CHAPTER-I

Introduction to five and ten membered lactone natural

products
Introduction to five and ten membered lactone natural products

Synthesis is a very important area to all parts of chemistry.1 It

encompasses the distinctive capability of chemists to develop new

methods and to design molecules with a preferred set of properties. The

practical and inventive nature of the ‘chemical synthesis’ is distinctive

among all of the physical sciences. This is particularly true of research in

the synthesis of natural products. Although various techniques are

available to the natural product isolation chemists, it is not possible all

the time to establish the complete structure and stereochemistry of

natural product based on the spectroscopic techniques. Hence, chemical

synthesis is very useful method and plays an important role in

determination of structure.

The field of synthesis of natural products has been acknowledged

with the Nobel Prize in chemistry with regular recurrence over the whole

history of the award. These prizes have been awarded to E. Fischer

(1902) for the syntheses of purine and sugar, H. Fischer (1930) for his

research on the constitution of chlorophil, haemin and particularly for

the haemin synthesis, R. Robinson (1947) for his explorations on

biological importance of plant products, specifically the alkaloids, R. B.

Woodward (1965) for the outstanding accomplishment on the art of

organic synthesis and E. J. Corey (1990) for his theory and methodology

development of organic synthesis. Recently, the field of organic synthesis

comes into view as imperative as ever, and its prospect appears as

proficient as its history has been gratifying. There are several motivations

why the synthesis of natural products endured the test of time as a

rewarding and facilitating science and technology, its attractiveness as

an inventive and intellectual effort offering possibilities for discovery.

Even though the topic of synthesis of natural product is attracting a

vigorous attention in research laboratories all over the world today, the

causes for practicing it show a discrepancy. In general isolation of

natural product is in small amount, however biologically interesting.

Hence the synthesis of natural product in larger extent is important for

further extensive evaluation of medicinal or biological properties.

Furthermore the synthesis of a natural product still gives the absolute

evidence of the assigned structure. Finally, there are those who will

courageously and proudly declare that they enter campaign of total

synthesis for the intellectual challenge and complete exhilaration of the

endeavor. Due to this exciting information, we became involved in the

synthesis of biologically active compounds as a part of our research

work.

1.1. Five membered lactones:

Five membered lactone (γ-lactone) containing natural products are

known to exhibit various of biological activities2 such as cytotoxic,3

antitumor,4 cyclooxygenase or phospholipase A2 inhibition.5 These are of

fungal, bacterial or marine source. The natural products with γ-lactone

motif also showed valuable pharmacological properties. Biological

properties, structural complexities of γ-lactone molecules, and challenges

to synthesize in optically pure form, which are made them an attractive

target for various total syntheses. Isolation and biological properties of

some γ-lactone containing natural products are described below.

(R)-5-((S,2Z,4E)-1-hydroxydeca-2,4-dienyl)dihydrofuran-2(3H)-one

(1):6 It is a γ-lactone containing unsaturated side chain and hydroxy

group. The compound 1 was isolated from Lithophiton arboretum by

Tomas Rezanka et al. and it exhibits strong antibacterial activity against

Staphylococcus aureus (MIC = 7.8 µg/ml). The structure of 1 was

established by spectroscopic analysis and absolute configuration

determined by Mosher’s ester method.

OH

O
O

(R)-5-((S,2Z,4E)-1-hydroxydeca-2,4-dienyl)dihydrofuran-2(3H)-one (1)

Hamabiawalactone B (2) and akolactone B (3): Hyeong Kyu Lee et al.

isolated Hamabiawalactone B (2) and Akolactone B (3) from the leaves of

Litsea japonica.7 The molecules 2 and 3 found to have potent anti-

complement activity with IC50 values of 149 and 58 µg/ml respectively,

when compared to rosmarinic acid (IC50, 180 µg/ml), which was utilized

as a positive control.
 O
Hamabiawalactone (2)
O

O
Akolactone (3)
O

Sapinofuranones A and B (4 and 5): Two novel 5-substituted

dihydrofuranones, apinofuranones A and B (4 and 5),8 were isolated from

liquid cultures of Sphaeropsis sapinea, which is a phytopathogenic

fungus causing a variety of infection symptoms on conifers. They exhibit

more phytotoxic activity on internal bark tissues than on peripheral

ones. The structures of molecules were established by spectroscopic

analysis and absolute configuration determined by Mosher’s ester

method.

R2 O
R1 O

Apinof uranones A (4) R1=OH, R 2=H

Apinof uranones B (5) R1 =H, R2=OH

(+) Cardiobutanolide (6): The (+) cardiobutanolide9 (6) was isolated from

the stem bark of Goniothalamus cardiopetalus. The plant Goniothalamus

cardiopetalus exhibits a variety of therapeutic actions in traditional

medicine to cure the edema, rheumatism, and as mosquito repellents.

The structure of compound was established by spectroscopic methods.

OH OH OH

OH O

(+) Cardiobutanolide (6)

Syributin 1 (7) and Syributin 2 (8): Sims et al. isolated syributin 1 (7)

and syributin 2 (8)10 along with secosyrins, as co-isolates of syringolide

from Pseudomonas syringe. The plant from which these compounds

isolated, exhibited a variety of medicinal activities. The structures of

compounds were established by spectral methods.

OH OH
O O
O O
OH O OH O
O Syributin 1 (7) O Syributin 2 (8)

Sapinofuranones (9, 10 and 11): Simpson et al. isolated a novel

metabolite sapinofuranone B11 (9 ) from fermentation extracts of

Saphaeropsissapinae. Subsequently, closely related lactones

sapinofuranone A (10) and ent-sapinofuranone B (11) were isolated from

Saphaeropsissapinae liquid cultures.

 O O
O O
OH
OH

Sapinofuranone B (9) Sapinofuranone A (10)

O O
OH

ent-sapinofuranone B (11)

(4R,9Z)-9-Octadecen-4-olide (12):

(4R,9Z)-9-Octadecen-4-olide (12) is the female sex pheromone of

the female currant stem girdler, Janus integer, which is an occasional

pest of red currant in North America and was isolated by Cosse et al. The

compound 12 was isolated as a single enantiomer and its absolute

configuration was proposed as R-configuration by a bioassay of synthetic

samples.12

O
O C8H17

(4R,9Z)-9-Octadecen-4-olide (12)

Muricatacin (13): J. L. McLaughlin et al. isolated muricatacin (13) as a

novel metabolite from Annona muricata. The antitumor activities in

addition to the patented pesticidal applications of the bark and seed

extracts from this family hold admirable prospective for development.

The structure of 13 was established by spectral methods.13

O
O

OH
Muricatacin (13)

Iso-cladospolide-B (14): Ireland et al. isolated iso-cladospolide-B (14) 14

from a tissue sample of a marine sponge. The structure was determined

by spectral methods and the absolute configuration was established by

its total synthesis.

O
O

OH OH

Iso- cladospolide B (14)

(+)-Luffalactone (15): De Silva et al. isolated (+)-luffalactone (15) from

marine sponge Luffariella variabilis. It exhibits strong anti-inflammatory

activity. The structure was determined by spectral studies and the

absolute configuration at C-16 was established by Pilar Basabe et al. in

2009, by synthesis of the (+)-luffalactone.15

 O
AcO

(+)-Luffalactone (15)

Botryolides E (16): James B. Gloer et al. isolated botryolide E (16) from

the cultures of a fungicolous isolate of Botryo trichum sp. (NRRL 38180),

in 2008.16 The structure was determined by spectral data. The absolute

configuration of 16 was determined by modified Mosher’s method.

O OH

O
O

Botryolide E (16)

Pectinolide H (17): R. Perda-Miranda et al. isolated pectinolide H from

the chloroform extract of the aerial parts of a Mexican terrestrial plant

Hyptis pectinata. It displays strong antimicrobial activity against a panel

of multidrug-resistant strains of Staphylococcus aureus. 17

 OAc OH

O
O

Pectinolide H (17)

1.2. Ten membered ring containing macrolides

Natural products containing a macrolactone structure can be

originated in bacteria, plants, insects and they may be of marine or

terrestrial source. The valuable activities of macrolides vary from

perfumery to medicinal and biological properties. The new results in the

field of antibiotic and other antitumor active macrolides, accompanied by

pheromones and plant growth regulators with macrolactone skeleton, are

a motivation to chemists to study macrolides.

In relation to lactone structures and biosynthesis, these are

classified into monocyclic oxylipins, monocyclic polyketides, aromatic

bicyclic and aliphatic bicyclic lactones. In every subsection, these

macrolides are explained in sequential order of their isolation.

1.2.1. Diplodialides:

Diplodialides (18-21) are monocyclic ten-membered-ring

containing lactones. In 1975, diplodialides A, B and C were isolated by

Ishida and Wada, from the plant pathogenic fungus Diplodia pinea.18 The

isolation of diplodialide D (21)19 and the structural elucidation of the

metabolites,20 were established by the same authors. (+) Diplodialide A

(18) exhibited inhibitory activity against steroid 31674 hydroxylase.

 O O
10
2 1 O 9 8 O
3
5 7 HO
O 4 6
(+)-Diplodialide A (18) (-)-Diplodialide B (19)

O O

O O

HO HO
O
(+)-Diplodialide C (20) Diplodialide D (21)

1.2.2. Phoracanthonolides: The phoracanthonolides I (22) and J (23)

were isolated from the secretion of the metasternal gland of eucalypt

longicorn Phoracantha synonyma in 197621 and are structurally simple

decalactones.

O O

O O

(-)-Phoracanthonolide I (22) (-)-Phoracanthonolide J (23)

1.2.3. Pyrenolides: Pyrenolides A, B and C (24–26) were isolated by

Nukina group, from the Pyrenophora teres22,23 in 1980. Pyrenolide A also

isolated from culture filtrates of Ascochyta hyalospora24 in 1992. These

show morphogenic and growth inhibition activities against fungi.

O O O
O O O
O
OH
O O O
(-)-Pyrenolide A (24) (-)-Pyrenolide B (25) (-)-Pyrenolide C (26)
1.2.4. Decarestrictines: A series of metabolites were generated by

various strains of Penicillium species were isolated in the early 1990s and

called as decarestrictines. These lactones exhibited to be inhibitors of

cholesterol biosynthesis and explained by both in vivo and in vitro

studies.25

Most of the decarestrictines consist of ten-membered lactone

moiety that varies in the oxygenation mold between C3 and C7. Five of

them bear an epoxide function at C6–C7 such as A1 (27), A2 (28), B (29),

E (30), and F (34), and eight of them A1 (27), A2 (28), C1 (31), C2 (32), D

(33), F (34), H (36), K (38) contain a double bond, and seven of the

decarestrictines B (29), E (30), F (34), G (35), H (36), J (37), K (38) are β-

keto lactones.

The most biologically active decarestrictine D (33), was individually

isolated from the Canadian Tuckahoe, the sclerotium of the Polyporus

tuberaster fungus and called as tuckolide.26

A C6-epimer of decarestrictine C1 was obtained from the fungus

Cordyceps militaris.27 Multiplolides A and B, the lactones with epoxy ring

(40 and 41) were isolated from Xylaria multiplex, and are closely

correlated with the decarestrictine family.28

O O R O O

O O O O

HO O O O HO HO OH
OH
OH OH
A1 (a-OH) (27) (+)-B R = H (29) C1 (b-OH) (31) (-)-D (33)
A 2 (b-OH) (28) (-)-E R = CH3 (30) C 2 (a-OH) (32)
 O O O
O
O O O
O
O O OH O OH
O OH
O OH H (36) (-)-J (37)
F (34) (-)-G (35)

O O O O

O O O O O
O O
O HO OH O
OH
OH OH OH
K (38) 6-epi -C1 (39) Multipolide A (40) Multipolide B (41)

1.2.5. Aspinolides:

Aspinolides A–C (42-44) were isolated from the cultures of Aspergillus

ochraceus, in 1997. The absolute configuration and structure elucidation

evaluated by X-ray alalysis and Helmchen’s method.29

O O
O HO
HO O
O
O
HO O
HO
O O

O O
Aspinolide A (42) Aspinolide B (43) Aspinolide C (44)

Aspinolides are characterized by the occurrence of a

methylcarbinol moiety in their structures and their C9-center is usually

with the (R)-configuration, represents the starter unit in the polyketides

biosynthesis.30
1.2.6. Pinolidoxins: Pinolidoxin (45), a decalactone isolated by evidente

et. al from Ascochyta pinoda in 1993,31 and also three similar macrolides,

dihydropinolidoxin (47), epipinolidoxin (46) and epoxypinolidoxin (48)

were isolated32 and evaluated on bean and pea leaves, initial three

molecules were exhibited to be highly toxic, but epoxypinolidoxin was

inactive.

HO HO
O O
O O
HO O HO O
O O

(+)-Pinolidoxin (b-OH) (45) Dihydropinolidoxin (47)

(+)-Epipinolidoxin (a-OH) (46)

O
HO
O
O
HO O
O
Epoxypinolidoxin (48)

1.2.7. Herbarumins: Rivero-Cruz et al.33,34 isolated three hexaketides

from fungus Phoma (P. herbarum), and named as herbarumins I–III (49-

51). These macrolides interact with the calmodulin of bovine brain and

inhibit the cAMP phosphodiesterase enzyme activation.

HO HO HO
O O O
HO HO OH
O O O

(+)-Herburamin I (49) (+)-Herburamin II (50) (+)-Herburamin III (51)

1.2.8. Microcarpalide: In 2001, Hemscheidt et al. isolated

microcarpalide (52) from the fermentation broths of an unknown

endophytic fungus.35 This molecule works as a microfilament-disrupting

agent, and it shows weak cytotoxic activity against mammalian cells. It

molecular formula similar with achaetolide (53)36, but differs in the

position of the double bond and the hydroxy groups.

OH OH
OH HO OH

C 6H 13
O C 7H15 O
O O
OH
(-)-Microcarpalide (52) (-)-Achaetolide (53)

1.2.9. Stagonolides: Evidente37,38 et al. isolated new phytotoxic

metabolites from Stagonospora cirsii, which is a fungal pathogen isolated

from Cirsium arvense and anticipated as a prospective mycoherbicide of

this perennial toxic weed, generates phytotoxic metabolites in solid and

liquid cultures. Stagonolides A-D (54-57), with remarkable phytotoxic

activities were isolated from a liquid culture. The same fungus, grown-up

in solid culture, showed an improved ability to produce five new

nonenolides, called stagonolides E-I (58-62).

 OH OH
O OH OH
O O O
OH OH
O O O
Stagonolide A (54) Stagonolide B (55) Stagonolide C (56)

OH OH
OH
H
O O
O
H
O
O O O
Stagonolide D (57) Stagonolide E (58) Stagonolide F (59)

OH OH HO OH
H
O
O O
OH H O
O O O
Stagonolide G (60) Stagonolide H (61) Stagonolide I (62)

1.2.10. Didemnilactones and Ascidiatrienolides:

In the early 1990s, Niwa et al. isolated didemnilactones A and B

(63 and 64), ascidiatrienolide A and neodidemnilactone (65 and 66). 39,40

These eicosanoid lactones were isolated from the marine tunicate

Didemnum moseleyi, and exhibited modest inhibitory activity toward

lipoxygenase.

O
O
O
O

OH
OH
(-)-D ide m nila c tone A (6 3) (-)-Did em nila ct one B (6 4 )

O O

O O

OH OH
(-)-Ascidiatrienolide A (65) (-)-Neodidemnilactone (66)
1.3. Mueggelone or Gloeolactone:

A lactone with 18-carbons and epoxy group (67) was isolated from

the Aphanizomenon flos-aquae, a cyanobacterium in 1997, it was

exhibited to be a fish development inhibitor, and called as mueggelone.41

The same lactone was isolated from the blue-green algae Gloeotrichia sp.,

and was named as gloeolactone.42

O
O

(+)-Muggelone or gloeolactone(67)
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