibitory and insecticidal effects on newly hatched larvae of the North American cotton pest, Pectinophora gossypiella (pink bollworm). Only TPA (20) and phorbol 12-(2-methyl)butyrate-13-decanoate (25) were found to be active as both growth inhibitors and insecticides against P. gossypiella. TPA was found to cause 100% mortality on second-stadium larvae of Culex pipiens at 0.6 ppm, but exhibited less pronounced effects toward Oncopeltus fasciatus and Tribolium confusum when applied at higher doses.32 3.5.4. Analgesic and Sedative Activities. Ma et al.66 reported that prostratin (75), which was isolated for the first time from Euphorbia fischeriana, showed significant analgesic and sedative activities. Inhibition levels of 92% and 62% were observed in sedation experiments with 20 mg/kg (p.o.) and 1 mg/kg (s.c.) doses of this compound in mice, respectively, whereas inhibition levels of 96% and 48% were found in analgesic experiments with 20 mg/kg (p.o.) and 1 mg/kg (s.c.) doses in mice, respectively. 3.5.5. Antimycobacterial Activity. Nine 4-deoxy or 4,20dideoxyphorbol derivatives (137, 159, 174, 175, 178, 190, 193, 194, and 196), which were isolated from the fruits of Sapium indicum, were evaluated for their antimycobacterial activity against Mycobacterium tuberculosis H37Ra. Of the compounds tested, 4-deoxyphorbol ester (137) exhibited potent antimycobacterial activity with a minimum inhibitory concentration (MIC) of 3.12 μg/mL, whereas the 4-deoxy-4α-phorbol esters (159 and 194) were inactive (MIC > 200 μg/mL).97 It is

4. SYNTHESIS Tigliane derivatives exhibit a variety of interesting biological activities. The complex structure and striking biological properties of tigliane diterpenoids have prompted chemists to devise a series of synthetic strategies and methodologies for the constructing of their complexes structural frameworks. The most well-known member of the tigliane diterpene family is phorbol (1), which possesses a polyhydroxylated tigliane carbon skeleton that contains eight contiguous asymmetric centers, six of which are sited around the six-membered C ring. The efficient construction of the complex tetracyclic network of phorbol is one of the many problems associated with the synthesis of compounds belonging to this structural class, in addition to other structural and stereochemical features associated with their synthesis. The tigliane and daphnane skeletons share close structural similarities, and most of the approaches developed for the synthesis of daphnane diterpenoids can be readily applied to the syntheses of tigliane diterpenoids. This section makes no attempt to provide a detailed review of the literature with regards to the methods available for the construction of AB-, BC-, and ABC-ring systems of the tigliane skeleton, and readers of this section should consult the references cited for more detailed information. Yue et al.158 have reviewed the construction of the daphnane skeleton in detail, and reviewed the many P


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approaches available for the construction of the AB-, BC-, and ABC-ring systems in detail. Herein, we have focused predominantly on reviewing the development of various strategies toward the total synthesis of phorbol and its derivatives.

Scheme 2. Synthesis of Key Intermediate Polycycle (264)161a

4.1. Intramolecular Diels−Alder Approach

Wender et al.159 published the first total synthesis of the phorbol skeleton in 1987, using an intramolecular Diels−Alder cycloaddition and an intramolecular aldol condensation as key steps in their synthesis (Scheme 1). The resulting phorboid 256 Scheme 1. First Total Synthesis of a Compound Possessing the Complete Tigliane Skeleton and Stereochemistry159a

a

Reprinted with permission from ref 161. Copyright 1990 American Chemical Society.

Scheme 3. First Synthesis of Phorbol (1) Using the Key Intermediate Polycycle (264)160a

a


was the first compound to be prepared synthetically possessing the complete tigliane skeleton and stereochemistry. However, it was devoid of oxygenation at C-12 and C-13 and did not possess the A-ring functionalities required for conformational rigidity or the attachment of lipophilic groups. 4.2. Intramolecular Oxidopyrilium [5+2] Cycloaddition Approach

In 1990, Wender et al.160,161 reported the development of a more efficient second generation total synthesis involving an oxidopyrylium [5+2] cycloaddition and a zirconium-mediated enyne cyclization (Schemes 2 and 3). These studies resulted in the first synthesis of phorbol (1) with polycycle (264) being used as the key intermediate. In 1997, Wender’s group reported the first formal asymmetric synthesis of 284, which is a highly flexible synthetic precursor possessing the ABC-ring skeleton, and the subsequent conversion of this intermediate to racemic phorbol (Scheme 4).162 This approach to the phorbol BC-ring system proceeded via an intramolecular oxidopyrylium-alkene [5+2] cycloaddition starting from furan 273.

a


intramolecular [3+2] cycloadditions and an intramolecular aldol condensation as the key transformations (Scheme 5). Although the resulting phorbol skeleton (293) lacked the C-18 methyl group and C-13 hydroxy of the natural product, this work represented the first reported example of the stereospecific synthesis of an optically pure phorbol analogue.

4.3. Intramolecular [3+2] Cycloaddition Approach

In 1995, Shibasaki et al.163 reported the stereocontrolled synthesis of the optically active phorbol skeleton using two Q


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Scheme 4. Synthesis of Racemic Phorbol162a

Scheme 6. Formal Synthesis of (+)-Phorbol164a

a


5. THE 1H NMR DATA OF TIGLIANE DITERPENOIDS 1 H NMR spectroscopy is probably the most important technique for effectively identifying the different protons of the tigliane diterpene skeleton (Table 9). Proton signals

a


Scheme 5. Synthesis of the First Optically Pure Phorbol Analogue163a

Figure 3. Diagnostic chemical shifts δH in CDCl3 of phorbol derivatives.

a

between 6.99 and 7.80 ppm and 5.06 and 6.18 ppm, together with the corresponding carbon signals, typically indicate the presence of two trisubstituted olefin groups. The signal furthest downfield has been assigned to the proton on C-1, whereas the proton on C-7 appears as a doublet in the range of 5.06−6.18 ppm because of coupling with the adjacent β-orientated proton

Reprinted with permission from ref 163. Copyright 1995 Elsevier.

4.4. Oxyallyl [4+3] Cycloaddition Approach

In 2001, Cha et al.164 reported the formal synthesis of (+)-phorbol using Wender’s advanced intermediate 284. As shown in Scheme 6, their synthetic plan was built upon a [4+3] oxyallyl cycloaddition and subsequent intramolecular Heck reaction for the stereocontrolled construction of the BC-ring system of phorbol, followed by an adaptation of Wender’s efficient method for the construction of the A ring.161,162 This synthesis of the phorbol intermediate 284 required more steps and was less efficient than the method developed by Wender, although this work effectively demonstrated the applicability of this strategy to the construction of tiglianes and daphnanes.

Figure 4. Diagnostic chemical shifts δC in CDCl3 of the phorbol derivatives. R


S

7 8 10 11

1 5

position

7 8 10 11 12 14 16 17 18 19 20

1 5

position

1439

s d (J = 19.0) d (J = 19.0) d (J = 4.6) m m m

27

34

br s d (J = 19.0) d (J = 19.0) d (J = 5.2) dd (J = 5.2, 5.3) br s m d (J = 10.3) d (J = 5.3) s s d (J = 6.4) br s d (J = 13.2) d (J = 13.2)

7.60 2.49 2.57 5.69 3.26 3.26 2.17

7.57 2.46 2.51 5.65 3.21 3.21 2.11 5.40 1.06 1.21 1.19 0.87 1.76 3.97 4.02

5.60 3.20 3.10 1.90 4.10 0.72 1.20 1.20 1.10 1.75 3.90

7 8 10 11 12 14 16 17 18 19 20

m bm bm m d (J = 11.0) d (J = 5.0) s s d (J = 6.0) m s

7.60 br s 2.50 ABq

127,a

1 5

position

7.57 2.46 2.51 5.65 3.21 3.23 2.12 5.39 1.06 1.21 1.19 0.87 1.76 3.97 4.02 28

5.70 br d (J = 4.7) 3.27 m 3.27 m

32

br s d (J = 18.5) d (J = 18.5) d (J = 5.6) dd (J = 5.0, 5.6) br s dq (J = 7.0, 10.2) d (J = 10.2) d (J = 5.0) s s d (J = 7.0) dd (J = 1.3, 2.9) d (J = 12.7) d (J = 12.7)

1539

dd (J = 2.4, 1.3) d (J = 19.0) d (J = 19.0) d (J = 5.5) t (J = 5.5) t (J = 2.4) m d (J = 10.2) d (J = 5.5) s s d (J = 6.5) d (J = 1.3) d (J = 13.0) d (J = 13.0)

7.59 br s 2.54 br s

7.60 2.49 2.57 5.69 3.27 3.25 2.18 5.43 1.10 1.21 1.28 0.89 1.77 4.00 4.05

531

7.60 2.50 2.58 5.70 3.29 3.26 2.20

s ABq (J = 19.4) ABq (J = 19.4) br d (J = 4.5) m m

br d br t br t m

t (J = 2.2) d (J = 18.0)

30

1.10−1.60 1.10−1.60 0.88 m 1.73 br s 4.11 br s

1.1−1.4 1.1−1.4 0.98 d (J = 6.0) 1.81 br s 3.99 br s

7.61 2.49 2.55 5.70 3.27 3.26 2.15

s d (J = 18.3) d (J = 18.3) d (J = 3.8) m m m

3634

1037

3832

5.41 d (J = 10.4) 1.09 d (J = 5.2) 1.20−1.40 1.20−1.40 0.88 m 1.76 s 3.97 ABq (J = 11.0) 4.06 ABq (J = 11.0)

s ABq (J = 18.9) ABq (J = 18.9) d (J = 5.6) m m

2032

d (J = 10.3) m s s m m d (J = 4.7)

7.58 2.46 2.59 5.69 3.24 3.24

5.63 0.93 1.25 1.25 0.93 1.77 4.03

5.71 d (J = 4.8) 3.30 m 3.30 m

7.62 s 2.57 s

5.69 br d (J = 5.2) 3.25 m 3.25 m

7.78 br s 2.53 br s

compound/δH (in ppm), J (in Hz)

5.42 d (J = 9.9)

5.46 d (J = 10.0)

31

5.68 br d (J = 4.7) 3.66 m 3.66 m

7.57 br s 2.33 br s

1932

5.46 d (J = 10.3) 1.10 d (J = 5.2) 1.21 s 1.27 s 0.89 m 1.76 br s 3.96 ABq (J = 12.9) 4.07 ABq (J = 12.9) compound/δH (in ppm), J (in Hz)

7.59 2.45 2.61 5.69 3.25 3.25

932


5.61 m 3.23 m 3.23 m

7.56 br s 2.53 s

1842

5.34 d (J = 10.1) 1.06 d (J = 5.3) 1.20−1.50 1.20−1.50 0.88 m 1.75 br s 4.01 s

5.67 br d (J = 5.4) 3.25 m 3.25 m

7.58 br s 2.55 br s

632

Table 9. 1H NMR Data for Diterpenes from the Euphorbiaceae and Thymelaeaceae Families

d (J = 10.0) d (J = 5.0) br s br s m m s

4252

5.39 1.08 1.25 1.25 0.90 1.75 3.99

5.66 br d (J = 6.0) 3.25 m 3.25 m

7.58 br s 2.54 s

2346

br s d (J = 18.0) d (J = 18.0) d (J = 5.0) dd (J = 5.0, 5.3) br t (J = 2.8) m d (J = 10.0) d (J = 5.3) s s d (J = 7.1) dd (J = 1.1, 2.8) d (J = 12.6) d (J = 12.6)

5.65 3.38 3.20 2.37

d (J = 4.4) dd (J = 4.4, 5.6) dd (J = 2.4) m

7.57 br s 2.53 d (J = 9.6)

7.57 2.46 2.51 5.65 3.20 3.23 2.11 5.40 1.06 1.21 1.19 0.85 1.76 3.94 4.02

1139

4353

br s br s m m s

5.72 3.33 3.29 2.36

d (J = 5.0) m m m

7.61 m 2.54 AB (J = 18.3)

1.25 1.25 0.90 1.78 4.03

5.42 d (J = 10.0)

5.68 br d (J = 6.0) 3.25 m 3.25 m

2446

d (J = 5.0) dd (J = 5.0, 5.3) br t (J = 2.8) m d (J = 10.0) d (J = 5.3) s s d (J = 7.1) dd (J = 1.1, 2.8) d (J = 12.6) d (J = 12.6)

7.60 m 2.53 s

5.65 3.20 3.23 2.11 5.40 1.06 1.21 1.19 0.85 1.76 3.94 4.02

7.57 br s 2.46 d (J = 18.0)

1332,39

Chemical Reviews Review


T

7 8 10 11 12 14 16 17 18 19 20

1 5

position

7 8 10 11 12 14 16 17 18 19 20

1 5

position

12 14 16 17 18 19 20

position

7.60 2.50 2.60 5.72 3.34 3.29 3.32 5.67 1.14 1.21 1.38 0.95 1.77 4.01 4.07

d d s s d s d d

4451

(J = 12.8) (J = 12.8)

(J = 6.4)

(J = 10.3) (J = 5.1)

2734

7.61 2.37 2.54 5.67 3.12 3.18 2.16 4.87 0.91 1.19 1.25 1.02 1.81 4.49

dd (J = 2.5, 1.0) d (J = 18.0) d (J = 18.0) br d br t t (J = 2.5) m d (J = 9.9) m s s d (J = 6.8) d (J = 1.0) d (J = 12.4)

5331

dq (J = 1.5, 2.5) d (J = 19.5) d (J = 19.5) d (J = 5.0) dd (J = 5.0, 5.0) dd (J = 2.5, 2.5) dq (J = 6.5, 10.0) d (J = 10.0) d (J = 5.0) s s d (J = 6.5) dd (J = 1.5, 2.5) d (J = 13.0) d (J = 13.0)

5.46 1.08 1.21 1.28 0.89 1.76 4.04 3.99

Table 9. continued

4553

5.71 3.32 3.28 2.32 5.67 1.14 1.20 1.37 0.95 1.77 4.02

7.59 2.42 2.60 5.72 3.27 5.23 2.21 5.36 1.09 1.23 1.25 0.90 1.75 4.45

br s (AB, J (AB, J m m m m d (J = d (J = s s m m (AB, J

5454

d (J = 5.0) m m m d (J = 9.8) d (J = 5.0) s s d (J = 6.7) dd (J = 1.5, 3.0) AB (J = 13.2)

7.62 m 2.54 AB (J = 19.7)

1.10−1.40 1.10−1.40 0.89 m 1.74 br s 4.02 br s

5.55 d (J = 10.3)

2832

= 12.8)

10.3) 5.1)

= 19.0) = 19.0)

7.61 2.50 2.60 5.72 3.32 3.29 2.32 5.66 1.14 1.21 1.38 0.95 1.77 4.01 4.07

5.42 1.03 1.17 1.21 0.86 1.71 4.42

7.57 2.55 2.37 5.68 3.20 3.11

4731

d (J = 10.2) d (J = 4.8) s s d (J = 6.1) dd (J = 2.9, 1.4) s

br s m m dd (J = 5.3, 1.4) m m

7.57 2.52 2.57 5.68 3.27 3.16 2.01 3.91 1.07 1.21 1.22 1.05 1.74 4.07 4.22

5.42 1.07 1.26 1.26 0.91 1.79 4.46

m br s m

d (J = 10.2) d (J = 5.0)

5.71 br d (J = 5.6) 3.26 m 3.26 m

7.60 br s 2.48 m

5632

compound/δH (in ppm), J (in Hz) 5556

3832

br s d (J d (J d (J m m m d (J m s s d (J d (J d (J d (J = = = =

5721

5.69 1.18 1.21 1.39 0.94 1.73 3.97 3.93

1.23 1.23 0.97 1.80 4.47

s s d m

5.71 d 3.10 3.30

7.61 m 2.57

6.6) 1.5) 11.7) 11.7)

= 9.9)

= 18.1) = 18.1) = 4.8)

5026,a

5.45 d (J = 10.4) 1.06 d (J = 5.1) 1.20−1.60 1.20−1.60 0.93 m 1.77 br s 4.01 br s

= 12.7) = 12.7) (in ppm), J (in Hz)

= 7.0)

= 10.4) = 5.0)

7.60 dd (J = 2.3, 1.3) 2.48 d (J = 19.0) 2.54 d (J = 19.0) 6.00 br d 3.25 m 3.25 m 2.14 dd (J = 10.5, 6.5) 5.42 d (J = 10.5) 1.07 d (J = 5.1) 1.20 s 1.25 s 0.86−0.94 m 1.70 m 4.02 ABq (J = 13.0)

5.47 d (J 1.11 d (J 1.23 s 1.28 s 0.91 d (J 1.79 s 4.04 d (J 4.00 d (J compound/δH

3634


dq (J = 1.5, 2.5) d (J = 19.0) d (J = 19.0) br d (J = 5.5) dd (J = 5.5, 5.5) dd (J = 2.5, 2.5) m d (J = 10.0) d (J = 5.5) s s d (J = 7.5) dd (J = 1.5, 2.5) d (J = 13.0) d (J = 13.0)

4651

5.45 d (J = 10.2) 1.05 d (J = 5.4) 1.10−1.20 m 1.10−1.20 m 0.89 d (J = 6.5) 1.77 m 4.00 d (J = 12.9) 4.05 d (J = 12.9)

3031 d d s s d d d d = = = = 5134

6.4) 1.6) 12.8) 12.8)

12.4) 12.4)

9.8)

19.0) 19.0) 4.5)

1.78 4.43

1.28 1.28

5.70 3.23 3.23

7.60

5821

7.57 s 2.37 d (J = 2.52 d (J = 5.66 d (J = 3.19 br m 3.12 br m 2.01 m 3.98 d (J = 1.01B 1.22 s 1.24 s 1.01B 1.77 s 4.48 d (J = 4.43 d (J =

(J (J (J (J

(J = 10.4) (J = 5.6)

4252

3.74 3.30 2.22 5.44 1.85 1.21 1.19 0.94 1.83 4.29

d (J = 5.6) t (J = 2.4) m d (J = 10.4) d (J = 5.6) s s d (J = 6.4) d (J = 1.6) d (J = 14.0)

6040

br s d (J = 19.0) d (J = 19.0) br d (J = 4.0) t (J = 5.3) br s m dd (J = 7.7, 2.2) d (J = 2.8) s s d (J = 6.8) s ABq (J = 12.4)

5231

d (J = 10.0) d (J = 5.0) s s d (J = 6.5) dd (J = 1.5, 3.0) AB (J = 18.3)

7.66 s 6.90 s

7.58 2.38 2.52 5.67 3.20 3.14 1.99 3.98 1.02 1.23 1.25 1.04 1.78 4.46

5.65 1.12 1.21 1.37 0.95 1.77 4.04

4353



U

1 5

position

1.07 1.87 1.20 0.89 1.82 4.15

14 16 17 18 19 20

7.62 br s 2.52 br s

7916,74

d (J = 5.3) s s d (J = 6.4) s ABq (J = 12.9)

2.14 m 4.65 br s

7 8 10 11 12

s s d (J = 19.0) d (J = 19.0) br s t (J = 5.3)

1 3 5

6.19 4.50 2.28 2.38 5.51 2.63

6960,a

= 14.2) = 14.2)

= 6.4)

= 10.4)

= 5.3)

m br s br s m m br s

7.37 br s

8079

0.90 1.30 1.30 0.90 1.79 3.55

br s d (J = 6.5) br s m d (J = 10.1)

7.57 br s 2.48 br s

8180

3.60 d (J = 12.4) 3.98 d (J = 12.4)

1.37 d (J = 6.5) 1.23 s 1.28 s

3.24 3.22 4.13 2.03 5.46

4.10 br s

2.15 d (J = 17.0) 2.49 d (J = 17.0) 3.32 d (J = 8.0) 2.20−2.10 m 3.45 m 2.20−2.10 m 5.40 d (J = 10.0)

7261,a

d (J m m d (J m s s d (J br s d (J d (J

7.63 br s

3.73 3.31 2.20 5.45 1.85 1.20 1.19 0.94 1.84 4.39 4.29

7.66 br s 6.90 br s

6348

7.60 m

7146

d (J = 5.5) q (J = 2.7) m d (J = 10.5) d (J = 5.5) s s d (J = 6.5) dd (J = 1.3, 2.7) dd (J = 1.5, 14.5) dd (J = 1.5, 14.5)

3.76 3.05 2.23 5.37 1.72 1.16 1.13 0.89 1.75 4.18 4.21

3.76 3.31 2.26 5.49 1.84 1.21 1.18 0.95 1.83 4.29 4.39

d (J = 5.6) t (J = 2.4) m d (J = 10.4) d (J = 5.6) s s d (J = 6.4) d (J = 1.6) d (J = 14.0) d (J = 14.0)

7.56 d (J = 1.3) 6.90 t (J = 1.5)

6258

5454 4.47 (AB, J = 12.8)

7.67 s 6.91 s

6140

4.45 d (J = 12.4)

5331

position

1 5 7 8 10 11 12 14 16 17 18 19 20

position

position

Table 9. continued

s m d (J = 4.5) m

7.56 s 2.45 d (J = 19.0)

8483

6551

7.56 dd (J = 2.4, 1.4) 2.43 d (J = 19.1)

8584

br s s d (J = 5.0) d (J = 5.0) m

8616

0.80 d (J = 5.0) 1.15C 1.15C 0.80 d (J = 5.0) 1.78 d (J = 2.5) 4.00 s

5.64 d (J = 4.0) 3.00 m 3.30 m

2.45 s

7.57 br s

7674

1.1−1.4 1.1−1.4 0.93 d (J = 6.0) 1.80 br s 4.33 s

5.43 d (J = 10.0)

7.64 6.93 4.21 3.79 3.26

6642

5821

7.59 br s 2.46 ABq (J = 19.0)

5721

d (J = 5.4) dd (J = 5.4, 5.3) dd (J = 2.5, 2.4) ddq (J = 11.5, 7.1, 6.6) dd (J = 14.7, 11.5) dd (J = 14.7, 7.1) d (J = 5.3) s s d (J = 6.6) dd (J = 2.9, 1.5) d (J = 12.7) d (J = 12.7)

2.53 br s

7566

dq (J = 1.5, 2.5) d (J = 2.0) dd (J = 2.0, 9.0) dd (J = 5.5, 9.0) dd (J = 2.5, 2.5) dq (J = 6.5, 10.0) d (J = 10.0) d (J = 5.5) s s d (J = 6.5) dd (J = 1.5, 2.5) d (J = 11.0) d (J = 11.0)

7.50 br s

5.73 3.18 3.48 2.13 1.70 2.01 0.88 1.09 1.02 0.98 1.70 m 1.58 4.30 s 3.79 3.86 compound/δH (in ppm), J (in Hz)

3.10 3.70 6.18 3.70

7.80 s

7463,b

7.66 dq (J = 1.5, 3.0) 7.66 6.42 d (J = 2.0) 6.42 4.80 dd (J = 2.0, 9.0) 4.81 2.93 dd (J = 5.5, 9.0) 2.94 3.02 dd (J = 3.0, 3.0) 3.02 2.36 dq (J = 6.5, 10.0) 2.35 5.72 d (J = 10.0) 5.71 1.70 d (J = 5.5) 1.70 1.28 s 1.28 1.36 s 1.36 0.98 d (J = 6.5) 0.97 1.80 dd (J = 1.5, 3.0) 1.80 4.25 d (J = 11.0) 4.25 4.49 d (J = 11.0) 4.48 compound/δH (in ppm), J (in Hz)

6451


5632


0.90 1.12 1.12 0.90 1.75 4.01

8946

t d d t d (J = 2.0) s

5.70 d (J = 4.2) 3.05 m 3.26 m

2.50 br s

7.57 br s

7774

dq (J = 1.5, 2.5) s d (J = 5.5) dd (J = 5.5,5.5) dd (J = 2.5, 2.5) dq (J = 6.5, 10.0) d (J = 10.0) d (J = 5.5) s s d (J = 6.5) dd (J = 1.5, 2.5) s

7.59 br s 2.52 s

7.68 4.38 5.73 3.54 3.06 2.24 5.64 1.12 1.20 1.35 0.98 1.78 4.23

6851

4.39 d (J = 14.0)

6040



V

7.58 br s 2.43 s

5.70 d (J = 4.8) 2.99 m 3.20 m

7 8 10 11

9163

5.66 3.00 3.27 1.96 1.57 2.07 0.84 1.18 1.06 0.90 1.78 4.00

5.72 d (J = 6.3) 3.02 m 3.26 br s

0.86 1.04 1.04 0.86 1.78 4.00

7.59 2.29 2.49 5.68 3.00 3.28 1.97 1.55 2.06 0.83 1.19 1.06 0.93 1.78 4.39 4.27

9386

5.70 d (J = 10.0) 3.00 d (J = 10.0) 3.30 s

7.60 s 2.45 s

11092

8584

5.67 2.97 3.24 1.96

d (J = 4.1) t (J = 5.1) br d (J = 2.2) m

7.56 s 2.41 ABq (J = 19.0)

11159

7.55 br s 2.43 d (J = 19.0) 2.53 d (J = 19.0) 5.65 d (J = 4.1) 2.99 m 3.23 br s 1.96 m 1.51 dd (J = 11.0, 14.2) 2.03 dd (J = 6.9, 14.2) 0.80 d (J = 5.2) 1.16 s 1.04 s 0.86 d (J = 6.2) 1.65 d (J = 1.7) 3.94 d (J = 12.6) 4.01 d (J = 12.6) (in ppm), J (in Hz) 7.56 2.01 2.80 5.23 2.37 3.27 1.58

11271

2.53 5.68 2.99 3.26 1.96 1.49 2.06 0.85 1.23 1.07 0.86 1.76 3.97 4.04

0.80 1.15 1.15 0.80 1.78 4.47

7.53 1.98 2.80 5.17 2.34 3.28 1.56

d d d d d (J = 2.6) s

5.65 d (J = 4.0) 3.00 m 3.30 m

7.58 br s 2.44 s

9774

ABq (J = 19.0) m m m m m m d (J = 3.5)B s s d (J = 6.5) m dq (J = 12.5, 5.0) dq (J = 12.5, 5.0)

8616

br s dd (J = 18.2, 10.5) br dd (J = 18.1, 9.0) br d (J = 5.5, 2.2) br t (J = 5.5) dddq (J = 4.5, 2.5, 2.5, 1.5) dq (J = 9.5, 6.5)

1.16 1.16 0.89 1.80 4.47

1.50−2.20

5.75 3.02 3.29

7.55 2.44

9621

2.49 d (J = 19.1) 5.65 m 2.96 dd (J = 5.4, 5.3) 3.25 dd (J = 2.9, 2.4) 1.94 ddq (J = 11.3, 6.9, 6.8) 1.54 dd (J = 15.1, 11.7) 2.03 m 0.82 d (J = 5.4) 1.16 s 1.04 s 0.86 d (J = 6.8) 1.76 dd (J = 2.9, 1.4) 3.97 d (J = 12.7) 4.02 d (J = 12.7) J (in Hz)

9466

2.55 d (J = 19.0) 5.65 d (J = 5.0) 3.00 s 3.20 s 1.96 m 1.53 m 2.05 m 0.80 d (J = 6.0) 1.18 s 1.07s 0.85 m 1.70 br s 3.92 d (J = 13.0) 4.00 d (J = 13.0) compound/δH (in ppm),

8483


s d (J = 12.3) d (J = 12.3) d (J = 4.0) dd (J = 4.0, 6.6) s m dd (J = 11.4, 14.7) dd (J = 7.1, 14.7) d (J = 6.6) s s d (J = 6.5) s d (J = 13.8) d (J = 13.8) compound/δH

d (J = 5.7) s s d (J = 5.7) m s

5.69 d (J = 4.0) 3.28 m 3.02 m

7.59 br s 2.44 s

10289

m m m m m m d s s m m ± 0.04 (AB)

7.59 m 2.49 (AB)

10116,80

7.63 br s 2.48 br s

br d (J = 6.0) m m m m m m s s m m s

9916,74,c

5.70 3.02 3.28 1.98 1.56 2.08 0.90 1.21 1.10 0.90 1.80 4.04

7.60 m 2.52 s

9046

1 5

position

14 16 17 18 19 20

7 8 10 11 12

1 5

position

s s s d (J = 6.0) m m

0.95 1.32 1.25 0.90 1.71 4.22

14 16 17 18 19 20

d (J = 5.0) d (J = 7.2) d (J = 7.2) d (3 J = 5.0) m s

1.90−2.18 m

2.20 m

0.90 1.16 1.16 0.90 1.78 4.05

5.64 d (J = 6.0) 3.00 m 3.28 m

8180

5.30 s 3.00 br s 3.29 br s

5.70 d (J = 4.8) 3.05 m 3.30 m

8079

7 8 10 11 12

7916,74

position

Table 9. continued

m s s m m s

9874,c

t d d t d (J = 2.5) s

br s dd (J = 18.2, 10.5) br dd (J = 18.2, 9.0) br dq (J = 5.5, 2.1) br t (J = 5.6) dddq (J = 4.5, 2.5, 2.5, 1.5) dq (J = 9.5, 6.5)

11371

0.88 1.12 1.12 0.88 1.77 4.41

5.62 d (J = 4.0) 2.97 m 3.20 m

7.48 br s 2.46 s

0.90 1.20 1.09 0.90 1.78 4.02

5.67 br d (J = 6.0) 3.02 m 3.26 m

8946



W

5.4) 7.2) 7.2) 5.4)

6.06 3.64 3.65 2.45 1.91 2.32 1.06 1.17 1.19 1.12 1.64 4.22 4.59

7 8 10 11 12

0.96 d (J = 5.5) 1.20 s 1.22 s

7 8 10 11 12

14 16 17

7.47 2.50 2.53 5.63 3.07 3.19 1.96 1.52 2.07 0.80 1.11 1.02 0.86 1.60 4.12 4.16

0.77 1.08 1.08 0.89 1.82 4.46

0.97 1.22 1.23 0.91 1.72 4.42 4.73

11671

0.90 1.20 1.10 0.90 1.80 4.45

d (J s s d (J br s d (J d (J

7.56 2.05 2.83 5.19 2.37 3.26 1.56 1.94

br s dd (J = 18.2, 10.5) br dd (J = 18.2, 9.2) br d (J = 5.5, 2.3) br t (J = 5.4) dddq (J = 4.5, 2.5, 2.5, 1.5) dq (J = 9.5, 6.5) br d (J = 9.2)

12271

0.95 1.21 1.21 0.89 1.72 4.41 4.74

11871

= 12.8) = 12.8)

= 6.5)

= 5.5)


7.61 2.38 2.51 5.72 3.00 3.29 1.96 1.56 2.06 0.81 1.19 1.07

= 12.8, H-α) = 12.8, H-β)

= 6.5)

= 5.5)

11371

0.97 1.23 1.24 0.88 1.71 4.42 4.73

11971

= 12.8) = 12.8)

= 6.5)

= 5.5)


3.25 2.82 3.93 1.80 1.54 2.02 1.11 1.17 1.05

br s d (J = 7.5) br s m m dd (J = 7.3, 15.0) d (J = 7.4) s s

7.69 br q (J = 1.4) 4.23 s

12539

= 12.8, H-α) = 12.8, H-β)

= 6.5)

= 5.5)

br s dd (J = 18.2, 10.5) br dd (J = 18.2, 9.0) br dq (J = 5.5, 2.1) br t (J = 5.6) dddq (J = 4.5, 2.5, 2.5, 1.5) dq (J = 9.5, 6.5) br d (J = 9.3)


7.53 1.98 2.80 5.17 2.34 3.28 1.56 1.94

0.97 1.23 1.24 0.88 1.71 4.42 4.72

1.94 br d (J = 9.3)

s d (J = 12.0) d (J = 12.0) d (J = 4.4) d (J = 4.4, 6.6) s m dd (J = 11.3, 14.8) dd (J = 7.1, 14.8) d (J = 6.6) s s

12486



7.56 2.01 2.80 5.23 2.37 3.27 1.58 1.94

0.95 1.21 1.21 0.89 1.72 4.41 4.73

br s dd (J = 18.2, 10.5) br dd (J = 18.1, 9.1) br dq (J = 5.5, 2.2) br t (J = 5.3) dddq (J = 4.5, 2.5, 2.5, 1.5) dq (J = 9.5, 6.5) br d (J = 9.1) 0.98 d (J = 5.5) 1.22 s 1.24 s

7.53 2.02 2.86 5.20 2.34 3.29 1.52 1.94

11271 1.94 br d (J = 9.2)

12371


11771

0.96 d (J = 5.5) 1.20 s 1.21 s 0.88 d (J = 6.5) 1.71 br s 4.43 d (J = 12.8, H-α) 4.72 d (J = 12.8, H-β) compound/δH (in ppm), J (in Hz)

0.96 d (J = 5.5) 1.20 s 1.22 s

7.54 2.10 2.82 5.18 2.33 3.28 1.53 1.94

= 12.8, H-α) = 12.8, H-β)

= 6.5)

= 5.5)

m m d (J = 5.3) s s d (J = 6.6) dd (J = 1.2, 2.8) ABq (J = 12.3, 7.3)


1.55 1.91 0.80 1.16 1.03 0.85 1.73 4.43

11159


d s s d d (J = 2−3) s

2.10 m

11092


6.0) 3.0) 3.0) 6.0)


0.98 d (J = 5.5) 1.22 s 1.24 s

7.53 2.02 2.86 5.20 2.34 3.28 1.52 1.94

= = = =

7.55 2.03 2.81 5.21 2.35 3.27 1.55 1.94

d (J d (J d (J d (J m s

10289

12171

br s m m d (J = 5.1) t (J = 4.9) m m dd (J = 10.9, 14.7) dd (J = 7.0, 14.7) d (J = 5.8) s s d (J = 6.5) d (J = 1.5) d (J = 11.8) d (J = 11.8)

11526,a

d (J = 6.0) s s d (J = 6.0) m s


12071

7.54 2.10 2.82 5.18 2.33 3.28 1.53 1.94

1 5

position

d (J = 5.2) m m m dd (J = 11.0, 14.5) dd (J = 6.6, 14.4) d (J = 5.7) s s d (J = 6.0) s m d (J = 11.5)

7.67 br s 3.01 br s

14 16 17 18 19 20

= = = =

11426,b

1 5

position

d (J d (J d (J d (J m s

0.87 1.04 1.04 0.87 1.79 4.49

0.90 1.18 1.18 0.90 1.79 4.44

14 16 17 18 19 20

10116,80

1.90−2.18 m

9916,74,c

12

position

Table 9. continued



X

7 8 10 11 12 14 16 17 18 19 20

1 4 5

position

14 16 17 18 19 20

1 5 7 8 10 11 12

position

18 19 20

position

12071

s s d (J = 4.4) dd (J = 4.4, 7.5) s m dd (J = 7.3, 15.3) dd (J = 9.3, 15.3) d (J = 7.5) s s d (J = 6.6) s s

br s m dd (J = 17.1, 9.3) dd (J = 17.1, 8.5) br s m br s m d (J = 10.5) d (J = 5.0) s s d (J = 6.6) br s br d (J = 15.5) br d (J = 15.5)

13696

7.71 4.26 3.26 2.82 3.91 1.84 2.06 1.56 1.13 1.19 1.07 0.92 1.77 3.83

12786

d (J = 6.5) br s d (J = 12.8, H-α) d (J = 12.8, H-β)

7.63 2.54 2.12 2.78 5.45 2.30 3.15 1.36 4.04 0.74 1.26 1.12 1.08 1.75 3.93 3.98

0.87 1.72 4.42 4.73

Table 9. continued

7.56 2.52 2.17 2.86 5.55 2.44 3.27 1.73 5.65 1.12 1.19 1.32 0.96 1.73 4.02

13797

7.69 4.24 3.25 2.82 3.93 1.83 1.59 2.05 1.15 1.19 1.06 0.89 1.75 3.80

5.55 2.38 3.26 1.62 5.47 1.11 1.26 1.20 0.94 1.73 4.02

12271

13841

1.21 1.09 1.21 0.92 1.78 3.76 3.85

7.68 4.26 3.25 2.83 3.95

d (J = 1.3) m m m d (J = 9.7) d (J = 7.2) s s m s s

13086

7.60 2.33 2.20 2.45 5.52 2.34 3.25 1.57 5.54 1.05 1.20 1.20 0.92 1.72 4.00

br s m m d (J m m m m d (J d (J s s d (J m s = 6.0)

= 10.0) = 5.0)

= 15.0)

142103,d

br s m m d (J = 15.0) m m m d (J = 10.0) d (J = 5.0) s s d (J = 6.0) m s

7.60 2.27 2.20 2.45 5.52 3.28 1.57 5.48 1.05 1.20 1.20 0.92 1.72 4.02

145103,d

7.69 s 4.28 s 3.14 d (J = 4.6) 2.82 dd (J = 4.6, 7.6) 3.90 s 1.84 m 1.57 dd (J = 9.0, 15.5) 2.03 dd (J = 7.3, 15.5) (obscured) 1.12 d (J = 7.6) s 1.19 s s 1.09 s d (J = 5.0) 0.93 d (J = 6.7) br s 1.78 s 4.80 d (J = 12.0) ABq (J = 12.0) 3.82 d (J = 12.0) compound/δH (in ppm), J (in Hz)

br s s s d (J = 7.0) br s

12994

12371 0.90 d (J = 6.5) 1.74 br s 4.43 d (J = 12.8, H-α) 4.73 d (J = 12.8, H-β) J (in Hz)

compound/δH (in ppm), J (in Hz) 0.87d (J = 6.5) 1.72 br s 4.43 d (J = 12.8, H-α) 4.73 d (J = 12.8, H-β) compound/δH (in ppm),

7.56 s 2.59 m 2.83 dd (J = 9.0)

br q (J = 1.7) br s br s d (J = 7.5) br s m dd (J = 9.4, 15.3) dd (J = 7.4, 15.3) d (J = 7.5) s s d (J = 6.7) dd (J = 1.4, 2.7) br s

12839,94

d (J = 6.5) br s d (J = 12.8, H-α) d (J = 12.8, H-β)

br s dt (J = 5.0, 9.5) dd (J = 10.0, 18.0) dd (J = 9.5, 18.0) m br t (J = 5.0) m m d (J = 10.0) d (J = 5.0) s s d (J = 6.5) s AB (J = 13.5)

0.90 1.74 4.43 4.74

12171

7.60 2.27 2.20 2.45 5.53 2.34 3.26 1.62 5.47 0.95 1.21 1.21 0.95 1.72 4.02

s ABq (J = 19.5) q (J = 2.1) t (J = 5.5) s m m m d (J = 5.4) s s d (J = 6.4) s s

br s m m d (J m m m m d (J d (J s s d (J m s

= 6.0)

= 10.0) = 5.0−6.0)

= 15.0)

146103,d

7.54 2.60 6.71 3.38 3.06 2.05 1.61 2.17 1.01 1.08 1.25 0.89 1.76 9.41

d (J = 6.0) s d (J = 12.4) d (J = 12.4)

13459

0.91 1.78 4.48 4.45

12486

7.55 2.46 2.14 2.82 5.54 2.36 3.24 1.56 5.38 1.03 1.20 1.20 0.90 1.72 3.99 4.01

s ABq (J = 19.6) q (J = 2.1) t (J = 5.4) s m m (H-α) m (H-β) d (J = 5.3) s s d (J = 6.8) t (J = 1.1) s

br s ddd (J = 10, 9.5, 4.5) dd (J = 18.0, 10.0) br dd (J = 18.0, 9.5) br dq (J = 5.5, 2.0) br t (J = 5.5) dddq (J = 4.5, 2.5, 2.5, 1.5) dq (J = 10.0, 6.5) d (J = 10.0) d (J = 5.5) s s d (J = 6.5) dd (J = 2.5, 1.5) br d (J = 15.0) br d (J = 15.0)

147104

7.54 2.66 6.71 3.38 3.06 2.04 1.62 2.14 0.98 1.07 1.23 0.89 1.76 9.41

13559

0.90 d (J = 6.6) 1.75 dd (J = 1.4, 2.9) 3.88 br s

12539



Y

7

1 4 5

position

7 8 10 11 12 14 16 17 18 19 20

1 4 5

position

5.31 m

7 8 10 11 12 14 16 17 18 19 20

156104

br s br s d (J = 6.0) m br s

7.56 2.49 2.16 2.84 5.55 2.40 3.26 1.61 5.47 1.03 1.24 1.21 0.91 1.73 3.99 4.04

br s m dd (J = 15.3, 5.1) br d (J = 15.3) br s

165113

15096

7.05 2.79 2.48 3.57 5.12

m m m m m

d (J = 10.0) d (J = 5.5) s s d (J = 6.5) dd (J = 2.5, 1.5) br d (J = 15.0) br d (J = 15.0)

s m dd (J = 15.6, 5.0) dd (J = 15.6, 4.9) s

16634

5.66 1.03 1.20 1.20 0.90 1.72 4.01 3.99

3.30 m

7.50 2.62 2.51 2.80 5.52

157109

br s ddd (J = 10.3, 9.4, 4.6) dd (J = 18.3, 10.3) dd (J = 18.3, 9.4) br d (J = 4.4) t (J = 6.0) m m d (J = 9.6) d (J = 6.0) s s d (J = 6.0) d (J = 1.2) bd (J = 13.5) bd (J = 13.5)

br s m dd (J = 18.0, 10.0) br dd (J = 180, 9.0) mC br t (J = 6.0) dddq (J = 4.5, 2.5, 2.5, 1.5) dq (J = 9.5, 6.5) d (J = 9.5) d (J = 6) s s d (J = 6.5) t (J = 1.5) br d (J = 12.5) br d (J = 12.5)

7.03 2.75 2.43 3.42 5.09

7.55 2.44 2.13 2.84 5.55 2.37 3.24 1.60 5.38 1.00 1.20 1.20 0.90 1.72 4.46 4.42

1.22 1.22 0.95 1.78 5.04

5.48 d (J = 9.0)

3.30 m

7.58 br s

148/149106

1 4 5

position

Table 9. continued

7.04 2.77 2.45 3.39 5.07

s m dd (J = 15.6, 5.1) dd (J = 15.6, 4.9) s

16734

7.54 2.46 2.13 2.82 5.49 2.36 3.23 1.61 5.52 0.97 1.20 1.03 0.92 1.72 3.99

7.06 2.79 2.49 3.46 5.12

s m dd (J = 15.6, 5.2) dd (J = 15.6, 5.1) s

16834 7.05 2.70 2.30 2.45 5.15

15396

169103,d

br s m dd (J = 15.0, 5.0) dd (J = 15.0, 5.0) br s br s m dq (J = 10.0, 6.0) d (J = 10.0) d (J = 5.0) s s d (J = 6.0) s d (J = 12.0) d (J = 12.0)

161112

br s m m dd (J = 5.0, 15.0) m

6.97 2.72 2.42 3.37 5.05 1.89 3.44 1.64 5.46 0.73 1.11 1.14 1.03 1.71 3.82 3.94 compound/δH (in ppm), J (in Hz)

7.04 s 2.80 m 2.49 dd (J = 4.4, 15.4) 3.40 m 5.12 d (J = 6.0) 2.43−2.31 m 3.49 m 1.68 m 5.47 d (J = 10.3) 0.79 d (J = 5.2) 1.25 s 1.17 s 1.09 d (J = 6.3) 1.79 m 3.95 ABq (JAB = 28.0)

160111

m m m m m m m m d (J = 9.7) d (J = 8.0) s s d (J = 8.0) m s

152107

compound/δH (in ppm), J (in Hz) 7.56 br s 2.46 ddd (J = 10.0, 8.7, 4.8) 4.9) 2.14 dd (J = 18.0, 10.0) 2.8) 2.85 dd (J = 18.0, 8.7) 5.55 d (J = 5.9) 2.36 t (J = 5.2) 4.3, 2.2) 3.25 m 6.6) 1.56 dq (J = 9.8, 6.6) 5.40 d (J = 9.8) 1.05 (J = 5.2) 1.19 s 1.23 s 0.93 d (J = 6.6) 1.75 s 4.42 d (J = 12.6) 4.48 d (J = 12.6) compound/δH (in ppm), J (in Hz)

s m dd (J = 5.0, 16.0) dd (J = 3.5, 16.0) br s m m m d (J = 10.5) d (J = 5.0) s s d (J = 6.5) s AB (J = 12.5)

15997

br s m dd (J = 15.8, dd (J = 15.8, br s br s ddd (J = 6.6, dq (J = 10.3, d (J = 10.3) d (J = 5.1) s s d (J = 6.4) d (J = 1.4) d (J = 12.1) d (J = 12.1)

7.08 2.80 2.51 3.45 5.14 2.03 3.54 1.87 5.72 0.84 1.17 1.33 1.12 1.80 4.01

7.06 2.79 2.49 3.47 5.13 1.98 3.51 1.75 5.53 0.75 1.25 1.18 1.08 1.79 3.90 4.03

15196

6.99 2.73 2.47 3.40 5.18

3.51 1.62 5.54 0.95 1.21 1.21 0.95 1.62 3.95

7.05 2.70 2.20 2.45 5.13

d (J = 9.7) d (J = 5.3) s s d (J = 6.6) dd (J = 2.4, 1.2) s

m m m m m

170109

m m d (J = 10.0) d (J = 5.0) s s d (J = 6.0) m s

br s m m dd (J = 5.0, 15.0) m

162103,d

5.44 1.03 1.19 1.20 0.92 1.72 4.44

5.60 d (J = 7.0) 2.45 m 3.24 br s

7.55 br s 2.60 m 2.84 m

15456

7.05 2.78 2.47 3.45 5.10 1.95 3.50 1.68 5.41 0.75 1.16 1.20 1.06 1.78 4.00 3.88

m m m dd (J = 16.0, 7.0) m

164104

d (J = 10.0) d (J = 5.0) s s d (J = 6.5) m ± 0.08 (AB, J = 12.0)

7.03 2.75 2.48 3.42 5.21

m m m m m

171109

br s ddd (J = 5.2, 2.5, 2.5) dd (J = 15.5, 5.2) dddd (J = 15.5, 2.5, 2.5, 2.5) br s m dddq (J = 2.5, 2.5, 2.5, 1.5) dq (J = 10.5, 6.5) d (J = 10.5) d (J = 5.0) s s d (J = 6.5) t (J = 1.5) br d(J = 12.0) br d (J = 12.0)

5.45 0.80 1.20 1.38 1.10 1.60 4.43

3.31 m

7.59 2.65 2.50 2.80 5.21

155109



Z

3.24 m 1.54 m 1.28 m

3.28 br s

1.61 dd (J = 15.0, 4.0)

5.52 m

5.24 br s

7 8 10 11 12

7.54 m 2.42 m 2.82 dd

18163

s m dd (J = 15.5, 3.2) dd (J = 15.5, 3.2) s br s m m d (J = 9.7) d (J = 5.2) s s d (J = 6.2) s d (J = 12.4) d (J = 12.4)

17334

= 12.9) = 12.9)

= 6.4)

= 10.4) = 5.1)

7.02 2.71 2.46 3.27 5.17 1.96 3.46 1.60 4.04 0.78 1.20 1.24 1.24 1.76 4.47 4.34

br s m m d (J d (J s s d (J s d (J d (J

7.56 br s 2.42 ddd (J = 10.0, 9.0, 4.0) 3.16 dd (J = 18.0, 9.0)

s m dd (J = 9.3, 2.1) dd (J = 9.3, 2.1) s br s m m d (J = 9.6) d (J = 5.0) s s d (J = 6.2) s d (J = 12.4) d (J = 12.4)

1.98 3.51 1.72 5.53 0.75 1.18 1.25 1.08 1.78 4.02 3.90

1 4 5

7.02 2.71 2.46 3.27 5.17 1.96 3.47 1.59 4.04 0.78 1.20 1.24 1.26 1.76 4.47 4.34

17234

br d dq (J = 10.8, 6.3) d (J = 10.0) d (J = 5.1) s s d (J = 6.3) s d (J = 12.3) d (J = 12.3)

16634

180114

1.94 3.46 1.67 5.45 0.75 1.14 1.18 1.07 1.76 4.00 3.89

e

165113

position

7 8 10 11 12 14 16 17 18 19 20

1 4 5

position

8 10 11 12 14 16 17 18 19 20

position

Table 9. continued

1.95 3.50 1.72 5.57 0.72 1.02 1.21 1.08 1.77 3.97 3.86

5.21 2.11 3.71 1.87 5.72 0.92 1.19 1.34 1.16 1.82 4.15 = 6.5)

= 10.5) = 4.5)

= 1.5)

183114

d (J m m m d (J d (J s s d (J m br s

7.11 br s 3.21 m 4.57 br s

17497

= 12.5) = 12.5)

= 6.4)

= 10.5) = 5.0)

5.62 2.35 3.59 1.68 5.65 1.13 1.20 1.29 0.97 1.75 4.25

d (J = 5.0) br t (J = 5.0) m m d (J = 10.0) d (J = 5.0) s s d (J = 6.0) m AB (J = 13.0)

7.71 br s 2.64 t (J = 4.5) 5.20 d (J = 4.5)

17597

7.57 2.46 2.22 2.93 5.66 2.16 3.32 1.43 1.55 2.13

176100

5.58 2.28 3.56 1.62 5.45 1.08 1.25 1.21 0.92 1.76 4.25 3.82

7.56 2.45 2.25 2.94 5.65 2.17 3.31 1.43 1.57 2.15

1.95 3.47 1.76 5.45 0.77 1.16 1.22 1.06 1.78 4.41

170109

7.06 2.90 3.26 3.36 6.08 2.02 3.59 1.97 5.71 0.88 1.44 1.19 1.12 1.73 9.33

7.06 2.78 2.54 3.23 5.16 1.74 3.52 1.54 1.82 2.17

m m dd dd m m m m m m

18663

s m dd (J = 3.1, 15.4) dd (J = 5.8, 15.4) s m m dd (J = 3.7, 10.3) d (J = 10.3) d (J = 6.6) s s d (J = 6.3) s s

17798

m m m d (J = 10.0) d (J = 5.0) s s d (J = 6.0) m ± 0.09 (AB, J = 12.0)

m dt (J = 10.4, 4.8) m dd (J = 18.2, 4.8) br s m br s m m m

185115

d (J = 1.3) m m m d (J = 9.6) d (J = 5.2) s s m s ABq (JAB = 27.4) d (J = 12.0)

7.69 s 2.58 m 5.17 d (J = 3.3)

m dt (J = 4.8, 10.4) dd (J = 18.6, 10.4) dd (J = 18.6, 4.8) dd (J = 5.4, 2.4) m m ddq (J = 10.2, 7.2, 6.6) dd (J = 15.3, 10.2) dd (J = 15.3, 7.2)

184115


1.56 dd (J = 15.0, 4.0)

3.26 br s

5.56 br s

169103,d

1.97 br s 3.51 m 3.50 m 1.72 m 1.57 m 5.52 d (J = 10.4) 5.52 d (J = 10.0) 0.78 d (J = 5.0) 1.05 d (J = 5.0) 1.20 s 1.20 s 1.24 s 1.20 s 1.08 d (J = 6.4) 0.92 d (J = 6.0) 1.78 s 1.72 m 3.89 d (J = 12.1) 3.95 s 4.12 d (J = 12.1) compound/δH (in ppm), J (in Hz)

16834


7.55 br s 2.40 m 3.15 dd (J = 18.0, 9.0)

br s m m d (J d (J s s d (J s d (J d (J

16734 2.06 3.50 1.89 5.72 0.83 1.38 1.25 1.12 1.78 4.44

3.52 1.54 1.72 2.11

m m m m

m m m m m

18763

br s br t (J = 6.5) m m d (J = 10.0) d (J = 4.5) s s d (J = 6.5) m s

7.04 2.79 2.48 3.47 5.10

6.57 2.70 3.10 1.80 5.69 1.25 1.24 1.33 0.98 1.73 9.45

7.51 br s 2.53 m 2.76 d (J = 11.0)

17897

m m m d (J = 10.0) d (J = 5.0) m m d (J = 6.0) m ± 0.09 (AB, J = 12.0)

171109



AA

1 4 5 7 8 10 11 12 14 16 17 18 19

position

14 16 17 18 19 20

7 8 10 11 12

1 4 5

position

14 16 17 18 19 20

position

180114

7.11 2.85 2.54 3.54 5.15 1.82 3.57 1.58 1.75 2.16 0.58 1.19 1.09 1.12 1.83 4.06 3.93

7.07 3.14 4.46 4.89 2.06 3.65 1.85 5.70 0.82 1.20 1.34 1.15 1.82

63

0.85 1.19 1.02 0.92 1.74 4.02

m m dd m m m m m m m d s s d m ± 0.06

189 6.99 2.75 2.46 3.43 5.17 1.80 3.48 1.60 1.73 2.15 0.57 1.17 1.06 1.04 1.76 4.41

br s dd (J = 6.5, 4.5) dd (J = 12.0, 4.5) br s m m m d (J = 10.0) d (J = 4.5) s s d (J = 6.5) br s

195117

br s ddd (J = 6.7, 5.0, 3.0) dd (J = 15.4, 5.0) dm (J = 15.4) br s m br s m dd (J = 14.5, 12.0) dd (J = 14.5, 6.4) d (J = 5.0) s s d (J = 6.4) br s d (J = 12.1) d (J = 12.1)

188

116

1.71 br s 4.06 br d (J = 11.0) 4.03 br d (J = 11.0)

0.77 d (J = 5.0) 1.06 s 1.20 s

Table 9. continued

7.70 2.63 4.87 5.33 2.34 3.54 1.66 5.65 1.09 1.20 1.29 0.97 1.75

190

97

d (J = 5.5) s s d (J = 6.5) m s

br s t (J = 4.5) br d (J = 3.5) m br s m m d (J = 9.5) d (J = 5.5) s s d (J = 6.5) m

183114

7.69 2.59 4.84 5.29 2.18 3.51 1.62 5.45 1.04 1.21 1.72 0.92 1.75

0.83 1.20 1.04 0.92 1.75 4.72

d (J = 5.4) s s d (J = 6.6) dd (J = 2.7, 1.5) s

184115

1.04 1.34 1.22 0.97 1.73 1.47

7.58 2.49 2.03 2.86 5.26 2.42 3.33 1.71 5.65

s t (J = 4.4) br s d (J = 1.3) m m m d (J = 9.6) d (J = 5.2) s s m s

7.70 2.64 4.86 5.36 2.36 3.54 1.68 5.64 1.08 1.31 1.23 0.98 1.76

m m m m m m m d (J = 10.0) d (J = 6.0) s s d (J = 7.0) m

201109

192106

d (J = 5.1) s s d (J = 6.2) s s

s s d (J = 6.0) m

1.22 1.22 0.92 1.77

br s br s m m

1.27 1.24 0.99 1.78

s s d (J = 6.0) m(

5.66 d (J = 9.0)

br s m m m

4.89 5.34 2.31 3.56

204106

d (J = 4.5) s s d (J = 6.0) br t (J = 1.5) br s

br s m m m d (J = 10.0)

4.83 5.27 2.28 3.51

0.86 1.18 1.31 1.12 1.81 1.88

4.88 2.05 3.64 1.85 5.70

7.67 m

1.16 1.03 0.92 1.74

s s d (J = 6.0) m

19497

d s s d m ± 0.06 (AB)

7.07 br s 3.12 dd (J = 4.5, 6.5) 4.45 br s

0.53 1.15 1.03 1.06 1.76 3.93

18763

7.68 br s

203106

d (J = 5.0) s s d (J = 6.0) m s

s m dd (J = 4.5, 15.0) br d (J = 15.0) br s br s m m d (J = 10.5)

5.39 d (J = 9.0)

m m s m m m

0.83 1.15 1.32 1.09 1.80 1.74

7.05 2.70 2.37 3.41 4.83 1.95 3.45 1.84 5.71

d s s d m ± 0.02 (AB)

19397

0.39 1.21 0.99 1.08 1.78 3.94

18663

5.44 d (J = 9.6)

7.68 2.56 4.82 5.31 2.24 3.51

202107

d (J = 5.5) s s d (J = 6.5) dd (J = 1.5, 3.0) s


d (J = 5.5) s s d (J = 6.5) br s br s

br s ddd (J = 10.5, 9.0, 4.5) dd (J = 18.2, 10.5) br dd (J = 18.2, 9.0) br dq (J = 5.5, 2.0) br t (J = 5.5) dddq (J = 4.5, 2.5, 2.5, 1.5) dq (J = 9.5, 6.5) d (J = 9.5)

191104

0.83 1.33 1.04 0.93 1.75 4.72

185115

m ddd (J = 9.0, J = 10.0, J = 4.5) dd (J = 10.0, J = 18.0) dd (J = 9.0, J = 18.0) m m (dd, J = 2.5, J = 5.0, J = 2.5) m d (J = 9.5)



197100

0.96 1.20 1.20 0.89 1.72 1.72

7.56 2.43 2.00 2.82 5.21 2.32 3.28 1.55 5.37

1.69 br s 4.42 br d (J = 12.0) 4.35 br d (J = 12.0)

0.75 d (J = 5.0) 1.03 s 1.19 s

br s dt (J = 4.5, 10.5) dd (J = 10.5, 18.5) dd (J = 9.0, 18.5) m br t (J = 5.0) m m d (J = 9.5)

19697

1.05 1.19 1.32 0.95 1.73 1.75

7.59 2.49 2.04 2.87 5.25 2.40 3.32 1.71 5.65

d s s d m ± 0.03 (AB)

18163



1.16 s

1.03 0.92 1.74 1.83

14 16

17 18 19 20

AB

7.57 s 2.42 d (J = 19.2) 2.48 d (J = 19.2) 5.60 d (J = 4.7) 2.97e 3.24 br s 1.98 m 1.60 dd (J = 15.1, 7.1) 2.12 dd (J = 15.1, 7.1) 1.18 d (J = 6.0) 4.30 d (J = 11.8) 3.57 d (J = 11.8) 1.19 s 0.88 d (J = 6.4) 1.75e 4.02 d (J = 13.1) 3.97 d (J = 13.1)

1 5

17 18 19 20

14 16

7 8 10 11 12

214123

position

s d (J = 6.0) m m

5.49 d (J = 10.0)

5.50 d (J = 9.6)

215123

s d (J = 6.4) m m

7.58 m 2.46 d (J = 19.2) 2.53 d (J = 19.2) 5.60 br d (J = 5.6) 3.06e 3.28 br s 2.00 m 1.60e 2.13 dd (J = 14.9, 7.0) 0.94 d (J = 5.2) 4.81 d (J = 11.2) 3.13 d (J = 11.2) 1.08 s 0.89 d (J = 7.4) 1.78 dd (J = 1.2, 2.8) 4.03 dd (J = 12.9, 5.6) 3.98 dd (J = 12.9, 5.6)

1.04 0.89 1.78 1.83

0.95 d (J = 5.8) 1.20 s

5.37 m 3.29 m 3.52 m

5.25 m 2.24 m 3.48 m

7 8 10 11 12

216123

s d (J = 6.4) m m

1.86 s

201109


dd (J = 15.0, 4.0) dd (J = 15.0, 6.0) d (J = 5.0) s

7.55 m 2.41 d (J = 19.1) 2.47 d (J = 19.1) 5.59 d (J = 4.2) 2.95e 3.24 br s 1.96 m 1.54e 2.09e 1.16 d (J = 6.0) 4.18 d (J = 11.9) 3.57 d (J = 11.9) 1.16 s 0.87 d (J = 6.5) 1.74 dd (J = 1.2, 2.7) 4.00 dd (J = 12.8, 6.0) 3.95 dd (J = 12.8, 6.0)

217123

3.53 3.32 2.08 1.62 2.10 1.95 4.17 4.07 1.16 0.96 1.83 4.37 4.25 218123

d (J = 5.5) br s m dd (J = 14.0, 11.0) m d (J = 5.5) d (J = 11.5) d (J = 11.5) s d (J = 6.4) d (J = 1.5) d (J = 14.2) d (J = 14.2)

6.90 s

7.65 s

211121

1.83 m

202107

7.55 m 2.41 d (J = 19.1) 2.47 d (J = 19.1) 5.59 d (J = 4.2) 2.95e 3.24 br s 1.96 m 1.54e 2.09e 1.16 d (J = 6.0) 4.19 d (J = 11.9) 3.54 d (J = 11.9) 1.16 s 0.87 d (J = 6.5) 1.74 dd (J = 1.2, 2.7) 4.00 dd (J = 12.8, 6.0) 3.95 dd (J = 12.8, 6.0)


1.71 br s

1.19 s 0.91 d (J = 6.5)

1.53 2.10 0.75 1.02

br s ddd (J = 10.0, 9.0, 4.0) dd (J = 18.0, 10.0) dd (J = 18.0, 9.0) br s br dd (J = 6.5, 4.0) br s

210114

1.88 m compound/δH (in ppm), J (in Hz) 7.56 2.40 1.98 2.81 5.22 2.07 3.29

197100

7.55 br s 2.43 d (J = 19.2) 2.48 d (J = 19.2) 5.59 d (J = 5.2) 3.05e 3.24 br s 1.98 m 1.62 dd (J = 15.0, 11.7) 2.12 dd (J = 15.0, 7.1) 0.96 d (J = 5.1) 4.14 d (J = 11.6) 3.52 d (J = 11.6) 1.15 s 0.88 d (J = 6.5) 1.74 dd (J = 1.3, 2.8) 4.00 d (J = 13.0, 5.5) 3.95 d (J = 13.0, 5.5)

1.04 0.89 1.78 1.83

0.95 d (J = 5.8) 1.20 s

5.44 d (J = 10.0)

5.43 m 3.29 m 3.55 m

4.27 m

4.27 m

209107 7.79 m

19697

7.77 m

208107

1.88 s

7.66 m 2.56 m 4.82 s

205107

1.91 br s

195117

1 4 5

position

20

position

Table 9. continued

s d d d d

(J (J (J (J 22570

1.29 0.99 1.83 4.31 4.10

= = = =

6.1) 1.5) 15.8) 15.8)

0.95 d (J = 6.0) 1.82 m 4.02 s

4.15 ± 0.21 (AB, J = 11.0)

5.66 d (J = 6.0) 3.07 m 3.30 m

7.59 m 2.53 m

d (J = 4.2) br s m d (J = 10.1) 2.03 d (J = 5.3) 3.83 s

4.01 3.14 2.36 5.45

6.86 s

7.61 br s

21248

1.86 br s

203106

1.13 0.87 1.77 3.98

s d (J = 6.0) m s

0.87 d (J = 6.0) 4.08, 3.86 ABq (J = 11.5)

5.59 d (J = 5.0) 3.02 m 3.26 br s

22880

d (J = 9.4) dd (J = 9.4, 5.4) s m dd (J = 14.9, 11.8) dd (J = 11.8, 4.3) d (J = 5.5) d (J = 11.3) d (J = 11.3) s d (J = 6.5) d (J = 1.4) s

7.55 s 2.47 s

4.65 2.60 3.07 2.08 1.60 2.18 1.71 4.51 3.99 1.13 0.94 1.80 2.04

6.04 s

7.58 s

213121

1.89 br s

204106



AC

a

3.81 s

1.33 0.91 1.76 4.00

17 18 19 20

1.53 1.51 1.71 4.24

s d dd s

4.42, 4.20 (AB)

4.48 4.07 0.92 1.72 1.73

7.51 2.44 2.00 2.74 5.20 2.25 3.24 1.60 5.38 1.15 1.29

d m m dq d

1.58 1.63 1.69 4.36

s d dd s

4.60 q

6.13 4.05 3.64 2.90 6.04

2.96 m

7.74 m

24321,132,b

2.45 2.53 5.59 3.34 3.09 1.93 4.03 1.01 4.15 4.26 1.20 1.09 1.78 3.93 3.97

d (J d (J br s br s br s m d (J d (J d (J d (J s d (J s d (J d (J

7.66 br s

11.0) 5.5) 11.0) 11.0)

= 12.8) = 12.8)

= 6.7)

= = = =

= 18.9) = 18.9)

244128

1.25 1.00 1.79 3.98

7.05 2.81 2.51 3.39 5.09 2.34 3.51 1.70 5.46 0.82 3.95

br s ddd (J = 10, 9.5, 4.5) dd (J = 18.0, 10.0) br dd (J = 18.0, 9.5) br dq (J = 5.5, 2.0) br t (J = 5.5) dddq (J = 4.5, 2.5, 2.5, 1.5) dq (J = 10, 6.5) d (J = 10.0) d (J = 5.5) s

237104

d (J = 12.5) 4.50 d (J = 12.5) d (J = 12.5) 4.08 d (J = 12.5) d (J = 6.5) 0.93 d (J = 6.5) t (J = 1.5) 1.72 dd (J = 2.5, 1.5) dd (J = 2.0, 1.5) 4.00 br s compound/δH (in ppm), J (in Hz)

br s m dd (J = 18.0, 10.0) br dd (J = 18.0, 9.0) br dq (J = 5.5, 2.0) br t (J = 5.5) dddq (J = 4.5, 2.5, 2.5, 1.5) dq (J = 9.5, 6.5) d (J = 9.5) me s

7.50 2.47 2.10 2.73 5.52 2.33 3.20 1.67 5.40 1.20 1.29


d (J = 5.5) m m me d (J = 9.9) br s ABq (J = 23.9)

s d (J = 7.3) br s ABq (J = 20.0)

br s m dd (J = 4.0, 14.6) m br s m m m d (J = 10.6) m q (J = 19.0)

245/246111

0.89 m 1.77 d (J = 1.5) 4.02 ABq (J = 16.3)

1.18 s

5.65 3.08 3.29 1.73 5.42 1.15 4.17

7.59 s 2.31 dd (J = 15.1, 7.4) 2.51 br s

238111

Recorded in CD3OD. bRecorded in C5D5N. cRecorded in CCl4. dRecorded in CDCl3 + D2O. eOverlapping signal; signals without a superscript were recorded in CDCl3.

s d (J = 6.4) s s

5.45 d (J = 10)

(AB) (AB) d m m dq d

2.91 3.07 6.10 3.87 3.63 2.72 4.49

2.41 2.63 5.67 3.21 3.34

d (J = 19.4) d (J = 19.4) s m m

7.86 m

24221,132,b

7.57 s

241130

7 8 10 11 12 14 16

1 4 5

position

0.87 d (J = 6.0) 1.77 m 4.38 s

0.89 d (J = 6.0) 1.79 m 4.44 s

18 19 20

0.87 d (J = 6.0) 4.08, 3.86 ABq (J = 11.5)

4.14 ± 0.20 (AB, J = 11.0) 1.13 s

5.62 br s 3.10 m 3.20 br s

2.38 s

2.44 m

23380,c

5.70 d (J = 6.0) 3.06 m 3.27 m

7.51 br s

7.60 m

23070

17

7 8 10 11 12 14 16

1 4 5

position

Table 9. continued

br s m dd (J = 18.1, 9.1) dd (J = 18.1, 9.1) br s br s br s m d (J = 9.8) d (J = 5.5) d (J = 10.9) d (J = 10.9) s

3.57 1.01 1.71 3.82 3.90

br s d (J = 6.3) s d (J = 13.1) d (J = 13.1)

7.00 br s 2.75 m 2.33 dd (J = 15.3, 4.8) 3.33e 5.06 br s 1.89 br d 3.43 br d 1.64 dd (J = 10.8, 6.3) 5.45 d (J = 10.5) 0.72 d (J = 4.8) 1.15 s

248113

1.05 d (J = 6.7) 1.70 d (J = 2.5) 3.92 s

7.65 2.60 2.14 2.75 5.46 2.32 3.15 1.40 4.02 0.99 4.13 4.19 1.15

239128



Chemical Reviews

Review

Table 10. 13C NMR Data of Diterpenes from the Families Euphorbiaceae and Thymelaeaceae compound/δC (in ppm) carbon

25,a

1

30

2

30

3

30

4

31

5

1139

1332,39

1439

1539

2032

2530

2734

3031

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20

163.5 141.3 212.3 75.3 37.8 134.9 130.6 39.8 80.0 58.6 45.7 81.8 63.1 36.6 27.1 17.6 23.9 15.5 10.6 67.8

160.0 140.7 208.5 73.4 38.7 133.4 129.1 39.0 78.2 56.6 43.3 87.5 60.7 35.2 27.7 17.1 22.2 15.9 10.0 68.0

160.2 140.6 208.4 74.1 38.6 133.1 129.3 39.1 78.2 56.7 45.1 76.9 67.2 35.4 25.1 17.2 22.6 15.0 10.0 68.1

160.7 140.5 208.8 73.7 38.6 132.9 129.1 39.1 78.1 56.1 42.9 77.0 65.6 36.3 25.8 16.7 23.8 14.4 10.0 68.0

160.8 132.8 209.0 73.5 38.5 140.4 129.2 39.0 78.3 56.1 43.1 76.6 65.7 36.3 25.7 16.9 23.8 14.4 10.1 68.0

160.5 160.5 160.9 132.9 132.9 132.6 208.8 208.8 207.3 73.7 73.7 73.7 38.8 38.8 38.5 140.0 140.0 140.4 129.3 129.3 129.4 39.2 39.2 39.1 78.1 78.1 78.4 56.3 56.3 56.1 43.0 43.0 42.8 76.8 76.8 76.6 65.6 65.6 65.6 36.2 36.2 36.1 25.4 25.4 25.7 16.7 16.7 16.5 23.5 23.5 23.5 14.2 14.2 14.1 10.1 10.1 9.9 67.9 67.9 68.1 compound/δC (in ppm)

160.5 132.6 207.3 73.6 38.8 140.3 129.0 39.0 78.0 56.0 42.7 76.9 65.3 36.3 25.5 16.5 23.8 14.4 10.0 67.9

160.7 140.5 208.8 73.8 38.7 132.9 129.2 39.1 78.2 56.2 43.0 76.5 65.8 36.3 25.6 16.8 23.9 14.4 10.1 68.0

160.7 140.3 208.8 73.7 38.7 132.8 129.2 39.1 78.1 56.2 43.0 76.7 65.4 36.3 25.8 16.8 23.8 14.4 10.0 68.0

160.8 132.8 209.0 73.7 38.6 140.4 129.3 39.1 78.3 56.2 43.3 73.7 65.5 36.5 27.7 16.9 23.8 14.4 10.1 68.1

161.1 132.8 209.4 73.9 38.5 140.4 127.4 39.0 78.4 56.1 43.3 76.6 65.3 36.5

carbon

3634

4030

4252

4451

4651

4731

4930

5026,b

5134

5231

5331

5454

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20

160.9 132.8 209.0 73.7 38.7 140.3 129.4 39.2 78.2 56.2 43.0 76.5 65.3 36.5 26.7 16.9 23.9 14.4 10.1 68.1

160.7 140.6 208.8 73.8 38.8 133.0 129.3 39.4 78.4 56.4 43.6 77.9 66.2 37.0 26.7 17.2 23.9 14.7 10.2 68.1

160.5 134.7 210.3 74.8 38.5 143.0 129.3 40.1 79.9 57.4 44.7 79.3 67.0 37.6 27.5 17.7 24.2 15.0 10.3 68.0

160.8 132.9 209.0 73.7 38.6 140.5 129.2 39.1 78.3 56.2 43.3 77.6 65.6 36.6 26.0 17.0 23.8 14.5 10.1 68.1

160.7 132.9 208.9 73.7 38.6 140.5 129.2 39.1 78.3 56.2 43.3 77.6 65.7 36.6 26.0 17.0 23.8 14.5 10.1 68.0

160.9 132.8 209.0 73.7 38.6 140.3 129.2 39.0 78.2 56.1 41.8 76.3 65.3 36.3

160.7 160.3 140.3 135.8 208.7 208.4 74.0 73.3 38.7 39.0 132.4 133.1 129.2 132.4 39.2 39.3 78.3 78.2 56.2 56.6 43.0 45.1 76.6 77.1 65.8 68.0 36.4 35.3 25.7 26.5 16.9 16.8 16.8 23.9 23.8 23.6 11.6 14.4 15.1 10.1 10.0 10.0 68.0 68.0 69.3 compound/δC (in ppm)

161.1 134.5 210.7 74.8 39.0 139.7 132.4 40.2 79.9 57.7 46.1 77.6 69.5 36.6 27.2 17.5 24.1 15.5 10.2 76.0

160.3 132.3 208.7 73.3 38.9 136.2 129.7 39.2 78.2 56.7 44.9 77.3 65.1 35.3 27.1 16.9 23.6 14.1 10.1 69.1

160.4 133.1 208.7 73.3 38.9 136.1 132.3 39.2 78.2 56.7 44.9 77.5 68.0 35.2

160.4 133.4 208.7 73.3 39.0 135.9 132.5 39.2 79.0 56.6 43.5 87.3 60.7 35.0

16.9 23.6 15.0 10.1 69.2

17.0 10.1 69.2

161.1 136.0 209.2 73.9 39.1 133.2 132.9 39.6 78.4 56.4 43.3 77.2 65.9 36.4 26.1 17.1 24.2 14.8 10.5 69.7

carbon

5556

5930

6040

6140

6258

6348

6451

6551

6747

6851

6960,b

7261,b

7566

1 2 3 4 5 6 7 8 9 10 11 12 13 14

160.8 135.7 208.5 73.6 38.8 132.9 132.7 39.4 78.2 56.2 43.2 76.1 65.7 36.1

155.6 140.5 208.0 76.9 34.3 131.7 126.0 40.8 78.0 55.6 42.9 75.5 65.0 36.1

159.7 135.0 204.8 73.1 137.4 148.4 201.4 54.8 75.5 59.1 44.4 76.1 65.6 29.4

159.8 135.0 204.9 73.1 137.3 148.4 201.4 54.8 75.6 59.2 44.7 76.1 65.7 29.6

159.1 137.0 205.8 74.0 138.7 149.8 202.5 55.9 77.2 60.5 46.0 78.2 67.4 30.6

159.8 135.2 204.9 73.2 137.4 148.5 201.5 54.9 75.6 59.2 44.5 76.1 65.7 29.4

160.2 134.1 206.2 72.5 133.8 150.6 83.1 46.0 74.9 57.3 44.7 77.7 65.8 31.8

160.3 134.1 206.2 72.5 133.7 150.6 83.1 46.0 75.0 57.3 44.7 77.7 65.8 31.8

160.4 134.1 206.6 72.5 133.5 150.8 83.0 45.8 75.2 57.2 44.2 76.6 66.1 31.4

161.9 134.1 209.6 73.4 71.7 140.2 132.8 38.9 77.3 53.8 44.1 77.6 65.4 36.7

126.1 132.7 77.5 137.6 34.0 136.2 128.3 38.9 80.7 132.9 31.2 75.6 75.4 29.7

163.2 135.1 209.9 74.5 70.3 64.5 65.7 36.9 79.0 50.5 46.9 78.4 67.4 36.8

160.6 132.9 209.2 73.8 38.7 140.4 130.4 39.1 76.0 56.2 36.6 32.3 63.8 32.8

4830

AD

17.0 23.8 14.4 10.1 68.0


Chemical Reviews

Review

Table 10. continued compound/δC (in ppm) carbon

55

56

59

30

60

61

62

6348

6551

6747

6851

6960,b

7261,b

7566

25.3 26.1 26.1 16.8 16.8 16.8 23.6 23.8 23.8 14.6 14.8 14.8 10.4 10.2 10.2 63.7 66.6 66.5 compound/δC (in ppm)

25.8

10.3 66.1

26.2 17.0 23.7 15.0 10.0 67.8

20.7 16.2 25.1 19.0 20.2 64.2

28.1 17.5 23.8 15.3 9.9 64.7

22.5 15.3 23.2 18.8 9.9 67.9

11159

11271

11371

11426,c

11526,b

40

40

58

6451

15 16 17 18 19 20

25.7 16.7 23.8 14.4 10.1 69.4

24.5 16.5 24.1 11.9 10.5 68.5

25.2 16.7 23.5 14.5 10.3 63.5

25.4 16.7 23.5 14.5 10.3 63.5

26.8 17.2 23.9 15.0 10.5 62.5

carbon

7914,74

8483

8584

8614

9386

9466

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20

161.3 132.7 209.4 73.7 38.5 139.9 130.4 39.1 76.2 55.7 36.3 31.9 63.2 32.8 22.9 15.4 23.6 18.6 10.1 68.2

161.2 132.7 209.5 73.7 38.3 140.1 130.1 38.9 76.2 55.5 36.1 31.8 63.3 32.4 22.6 15.3 23.2 18.5 10.0 68.1

161.2 132.8 209.1 73.8 38.7 139.8 130.3 39.2 75.9 55.8 36.3 32.2 63.8 32.5 22.9 15.4 23.2 18.6 10.1 68.3

161.4 132.7 209.3 73.8 38.6 139.8 130.5 39.2 76.0 55.7 36.3 32.0 63.2 32.5 26.6 15.4 23.1 18.6 10.1 68.3

161.2 132.8 209.3 73.8 38.7 139.8 130.3 39.2 76.0 55.8 36.3 31.8 63.4 32.6 22.7 15.3 23.2 18.5 10.1 68.3


161.3 132.9 208.9 73.7 38.9 135.2 133.7 39.5 75.9 55.8 36.3 31.9 63.6 32.4 22.6 15.3 23.2 18.6 10.1 69.4

160.3 136.3 210.2 44.5 34.0 139.6 125.0 42.2 77.9 54.3 42.3 56.7 65.0 35.9 25.8 17.0 23.9 15.1 10.2 62.2

160.3 136.3 210.3 44.5 34.0 139.6 125.7 42.2 77.9 54.3 42.3 56.7 65.0 35.8 25.8 17.0 23.9 15.1 10.2 66.4

160.1 133.6 209.4 74.2 39.1 138.6 132.2 39.7 76.5 57.3 37.1 33.1 64.6 32.5 23.5 15.9 23.3 19.4 10.5 75.3

161.3 134.9 210.8 74.7 39.0 138.8 133.6 40.0 77.9 57.1 37.5 33.0 64.6 32.9 24.2 15.9 23.3 19.1 10.2 76.6

carbon

11671

11771

11871

11971

12071

12171

12371

12486

12539

12786

12839,94

13086

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20

160.2 136.2 210.3 44.6 34.1 139.7 125.7 42.2 77.9 54.3 42.3 56.8 65.0 35.9 25.8 16.9 23.9 15.1 10.3 67.4

160.3 136.2 210.3 44.6 34.0 139.6 125.7 42.2 77.9 54.4 42.3 56.7 65.1 36.0 25.8 16.9 24.0 15.2 10.3 68.2

160.3 136.3 210.3 44.5 34.0 139.6 125.7 42.2 77.9 54.3 42.3 56.7 65.0 35.9 25.8 16.9 23.9 15.1 10.2 66.9

160.3 136.3 210.2 44.5 34.0 139.6 125.6 42.2 77.9 54.3 42.3 56.7 65.0 35.9 25.8 16.9 23.9 15.2 10.3 66.7

160.3 136.2 210.3 44.6 34.0 139.6 125.6 42.2 77.3 54.3 42.3 56.8 65.0 36.0 25.8 16.9 23.9 15.2 10.3 67.2


161.5 132.8 209.1 73.7 39.0 135.0 133.8 39.5 75.9 55.8 36.4 31.8 63.3 32.5 22.7 15.3 23.2 18.5 10.1 69.5

164.1 134.1 210.1 72.4 71.7 61.8 65.7 36.2 75.3 49.6 38.3 31.8 63.9 31.8 23.9 15.7 22.8 19.0 9.8 64.5

163.9 134.2 210.0 72.6 71.6 61.9 65.7 36.3 75.4 49.7 38.2 31.9 64.1 31.8 23.9 15.7 22.8 19.0 9.7 64.8

164.5 133.9 209.0 72.3 71.9 61.5 65.8 36.5 75.1 49.2 38.4 32.1 63.3 32.0 23.6 15.8 22.9 19.1 9.9 64.9

163.6 134.3 209.8 72.5 69.6 60.7 65.7 36.2 75.3 49.8 38.1 31.9 64.2 31.9 24.0 15.8 22.8 19.0 9.8 65.7

carbon

13459

13559

13696

13797

147104

15096

15196

15396

15457

156104

15997

161112

164104

1 2 3 4 5 6

160.4 133.5 208.3 72.8 34.4 142.9

160.5 133.5 208.4 72.8 34.6 142.9

161.4 136.7 211.7 44.7 29.6 141.9

159.5 136.4 209.5 44.2 29.6 142.1

159.8 136.4 209.7 44.2 29.6 142.0

159.9 136.4 209.8 44.2 29.6 142.0

156.2 137.0 213.3 49.6 25.2 143.3

159.6 136.5 209.5 44.0 29.9 137.3

159.7 137.3 208.8 42.5 35.1 136.5

159.8 136.5 209.6 44.1 30.0 137.2

156.5 137.5 213.8 49.7 24.9 143.7

156.1 143.3 213.2 49.6 25.1 137.0

156.2 143.3 213.3 49.6 25.1 137.0

9914,74

12271

AE

10114,80


Chemical Reviews

Review

Table 10. continued compound/δC (in ppm) carbon 7 8 9 10 11 12 13 14 15 16 17 18 19 20

59

59

96

97

104

134

135

136

137

147

15096

15196

15396

15457

156104

15997

161112

164104

158.1 41.4 77.1 55.8 36.5 31.7 63.0 32.0 22.9 15.3 23.1 18.5 10.1 193.8

158.2 41.5 77.1 55.8 36.5 31.8 63.0 32.1 22.7 15.3 23.2 18.6 10.1 193.8

127.8 42.4 78.0 55.4 43.9 81.2 61.9 35.6 26.5 17.1 23.4 15.7 10.2 66.9

126.5 42.1 77.8 54.1 42.6 76.2 65.5 35.7 25.7 16.8 23.7 15.0 10.1 67.4

126.5 42.1 77.8 54.2 42.4 76.7 65.0 35.8 25.9 16.9 23.8 15.1 10.2 67.5

126.5 126.5 130.0 42.1 40.8 42.1 76.9 78.1 76.8 54.2 47.4 54.0 42.8 43.7 42.2 77.8 75.6 77.7 65.0 64.9 65.1 35.9 37.3 35.3 26.0 25.4 25.7 16.9 16.6 16.6 23.7 24.2 23.7 15.1 11.9 15.1 10.2 10.5 10.2 67.4 69.4 68.8 compound/δC (in ppm)

130.2 42.3 77.8 54.1 44.1 76.1 65.4 35.4 25.7 16.7 23.7 15.1 10.2 68.9

130.3 42.2 77.8 54.0 42.3 76.4 64.8 35.5 25.8 16.8 23.8 15.0 10.3 68.9

126.7 40.5 78.1 47.3 43.3 74.9 65.3 36.9 24.9 16.2 23.8 11.5 10.0 69.2

126.4 40.6 78.0 47.4 43.3 74.7 65.2 36.9 25.1 16.3 24.1 11.8 10.4 69.2

126.5 40.7 78.1 47.4 43.2 75.3 64.8 37.1 25.3 16.5 24.2 11.9 10.5 69.3

carbon

165113

16634

16734

16834

170109

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20

156.1 143.2 213.1 49.6 25.2 137.1 126.4 40.7 78.0 47.3 43.1 74.8 64.8 37.1 25.2 16.4 24.1 11.8 10.4 69.3

156.2 143.3 213.2 40.7 25.2 137.1 126.4 43.7 78.1 49.6 47.4 75.6 64.9 37.3 24.1 16.2 25.4 12.3 10.4 69.3

156.1 143.4 213.1 40.7 25.2 137.1 126.3 43.4 78.1 49.6 47.4 75.4 65.6 37.0 24.0 16.4 25.1 12.3 10.4 69.3

156.1 143.3 213.2 40.7 25.2 137.1 126.5 43.5 78.1 49.6 47.4 75.5 65.0 37.2 24.2 16.5 24.5 12.3 10.4 69.3

carbon

184115

185115

188116

19097

191104

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20

160.2 136.8 210.0 44.1 30.4 136.6 131.6 42.3 75.2 53.8 35.5 31.8 62.8 31.8 22.8 15.3 23.1 19.2 10.2 69.8

160.1 136.8 209.8 44.2 29.7 136.6 131.6 42.3 75.3 53.9 35.5 31.9 63.0 31.8 22.7 15.2 23.1 19.2 10.2 69.8

156.9 143.0 213.8 50.1 25.1 136.3 127.7 41.0 75.5 47.1 37.1 30.5 62.7 33.1 22.5 15.2 23.7 15.9 10.4 69.5

160.0 136.4 210.1 44.6 34.0 139.0 125.7 42.2 77.9 54.3 42.5 76.3 65.6 35.8 25.4 16.9 23.7 15.1 10.2 25.7

160.2 136.3 210.2 44.5 34.0 139.0 125.8 42.2 77.9 54.3 42.3 76.7 65.0 35.9 25.8 16.9 23.9 15.1 10.2 25.4

171109

17234

17334

17497

17597

155.6 143.1 210.9 45.1 34.2 132.2 128.7 40.9 77.7 48.7 47.1 75.1 67.8 35.6 25.8 16.4 24.0 14.0 10.4 70.5

155.6 143.2 210.9 45.1 34.2 132.2 128.7 40.9 77.7 48.7 47.1 75.2 67.8 35.6 25.9 16.3 24.0 14.1 10.4 70.5

154.9 144.2 207.9 55.9 67.3 139.9 126.8 40.1 78.5 47.9 43.4 73.9 65.3 37.7 25.5 16.6 24.0 11.8 10.5 68.2

162.7 138.5 208.4 51.4 71.1 143.1 130.3 42.5 78.6 52.1 43.2 76.3 65.7 36.3 26.0 17.1 23.9 15.5 10.3 67.1

19397

19497

195117

19697

201109

156.1 143.6 212.6 49.0 29.7 135.2 124.5 40.6 78.1 46.9 43.2 75.1 65.4 37.3 24.8 16.2 23.8 11.4 10.0 28.5

154.6 144.0 207.5 56.1 70.9 137.7 125.4 40.1 78.5 47.8 43.4 74.0 65.3 38.1 25.3 16.5 24.1 11.7 10.4 27.1

154.4 143.8 207.6 56.0 70.7 136.9 125.5 40.1 78.2 47.8 43.5 75.5 64.7 38.6 25.7 16.6 23.8 11.8 10.5 27.2

162.6 138.3 208.5 51.4 71.1 140.6 127.3 42.4 78.3 51.5 43.0 76.3 65.6 36.5 25.8 16.9 23.7 15.3 10.1 21.7

162.7 138.2 208.5 43.3 71.0 140.5 127.2 42.0 78.3 51.4 36.7 77.6 65.0 34.1 26.1 16.9 23.6 15.2 9.9 21.6

155.2 155.2 132.6 133.2 211.0 211.1 48.8 48.9 24.1 24.1 143.3 143.4 128.7 128.7 41.0 41.1 75.3 76.4 46.7 46.9 43.0 43.4 70.7 70.7 64.8 64.9 36.8 37.2 26.3 26.3 16.4 16.7 25.2 25.6 11.8 11.9 10.4 10.5 64.8 64.9 compound/δC (in ppm)

AF


Chemical Reviews

Review

Table 10. continued compound/δC (in ppm) carbon 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20

123

123

123

214

215

216

161.2 133.4 208.7 74.0 39.1 140.9 129.5 38.9 76.4 56.1 36.7 32.0 63.4 33.4 25.9 74.0 12.0 18.7 10.1 68.4

161.2 133.0 208.8 73.6 38.8 140.4 129.4 38.3 75.9 55.7 36.3 31.7 64.3 30.0 26.1 68.7 10.6 18.4 10.2 68.2

160.8 133.1 208.7 74.0 38.9 140.7 129.1 38.5 76.0 55.9 36.5 31.9 64.4 30.2 26.3 69.4 10.9 18.6 10.2 68.2

123

217/218

236104

237104

239128

241130

244128

248113

161.0 133.3 208.9 74.2 38.8 140.8 129.3 38.8 76.2 55.9 36.5 31.9 63.4 33.2 25.5 73.9 12.1 18.5 10.2 68.2

159.4 136.5 210.1 44.3 33.6 139.3 125.0 42.6 77.5 53.9 42.5 76.2 65.3 36.5 29.8 19.5 63.5 15.2 10.3 25.4

160.0 136.6 209.7 44.0 29.0 142.4 125.3 42.4 d 53.8 42.4 76.1 65.2 36.4 30.0 e 63.3 15.2 10.3 67.1

161.8 137.5 212.5 45.7 30.5 143.4 128.6 42.9 79.2 58.1 45.0 81.9 63.2 35.2 30.7 71.9 13.1 16.1 10.2 67.9

160.6 133.2 209.5 73.4 38.2 140.8 128.8 39.0 78.1 55.8 42.9 76.3 65.8 36.5 31.7 62.1 14.1 14.5 10.0 67.9

160.8 133.9 210.3 74.1 38.1 141.6 129.6 38.9 79.2 58.1 45.1 80.9 62.6 34.8 30.1 71.4 12.8 15.2 10.2 67.7

156.5 143.3 213.0 49.8 25.3 136.0 125.2 40.7 78.0 47.2 42.9 74.9 65.7 37.0 25.3 24.0 70.4 11.7 10.3 68.8

a

Recorded in D2O. bRecorded in CD3OD. cRecorded in C5D5N. dObscured by the signal of CDCl3. eOverlapped with one of the isobutyrate methyl signals; signals without a superscript are recorded in CDCl3.

respectively, and the signal for C-12 is almost always about 10 ppm higher than that for C-13. The oxygenated carbon of C-20 generally resonated between 64.8 and 70.5 ppm. The carbon chemical shift of C-20 moves to 193.8 ppm when the hydroxymethyl (C-20) is replaced by an aldehyde group (as in 134 and 135), and the chemical shift of the C-7 position in these compounds is generally greater than that of the other tigliane diterpenes because of the effect of conjugation. Because of the α,β-unsaturated ketone in the skeleton, the carbon chemical shift of the methyl group at C-19 is usually upfield of the other methyl groups at C-16, C-17, and C-18 by about 10 ppm. When C-16 or C-17 is substituted with an oxygen group, its carbon chemical shift moves downfield from 16.2−25.2 to 60.3−70.3 ppm. Although the A/B ring junction is normally trans, some tiglianes possess a cis A/B ring junction, and the structure of these isomers can be elucidated from the 13C NMR data, because the chemical shifts of the cis A/B ring junction are higher than those of the A/B trans-fused junction, as shown in Figure 4.

on C-8. The chemical shifts of the oxygenated protons at C-12, as in the esters of phorbol, 4-deoxyphorbol (or 4αdeoyxphorbol), 20-deoxyphorbol, and 4,20-dideoxyphorbol, are generally shifted downfield from 3.91−4.87 to 5.34−5.72 ppm when the C-12 hydroxy group is acylated. The resonance signals between 1.49 and 1.94 ppm and 2.01 and 2.32 ppm are generally double peaks or two multiplets and indicate the lack of an oxygen substituent at C-12. The signal upfield generally belongs to the α-H. The protons on C-8 and C-10 usually appear as broad multiplets between 1.74 and 3.66 ppm, and the signals for the two protons at C-5 are typically observed between 1.98 and 3.46 ppm as a broad singlet or two doublets. Resonances signals at 0.87−1.44, 0.80−1.26, and 1.60−1.84 ppm belong to the four methyl groups attached to C-16/17, C18, and C-19, respectively. The resonance signals of the protons at C-20 appear between 3.80 and 4.80 ppm. The differences in the chemical shifts between phorbol, 4-deoxyphorbol, 12deoxyphorbol, 4,12-dideoxyphorbol, 4,20-dideoxyphorbol, and 12,20-dideoxyphorbol are summarized in Figure 3.

6. THE 13C NMR DATA OF TIGLIANE DITERPENOIDS Table 10 shows the 13C NMR data for the tigliane diterpenoids covered in this Review that can be found in the literature. The carbon chemical shifts of the tigliane skeleton display small variations at the same position, although the substituent groups are different from each other. The carbon signals around 155.2−161.4, 132.6−143.6, 132.2−143.3, 126.4−139.0, and 203.0−213.8 ppm are generally assigned to C-1, C-2, C-6, C-7, and C-3, respectively (except in 60−67, 69−73, 125−130, and 211−213), and indicate the presence of two double bonds and a carbonyl carbon. Signals between 73.3 and 74.8 ppm and 75.3 and 79.9 ppm are typically assigned to the C-4 and C-9 positions, which are substituted with a hydroxy group. The C12 and C-13 positions are usually substituted with an oxygen group, and the carbon chemical shifts of C-12 and C-13 are therefore bewteen 70.7 and 87.5 ppm and 60.7 and 68.0 ppm,

7. CONCLUSIONS About 248 of the tigliane diterpenoids isolated during the course of the past few decades have been covered in this Review. The tigliane diterpenoids are one of most important classes of diterpenoids from the Euphorbiaceae and Thymelaeaceae families, and have many interesting biological activities, especially antiviral activity, cytotoxic activity, and antiinflammatory activity, etc. To date, tigliane derivatives have been found in about 23 genera of plants belonging to the Euphorbiaceae and Thymelaeaceae families, with the majority being found in plants belonging to the Euphorbiaceae family. In this Review, we have summarized the 1H NMR and 13C NMR data of these diterpenoids, and briefly discussed their biological activities and their basic structural−activity relationships. According to this Review, the carbonyl, cyclopropane, C20AG


Chemical Reviews

Review

OH, and the type of 13-acyl groups in the tigliane framework represent the key structural features of the tigliane framework in terms of their cytotoxic activity or anti-HIV activity. We hope this Review will provide a useful reference for researchers working toward the elucidation and biological activity of tigliane diterpenoids, and it is envisaged that some of these tigliane derivatives will be developed into useful materials with a variety of different applications in the future.

with Professor Ting-Guo Kang from Liaoning University of Traditional Chinese Medicine. She is carrying out research on the isolation and structural elucidation of biologically active natural products.

AUTHOR INFORMATION Corresponding Author

*Tel.: (86-21) 6598-3693. E-mail: [email protected]. Notes

The authors declare no competing financial interest. Biographies Li-Ping Liu was born in Jiangxi Province, China, in 1989. She received her B.S. degree in Chemistry from Jinggangshan University in 2010. In the same year she joined the research group of Professor Hong-Bing Wang as a Masters student at Tongji University, where she focuses on the isolation and structural elucidation of biologically active natural products.

Hong-Bing Wang (born in 1976 in Datong, Shanxi Province) is Professor of Natural Products Chemistry at Tongji University. He reveived his B.S. degree from China Pharmaceutical University in 1998, Masters degree from Tianjin University in 2001, and obtained his Ph.D. from the Shanghai Institute of Materia Medica, Chinese Academy of Sciences, in 2004. After graduate study, he worked at the Shanghai Institute of Materia Medica as Assistant Professor and Associate Professor until 2009; during this period, he visited the University of Hong Kong as a visiting researcher in 2005. He then moved to Tongji University in 2009. His research interests are focused on the chemical constituents of medicinal plants and their biological activities.

Guo-Wei Qin was born in Shanghai, China, in 1941. He received his B.S. degree in medicinal chemistry in 1965 from Shanghai First Medical College and then joined the Shanghai Institute of Materia Medica, CAS. He was promoted to professor in 1994. He has been working in natural products chemistry for 47 years, and more then 200 reserarch papers have been published.

Xiao-Yang Wang was born in Liaoning Province, China, in 1986. She received her B.S. degree in Traditional Chinese Medicine from Liaoning University of Traditional Chinese Medicine in 2009. In the same year she joined the research group of Professor Hong-Bing Wang at Tongji University for postgraduate training for her Masters degree

Ting-Guo Kang was born in Liaoning Province, China, in 1955. He received his B.S. degree from Liaoning University of Traditional Chinese Medicine in 1982, and he has worked at this University up to AH


Chemical Reviews

Review

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now as a Professor. His research interests are focused on the identification and quality evaluation of Traditional Chinese Medicine.

ACKNOWLEDGMENTS We are thankful for financial support from the National Natural Science Foundation of China (Grant nos. 81001369 and 31170327) and the Fundamental Research Funds for the Central Universities (no. 2000219078) of the People’s Republic of China. REFERENCES (1) Cragg, G. M.; Newman, D. J.; Snader, K. M. J. Nat. Prod. 1997, 60, 52. (2) Newman, D. J.; Cragg, G. M.; Snader, K. M. J. Nat. Prod. 2003, 66, 1022. (3) Newman, D. J.; Cragg, G. M. J. Nat. Prod. 2007, 70, 461. (4) Butler, M. S. J. Nat. Prod. 2004, 67, 2141. (5) Chin, Y. W.; Balunas, M. J.; Chai, H. B.; Kinghorn, A. D. AAPS J. 2006, 8, 239. (6) Saklani, A.; Kutty, S. K. Drug Discovery Today 2008, 13, 161. (7) Crepet, W. L.; Daghlian, C. P. Am. J. Bot. 1982, 69, 258. (8) The Plant List. http://www.theplantlist.org/browse/A/ Euphorbiaceae (accessed Sep 21, 2013). (9) The Plant List. http://www.theplantlist.org/browse/A/ Thymelaeaceae (accessed Sep 21, 2013). (10) Jury, S. L, Reynolds, T., Cutler, D. F., Evans, J. F., Eds. The Euphorbiales: Chemistry, Taxonomy, and Economic Botany; Academic Press: London, 1987. (11) Shi, Q. W.; Su, X. H.; Kiyota, H. Chem. Rev. 2008, 108, 4295. (12) Ahmad, W.; Nazir, M.; Khan, S. A. Pak. J. Sci. Res. 1988, 31, 85. (13) Duarte, N.; Gyémánt, N.; Abreu, P. M.; Molnár, J.; Ferreira, M. J. U. Planta Med. 2006, 72, 162. (14) Itokawa, H.; Ichihara, Y.; Watanabe, K.; Takeya, K. Planta Med. 1989, 55, 271. (15) Wu, T. S.; Lin, Y. M.; Haruna, M.; Pan, D. J.; Shingu, T.; Chen, Y. P.; Hsu, H. Y.; Nakano, T.; Lee, K. H. J. Nat. Prod. 1991, 54, 823. (16) Fatope, M. O.; Zeng, L.; Ohayaga, J. E.; Shi, G.; McLaughlin, J. L. J. Med. Chem. 1996, 139, 1005. (17) Korin, Y. D.; Brooks, D. G.; Brown, S.; Korotzer, A.; Zack, J. A. J. Virol. 2002, 76, 8118. (18) Bocklandt, S.; Blumberg, P. M.; Hamer, D. H. Antiviral Res. 2003, 59, 89. (19) Gustafson, K. R.; Cardellina, J. H.; McMahon, J. B.; Gulakowski, R. J.; Ishitoya, J.; Szallasi, Z.; Lewin, N. E.; Blumberg, P. M.; Weislow, O. S.; Beutler, J. A.; Buckheit, R. W.; Cragg, G. M.; Cox, P. A.; Bader, J. P.; Boyd, M. R. J. Med. Chem. 1992, 35, 1978. (20) Wender, P. A.; Kee, J. M.; Warrington, J. M. Science 2008, 320, 649. (21) Evans, F. J.; Soper, C. J. Lloydia 1978, 41, 193. (22) Appendino, G.; Szallasi, A. Life Sci. 1997, 60, 681. (23) Goel, G.; Makkar, H. P. S.; Francis, G.; Becker, K. Int. J. Toxicol. 2007, 26, 279. (24) Vasas, A.; Redei, D.; Csupor, D.; Molnar, J.; Hohmann, J. Eur. J. Org. Chem. 2012, 27, 5115. (25) Neeman, M.; Simmons, O. D. Can. J. Chem. 1979, 57, 2071. (26) Pan, L. L.; Fang, P. L.; Zhang, X. J.; Ni, W.; Li, L.; Yang, L. M.; Chen, C. X.; Zheng, Y. T.; Li, C. T.; Hao, X. J.; Liu, H. Y. J. Nat. Prod. 2011, 74, 1508. (27) Mishra, N. C.; Estensen, R. D.; Abdel-Monem, M. M. J. Chromatogr. 1986, 369, 435. (28) Hecker, E.; Bartsch, H.; Bresch, H.; Gschwendt, M.; Harle, E.; Kreibich, G. Tetrahedron Lett. 1967, 33, 3165. (29) Gschwendt, M.; Hecker, E. Tetrahedron Lett. 1970, 8, 567. (30) Pieters, L. A. C.; Vlietinck, A. J. Magn. Reson. Chem. 1987, 25, 368. (31) El-Mekkawy, S.; Meselhy, M. R.; Nakamura, N.; Hattori, M.; Kawahata, T.; Otake, T. Phytochemistry 2000, 53, 457. AI


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AK


Tigliane Diterpenoids from the - American Chemical Society

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