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Nitrile-containing natural products

Fraser F. Fleming Department of Chemistry and Biochemistry, Duquesne University, Pittsburgh PA 15282-1530, USA
Received (in Cambridge) 30th April 1999 Covering: 1990 to 1998
CO2H R NH2 1 Amino acid

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1 2 2.1 2.2 2.3 3 3.1 3.2 3.3 3.4 4 5 6

Introduction Alkanenitriles a- and b-Amino nitriles Aryl-substituted alkanenitriles Cyanogenic glycosides a,b-Unsaturated nitriles Nitrilosides Methylbutenenitriles Calyculins Miscellaneous a,b-unsaturated nitriles Aromatic nitriles Miscellaneous nitrile-containing metabolites References

CO2H R 2 NHOH R NOH 3 Aldoxime R

S-Gly OSO3 N

6 Glucosinolate

S R CN R CN R 7 OSO3 N 4 Nitrile

O-Gly 5 Cyanogenic glycoside

Scheme 1

2 1 Introduction Naturally occurring nitriles comprise a small and surprisingly diverse set of secondary metabolites. The structures vary from simple, long-chain alkanenitriles to architecturally complex structures such as the calyculins, with new, more complex metabolites being continually reported. The number of nitrilecontaining natural products has risen from 33, in a 1981 review,3 to more than 1204 (excluding cyanogenic glycosides) and now includes metabolites from both terrestrial and marine sources.2 The increasing number of nitrile-containing natural products highlights the need for a general classification of these compounds with this review classifying metabolites according to the hybridization of the nitrile-bearing carbon. Three general categories result; alkanenitriles, a,b-unsaturated nitriles, and aromatic nitriles. This classification emphasizes the amino acid origin of the nitriles and combines some previous sub-groups into structurally-related classes. Nitrile-containing natural products are known to be derived from amino acids in plants,5 arthropods,6 bacteria and fungi1 (Scheme 1). N-Hydroxylation and decarboxylation of amino acids afford aldoximes 3 that are enzymatically converted to the corresponding nitrile 4 through a sequence that appears to be considerably more complex than a simple dehydration.7 Cyanogenic glycosides are derived from these nitriles by a stereoselective hydroxylationglycosylation sequence.8 Glucosinolates provide another biosynthetic route to nitrilecontaining metabolites. The biosynthesis of glucosinolates 6 is closely related to that of nitriles in proceeding through an aldoxime intermediate.9 Hydrolysis of glucosinolates affords numerous metabolites, including nitriles, where the formation of nitriles results from a complex dependence on pH, co-factors, and the nature of the substituent.10 Glucosinolate hydrolysis often occurs during cooking of Brassica crops (such as cabbage, brussel sprouts, and cauliflower) leading to increased levels of nitriles from these sources.11

Alkanenitriles

The simplest alkanenitriles are volatile sulfur-containing metabolites that largely occur in Cruciferae. The long-chain nitrile 5-methylthiopentanenitrile (8a) was isolated during the hydrolysis of broccoli12 while the higher homologues 8b and 8c were synthesized and shown to be constituents of watercress aroma.13 The structurally-related sulfoxide 9a is a non-volatile isolate from Dipthychocarpus strictus that exhibits high antihypoxic activity14 while 9b is a phytoalexin obtained from the cruciferous plant Rorippa sylvestris.15 Hydrolysis of several Cruciferae provides an abundant source of sulfur-substituted nitriles as seen in the epithionitriles 10ad16 that most likely arise from the corresponding glucosinolates during isolation. The hydroxylated epithionitrile 11 has been isolated from Crambe seed oil as a diastereomeric mixture of episulfides having a common stereochemistry at the hydroxy-bearing carbon.17 This stereochemistry is enantiomeric to the episulfide obtained from rutabaga seeds.18 Rutabaga seeds were also found to contain the nitrile 12, although 12 may arise from sulfur extrusion of 11 during isolation.
O MeS ( )
n CN

Me

( )n

CN

S 10a b c d

8a n = 4 b n=7 c n=8 S CN OH 11

9a n = 6 b n=8

CN ( )n n=1 n=2 n=3 n=4 CN

OH 12

For the last comprehensive reviews see refs. 1 and 2.

The hydroxylated butanenitriles 13,19 14,20 and 1520 are alkanenitriles that are formally derived by hydrolysis and glycosylation of the corresponding a,b-unsaturated nitriles (methylbutenenitriles, section 3.2). Some of these compounds seem to be cyanogenic20 although the mechanism through which this occurs is not obvious. In contrast, sarmentosin epoxide (16 of unspecified absolute stereochemistry from Sedum cepaea),21 osmaronin epoxide (17 from the shrub Osmaronica cerasiformis)22 and sutherlandin epoxide (18 from Nat. Prod. Rep., 1999, 16, 597606 597

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Exochorda serratifolia)19 are all cyanogenic, presumably resulting from hydrolysis of the epoxide and cyanide release from the corresponding cyanohydrin.
CN CN O--Glu O--Glu 13 OH CN O O--Glu 16 O O--Glu 17 CN O OH O--Glu 18 CN 14 CN MeO OH OH O--Glu 15 O

O O NH CN H N N O H H O 22 OMe 23 O O H N O MeO H O N N H OH CN

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2.1

a- and b-Amino nitriles

fermentation broth with sodium cyanide.27 Another member of this same series is Dnacin A1 (25),28 from Actinosynnema pretiosum, which exhibits similar antibacterial and antitumor properties. Halimedin 2629 is very unusual in being the only aamino nitrile from a marine source. Halimedin was isolated from the alga Halimeda xishaensis collected in the South China Sea.
OH HO MeO H H N N H O 24 OMe N N N 26 N H CN 25 O H N O CN H2N H O N N H OH CN

Several a-amino nitriles have been isolated from a variety of sources. The origin of the nitrile group in a-amino nitriles has not been determined but most probably arises by the addition of cellular cyanide to imines,1 as proposed for the biosynthesis of 19 and 20.23 These bisindole alkaloids 19 and 20 were isolated from the roots of Tabernaemontana elegans with the structure being determined by a combination of spectroscopy and chemical correlation. More recently two additional nitrilesubstituted indoles, lahadinines A (21a) and B (21b) were obtained from the leaf extract of Kopsia pauciflora Hook f.24
MeO2C H N

HO

Et

N H MeO2C MeO N H MeO2C H N NC N 19 N OMe H N

N H

HN N MeO2C 20 CN

b-Amino nitriles are less common than a-amino nitriles with most (27 and 28) being isolated from Lathyrus species. Interest in b-amino nitriles from Lathyrus species was stimulated by a search for metabolites associated with neural lesions (lathyrism) resulting from eating the seeds of these plants (mainly chickling vetch or chick pea).30 In contrast to the deleterious effects of 27 and 28, the structurally related b-cyanoglutamic acid 29,31 from Streptomyces, exhibits activity as an antifungal antibiotic. The most complex b-amino nitrile is 3032 where the origin of the propanenitrile fragment remains unknown, although the carbon skeleton is probably derived from co-occurring vallesamine alkaloids.
CO2H CO2H CN H2N 29 CN CN

CN R1 R2 MeO2C OH CO2Me 21a R1 = R2 = OCH2O 21b R1 = R2 = OMe N

HN

HN

R 27a R = H b R = glutamyl

R 28a R = H b R = glutamyl CN N

CO2H

Streptomyces cultures have yielded several a-amino nitriles exhibiting high antibiotic and antitumor activities. Saframycin A (22) was the first of these a-amino nitrile isolates from Streptomyces (lavendulae)25 although neither the absolute stereochemistry nor the nitrile stereochemistry was determined. Cyanocycline A (23) is another Streptomyces metabolite resembling Saframycin A in structure and biological activity, exhibiting both antimicrobial (5 ng mL21 against Staphylococcus aureus) and antitumor activities.26 Recently cyanocycline A (23) and the corresponding hydroquinone 24 were isolated from a different Streptomyces source (lusitanus) after treating the 598 Nat. Prod. Rep., 1999, 16, 597606

N H OH 30

CO2Me

2.2

Aryl-substituted alkanenitriles

A variety of phenyl and hydroxylated phenyl acetonitriles have been obtained from plant sources.33 Many, if not all, of these

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nitriles are derived from the corresponding glucosinolates as indicated by the dependence of nitrile-containing metabolites on the method of sample preparation.34 The parent phenyl acetonitrile (31a) and phenylpropanenitrile (32) have been isolated from Nasturtium officinale seeds27 while the mono- and dihydroxylated analogs 31b35 and 31c36 and d,36 were isolated from Erica scoparia and Moringa oleifera leaf extracts, respectively.
CN R1 R2 31a R1 = H, R2 = H 31b R1 = OH, R2 = OH
O

CN

possibly resulting from hydrolysis and the release of cyanide.43 The synthesis of dithyreanitrile (34d)44 was recently reported with the aim of determining the mechanism of action and the source of bioactivity associated with this unusual metabolite. A related indoleacetonitrile, 34e,45 bears a close structural homology to 34ad but is distinctly different in being isolated from a Demospongiae class of sponge (Pseudosuberites hyalinus) that contains several brominated indoles. The role of 34e is currently unknown. Two other marine metabolites are the pyrrole-containing nitrile 35 and the structurally-related cyanohydrin 36 that were both isolated from the Indo-Pacific sponge Laxosuberites sp.46
OH CN

32

31c

R1

= H,

R2

=
HO HO

O OH O

N H

( )5 35

( )5 O

N H

( )5 36

( )15

CN

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31d R1 = H, R2 = AcO
HO

O OH

2.3 Cyanogenic glycosides Cyanogenic glycosides are by far the most common naturallyoccurring nitriles. These nitriles have been isolated extensively from plants (over 1000 species representing more than 100 families),47 fungi, bacteria and a number of animals,48 particularly those that feed on cyanogenic plants.49 Cyanogenic glycosides50 are b-glycosides of 2-hydroxy nitriles (cyanohydrins) and therefore release hydrogen cyanide upon chemical or enzymatic hydrolysis. The function of these latent cyanide sources is the source of some discussion but cyanogenic glycosides are implicated in both plant and animal defense mechanisms.6 More recently cyanogenic glycosides have been suggested as a storage form for reduced nitrogen,51 which could account for the widespread occurrence of cyanogenic plants.52,47 The majority of the world food crops are cyanogenic53 although people, and most animals, can ingest small amounts of cyanogenic plants without symptoms of cyanide poisoning. Ingestion can be a serious problem, particularly in tropical countries where approximately 100 million tons of cyanogenic cassava is eaten annually as a dietary staple.54 The wide occurrence of cyanogenic glycosides belies their minimal structural differences.55,56 All of the known cyanogenic glycosides are derived from a glycoside and only 6 amino acids; phenylalanine, tyrosine, valine, isoleucine, cyclopent2-enylglycine, and nicotinic acid. Usually the sugar portion is glucose with most new metabolites, reported since the previous review,55 representing modifications of the glycoside residue. For example, a recent investigation of the root cortex of cassava (Manihot esculenta) led to the isolation of the glycoside 37,57 which is an apiosyl derivative of lotaustralin (38). The stereochemistry of the nitrile-bearing carbon was not determined, though the co-occurrence of lotaustralin (38) in the same extract implicates 38 as the precursor to 37 and suggests that the chirality of the cyanohydrin is the same as that of lotaustralin. Recent isolates 39a and 39b58 from the leaves of the South African shrub Oxyanthus speciosus show a similar type of sugar derivatization. These cyanogenic glycosides, and the more highly substituted derivative 39c (from Canthium schimperianum Lam.)59 are all 6A apiosyl derivatives of prunasin (45a), that co-occurs with 39a and 39b in Oxyanthus speciosus. The pcoumarates 40a and 40b, from the fronds of the Japanese fern Microlepia strigosa,60 and 41 from the fruits of Passiflora edulis61 are also derivatives of prunasin. An expedient synthesis of the cyanogenic glycosides prunasin (45a), linamarin (45b), and heterodendrin (45c) was recently reported (Scheme 2).62 The method relies on glycosylation of hydroxy carboxamides followed by a novel dehydration procedure that avoids the intermediacy of a cyanohydrin. The direct use of cyanohydrins is avoided in glycosidations since Nat. Prod. Rep., 1999, 16, 597606 599

Bursatellin (33) from sea hare (Bursatella leachii pleii) is a phenyl-containing nitrile whose structure elucidation proved elusive for some time. Initially (+)-bursatellin was isolated from samples collected near La Paguera, Puerto Rico and a dinitrile structure proposed (33 NHCHO = CN).37 Reisolation of bursatellin from the same organism, but collected at Naples, provided enantiomeric bursatellin whose structure was revised to the formamide 33.38 The stereochemistry was originally unable to be assigned, and was later determined from two syntheses that confirmed the threo configuration shown.39
HO OH

NHCHO

CN

33

Indoleacetonitrile (34a)40 occurs in a number of Cruciferae,11 and appears to play a fundamental role in plant growth. Indoleacetonitrile specifically inhibits seedling-growth of lightgrown cabbage (Brassoca olearea)41 retarding growth on the light exposed side of the plant stem and causing the young seedling to bend toward the light source. The authors propose that light stimulates the enzymatic formation of 34a from the
R2 R1 R1 CN R3 R4 34a 34b 34c 34d 34e N R5

R1 = H, R2 = H, R3 = H, R4 = H, R5 = H R1 = H, R2 = OMe, R3 = H, R4 = H, R5 = H R1 = H, R2 = H, R3 = H, R4 = H, R5 = OMe R1 = SMe, R2 = H, R3 = H, R4 = H, R5 = H R1 = H, R2 = H, R3 = Br, R4 = H, R5 = H

corresponding glucosinolate which, if correct, would account for the widespread occurrence of indoleacetonitriles. The methoxy- and methylthioacetal-derivatives 34b,42 34c42 and 34d43 were also isolated from Cruciferae (Brassica pekinensis, Chinese cabbage, and Dithyrea wislizenii, respectively). Dithyreanitrile (34d) inhibits feeding by the fall army worm (Spodoptera frugiperda) and the European corn borer (Ostrinia nubilalis) and is suggested to be a plant defense mechanism,

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O O HO HO OH 37 O O HO HO OH
6

HO O O OH CN HO HO O O OH 38 CN

(12% yield),62 although the process requires significant optimization before becoming synthetically viable. 3 a,b-Unsaturated nitriles

OH

OH

O O OH CN

OH OR 39a R = H b R = Bz

a,b-Unsaturated nitriles have diverse structures and similarly diverse biological profiles. The largest subgroup of a,bunsaturated nitriles are the nitrilosides that contain a cyanomethylenecyclohexane unit with variable hydroxylations around the ring. 3.1 Nitrilosides

c R=
O O OH HO O OH OH O MeO O

HO O HO O O OH 40a R = H b R = OH CN

HO HO HO O HO O HO HO

O O OH 41 CN

AcO AcO AcO O AcO O NH CCl3

HO R2 R1 CONH2 43

Nitrilosides are a group of cyanomethylene cyclohexanes that have been isolated exclusively from plant sources. The nitrilosides can be divided into two sub-groups depending on the presence, or absence, of additional unsaturation at C2C3, suggesting that an aromatic amino acid is the biogenetic precursor of these metabolites.64 The co-occurrence of the benzyl nitrile 47 with ehretiosides 48ac,65 is further support for the biosynthesis of nitrilosides from phenylalanine or tyrosine by a formal hydrogenation, although elucidation of nitriloside biosynthesis must await further studies. Ehretiosides A1 (48a), A2 (48b), and A3 (48c) were isolated from the stem bark of Ehretia philippinensis that is used as a folk remedy in the Philippines, although none of the ehretiosides elicit antiinflammatory activity.65 Lophirosides A1 (48d), A2 (48e), B1 (48f), and B2 (48g)66 are also from a bark extract of a tree (Lophira alata) that is used as a folk medicine in western Africa for inflammations and as an analgesic. The lophirosides exhibit weak antibacterial activity against Micrococcus luteus but do not act as defensive substances against insects and microorganisms. Three monoesters, lanceolin A (48h),67 B (48i),67 and C (48j)68 are related to the lophirosides and were isolated from sister species Lophira lanceolata and Lophira alata, respectively, that grow in the woody savannas of Cameroon. Simmonsin (48k), from seeds of the jojoba plant (Simmondsia californica)69 is the only other nitriloside without C2C3 unsaturation. The absolute configuration of simmonsin (48k) was verified through a recent synthesis that employed l-quebrachitol as the starting material.70
CN O--Glu R
1

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42

CN O--Glu

BF3.OEt2

AcO
Me3SiO H CN 46 Ph BF3.OEt2

R2
O AcO R1 CONH2 44a R1 = H, R2 = Ph 1 2 44b R = R = Me 44c R1 = i-Pr, R2 = H
1. (COCl)2, DMSO, Et3N 2. LiBH4 for 44a, K2CO3, MeOH for 44b and 44c

AcO AcO

R2

OH 47

HO HO HO O OH R1 45a R1 = H, R2 = Ph 45b R1 = R2 = Me 45c R1 = i-Pr, R2 = H CN O R2

R3 48a R1 = OH, R2 = (CH3)2C=CHCO2, R3 = OH 48b R1 = OH, R2 = OH, R3 = (CH3)2C=CHCO2 48c R1 = (CH3)2C=CHCO2, R2 = OH, R3 = OH 48d R1 = OH, R2 = OBz, R3 = OBz 48e R1 = OBz, R2 = OH, R3 = OBz 48f R1 = OH, R2 = PhCH=CHCO2, R3 = OBz 48g R1 = PhCH=CHCO2, R2 = OH, R3 = OBz 48h R1 = OBz, R2 = OH, R3 = OH 48i R1 = OH, R2 = OH, R3 = OBz 48j R1 = OH, R2 = OBz, R3 = OH 48k R1 = OH, R2 = OMe, R3 = OMe

Scheme 2

equilibration otherwise occurs, releasing cyanide that preferentially reacts with the activated glycoside rather than the cyanohydrin.63 An advance in this area is the demonstration that the trimethylsilyl cyanohydrin 46 can be directly glycosylated 600 Nat. Prod. Rep., 1999, 16, 597606

Nitrilosides generally have weak biological profiles, positive or negative, and appear to exhibit little toxicity. For example, Bauhinin (49a) isolated from Bauhinia championii (Leguminosae) collected from mountainous forests of Taiwan, was administered to mice in doses up to 300 mg kg21 without signs of toxicity.71 The roots of the West African plant Griffonia simplicifolia Baill. yielded griffonin72 that was later shown to be identical to lithospermoside (49b),73 originally isolated from roots of the plant Lithospermum purpureo-caeruleum.74 An-

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other root extract, from Thalictrum dasycarpum,75 led to the isolation of dasycarponin (49c). The berries of Ilex warburgii76 are a fruitful source of nitrilosides providing both 49d and the known nitriloside, menisdaurin (49e, isolated from the vines of Menispermum dauricum).77 Berries from the related plant Ilex aquifolium also contain menisdaurin.78
CN O--Glu R1 R2 R3 R1 = OH, R2 = H, R3 = H, R4 = OMe R1 = OH, R2 = H, R3 = H, R4 = OH R1 = OH, R2 = H, R3 = OH, R4 = H R1 = H, R2 = OH, R3 = H, R4 = OH R1 = H, R2 = H, R3 = H, R4 = OH R4

49a 49b 49c 49d 49e

this plant with rhodiocyanoside B (52b) and most likely arises by cellular metabolism of multifidin. Both 52a and 52b were assayed for biological activity,84 with multifidin exhibiting significant antiallergenic properties. Rhodiocyanoside B was biologically inactive. Further investigation of related Chinese medicinal plants (Rhodiola. sacra) led to the isolation of rhodiocyanoside D (54)85 that exhibits antiallergenic properties similar to that of multifidin. The hydroxymethyl analog of multifidin, sarmentosin (52c), has been isolated from the Chinese plant Sedum sarmentosum86 and from the Magpie moth Abraxas grossulariata L.87 In the latter case 52c was found to exhibit strong antifeedant properties88 that may be due to conversion to sarmentosin epoxide which spontaneously releases HCN.
R CN -D-GluO CN

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An unusual stereoisomeric nitriloside purshianin (50) has been isolated from the stem of Purshia tridentata79 that has the glucose substituent in the epimeric orientation. Coclauril (51), isolated from the leaves of the evergreen shrub Cocculus lauriforius, shares this unusual stereochemistry, and is further distinguished in being the only nitriloside with the E-configuration of the cyanomethylene group.80
CN O--D-Glu NC OH

-D-GluO 52a R = H
O O OH OH OH

54

52b R =

52c R = OH

OH 50

OH 51

3.2

Methylbutenenitriles

Conceptually, the biosynthesis of methylbutenenitriles is envisaged as an eliminationhydroxylation from cyanogenic glycosides such as lotaustralin (38) and heterodendrin (45c, Scheme 3). This elimination parallels synthetic methods for preparing
R CN -D-GluO 38 -D-GluO 52 CN -D-GluO CN R2 45c 53 R1 CN

Several related 3-methylbutenenitriles are known that differ in the position of the vinylic methyl group, reflecting a different amino acid origin. Sutherlandin (53a) was the first reported 3-methylbutenenitrile, originally being isolated from the Australian legume Acacia sutherlandii.89 Later sutherlandin and the des-hydroxy analog, osmaronin (53b), were obtained from the North American shrub Osmaronica cerasiformis.22 Full characterization of osmaronin allowed an earlier metabolite, from barley leaves (Hordeum vulgare cv Amsel),20 to be definitively assigned as the geometric isomer 53c. This material appears to have been first isolated as an antifeedant from scentless plant bugs (Jadera sanguinolenta),90 although the olefin geometry was not determined and the assignment based on the assumption that host cyanolipids of known configuration were metabolized with retention of stereochemistry. Secretions from another Heteroptera, the New Guinian bug Leptocoris isolata,91 contain a very similar nitrile 53d that acts as a potent chemical defense against predators. Originally the olefin geometry was not assigned and only later made possible by comparison with sutherlandin.87 Several 3-methylbut-2-enenitriles 53e and f occur as fatty acid esters. These cyanolipids, as they are usually called,92 are
CN

Scheme 3

unsaturated nitriles81 and, although the exact biochemical pathway remains speculative, radiolabelling experiments point to leucine and isoleucine as the precursors to these a,bunsaturated nitriles.82 Methylbutenenitriles differ in the position of the vinylic methyl group (C2 or C3) and the number and position of hydroxy groups that are often glycosylated or acylated (in the latter case the derivatives are usually referred to as cyanolipids). The simplest of the 2-methylbut-2-enenitriles is multifidin (52a), isolated from the latex of Jatropha multitida.83 Multifidin was later isolated from the underground part of Rhodiola quadrifida, a traditional Chinese medicine used as a liniment for burns, and named Rhodiocyanoside A.84 Multifidin co-occurs in

R1 R2 53a = O--Glu, R2 = OH 53b R1 = O--Glu, R2 = H 53c R1 = H, R2 = O--Glu 53d R1 = OH, R2 = O--Glu 53e R1 = O2CR, R2 = O2CR 53f R1 = O2CR, R2 = H R1

found only in the seeds of Sapindaceae plants whose oil is used in medicine, as a hair dressing, an edible oil, and as a raw material for soap production. The acyl group varies in length from C14 to C22 although is most often C18 or C20. The chemistry, biochemistry, and occurrence of these compounds has been collated and reviewed.92 The structure of acacipetalin (55) is unusual and was in dispute for a time, although a thorough investigation demonstrated that the original structure shown is, in fact, correct.93 Nat. Prod. Rep., 1999, 16, 597606 601

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Acacipetalin is cyanogenic and is reminiscent in both structure and cyanogenicity of triglochinin (56), a metabolite commonly found in flowering plants.94
-Glu-O -Glu-O CN HO2C HO2C 56 CN

OH MeO Me2N OH

O O N H N

H2O3PO O H CN Br OH Calyculin J 58 H O OMe

O OH

55

3.3

Calyculins

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The most biologically-potent unsaturated nitriles are the calyculins95 from the marine sponges Discodermia calyx96 and Lamellomorpha strongylata.97 These are potent (0.96.0 nM), selective, inhibitors of protein phosphatase 1 and 2A98 and exhibit varying antitumor activities. Calyculin A (57a) has antitumor activity against Ehrlich and P388 leukemia in mice95b and has been the focus of several synthetic endeavors.99 The calyculins have the same basic carbon skeleton with variations in the E/Z-geometry of the unsaturated nitrile, the C6C7 olefin, and the presence or absence of methyl substitution at C-32. DesN-methylcalyculin A (57i),100 dephosphocalyculin A (57j),101 and calyculin J (58)100 are all structurally related to calyculin A and may be derived by further metabolism of this major metabolite.
OH MeO R5 OH O N H R
4

mg, respectively), the greater number of related isocyanides,104 and the known rearrangement of isocyanides,105 raise the intriguing possibility that these nitriles may be derived from the corresponding isonitriles.
R2 R1O CN

CN

OR1

O
32

59a 59b 59c 59d

R3 R1 = H, R2 = R3 = CH2CH=C(CH3)2 R1 = R2 = H, R3 = CH2CH=C(CH3)2 R1 = R2 = R3 = H R1 = Me, R2 = R3 = H

R2
6

R3O H
7

O O OH

Cyanopuupehenone (62), is one of several quinomethanetype metabolites from the Hawaiian sponge Psammaplysilla purpurea.106 The major metabolite is puupehenone (60) that reacts with HCN by a 1,6-addition to afford cyanopuupehenol (61) which is easily oxidized107 to cyanopuupehenone (62, Scheme 4). The conjugate addition of HCN is interpreted as
OH O

R1

OH

OH

OMe

Calyculin A 57a R1 = H, R2 = CN, R3 = PO3H2, R4 = H, R5 = NMe2, C6-C7(E) Calyculin B 57b R1 = CN, R2 = H, R3 = PO3H2, R4 = H, R5 = NMe2, C6-C7(E) Calyculin C 57c R1 = H, R2 = CN, R3 = PO3H2, R4 = Me, R5 = NMe2, C6-C7(E) Calyculin D 57d R1 = CN, R2 = H, R3 = PO3H2, R4 = Me, R5 = NMe2, C6-C7(E) Calyculin E 57e R1 = H, R2 = CN, R3 = PO3H2, R4 = H, R5 = NMe2, C6-C7(Z) Calyculin F 57f R1 = CN, R2 = H, R3 = PO3H2, R4=H, R5 = NMe2, C6-C7(Z) Calyculin G 57g R1 = H, R2 = CN, R3 = PO3H2, R4 = Me, R5 = NMe2, C6-C7(Z) Calyculin H 57h R1 = CN, R2 = H, R3 = PO3H2, R4 = Me, R5 = NMe2, C6-C7(Z) Des-N-methylcalyculin 57i R1 = H, R2 = CN, R3 = PO3H2, R4 = H, R5 = NHMe, C6-C7(E) Dephosphocalyculin 57j R1 = H, R2 = CN, R3 = H, R4 = H, R5 = NMe2, C6-C7(E)

O H H 60
HCN

OH OH NC
O2

OH O NC

O H H 61 H 62 H

Scheme 4

3.4

Miscellaneous a,b-unsaturated nitriles

Several a,b-unsaturated nitriles are contained within very unusual skeletons and do not clearly fall into any of the previous categories. Three new dinitriles, epurpurins A(59a), B(59b) and C (59c), have recently been isolated as pigments from the fungus Emericella purpurea.102 This appears to be only the second report of natural products containing two nitrile groups with emerin (59d)103 being the first. Although no biosynthetic studies have been undertaken, the co-occurrence of a more prevalent isocyanide emericellin (59d CNNNC, 1.53 g and 30 602 Nat. Prod. Rep., 1999, 16, 597606

providing a detoxification of HCN that is detected when samples of the sponge are broken106 and is presumably employed by the sponge as a chemical defense. Puupehenonetype compounds exhibit cytotoxicity, antiviral, antifungal, and immunomodulatory activities in which the nitrile unit simultaneously reduces the cytotoxicity and enhances the antiviral activity against HIV II.106 Benthocyanin C (63) contains a similar quinomethane-type unit and was isolated during screening for free-radical scavengers from Streptomyces prunicolor.108 The quinone unit is

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presumably responsible for inhibition of lipid peroxidation in rat microsomes (0.29 mg mL21) although the nitrile unit appears to have minimal influence on this bioactivity. Borrelidin (64) is a nitrile-containing macrolide antibiotic that inhibits angiogenesis109 and has antiviral, antibiotic, insecticidal and herbicidal activity. The diverse bioactivity has stimulated a synthetic route110 to borrelidin, although the completed synthesis of this challenging Streptomyces metabolite111 has not been reported. Treponemycin is similar to borrelidin in being a Streptomyces antibiotic,112 containing unsaturated nitrile and lactone units that are essential for bioactivity. At present the full characterization of treponemycin is unavailable and only the identification of key fragments has been reported. Ambiguinine G nitrile (65) is a dienyl nitrile isolated from the terrestrial blue green algae Hapalaosiphon delicatulus.113 This minor metabolite co-occurs with several more prevalent
CO2H O HO N Ph CN NC H O H CO2H O OH

HO HO

HO OH

OH OH

O C O

C O CN

OO O HO OH 67

HO2C 68

CN

Aromatic nitriles

H N

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63 Cl

64

There are relatively few nitrile-containing natural products in which the nitrile is directly bound to an aromatic ring. The most common aromatic nitriles are those derived from nicotinamide116 such as 3-cyano-4-methoxypyridine (70a from Hernandia nymphaefolia),117 malloapeltine 70b (from Mallotus apelta),118 and mallorepine (71, from Mallotus repandus).119 Oxidation of the pyridine ring at C2 is most common as seen in ricinidine (72a from Trewia nudiflora),120 with nudiflorine (73 from Trewia nudiflora)121 being one of the few C6 oxygenated metabolites. The hydroxylated derivatives 72b, 72c, and 72d122 are present in all castor plant (Ricinus communis L.) tissue except the yellow leaves, with metabolic studies suggesting that 72b acts as a common intermediate for the recovery and translocation of these metabolites from senescent leaves.122
OMe CONH2 CN

CN

NH 65

N 69

N R 70a R = : 70b R = O R2

isonitriles, again raising the possibility that the nitrile unit is derived by rearrangement of an isonitrile. The tannins aleurinin A (66) and aleurinin B (67) from the Chinese plant Aleurites
HO HO O C O OO O O O O C H O OH HO HO O 66 OH OH C O CN C O HO OH OH

O CN

CN
2 6

CN

N OH Me 71

N R1

N Me 73

72a R1 = Me, R2 = H 72b R1 = Me, R2 = OMe 72c R1 = H, R2 = OMe 72d R1 = Me, R2 = OH

A few pyrrole-based nitriles have been reported, primarily from marine sponges. The simplest is the cytotoxin 74 that was obtained from the Maltese sponge Agelas oroides.123 Mycalisine A (75) and mycalisine B (76) are also from a marine sponge, Mycale sp., and are bioactive nucleosides.124 These metabolites inhibit the cell division of fertilized starfish eggs and are similar to the antibiotic toyocamycin (77 from Streptomyces) that exhibits antibiotic activity against Candida albicans and Mycobacterium B.125 5 Miscellaneous nitrile-containing metabolites

fordii, contain a relatively simple a,b-unsaturated nitrile unit with a complex glycosidic core.114 Aleurinin A and B are undoubtedly derived by the coupling of a tannin with 2-(hydroxymethyl)prop-2-enenitrile, but the origin of this nitrile unit is completely unknown and has not been isolated from living systems. Nitrile 68 is one of the few nitriles whose biosynthesis has been investigated and is currently the only known example of an acetylenic nitrile. This nitrile (68) is a fungal metabolite from Lepista diemii (Singer)115 in which the nitrile carbon is derived from the corresponding primary alcohol.

The two alkaloids 78a and 78b from Strychnos wallichiana comprise the only examples of natural products containing the N-cyano function.126 These N-cyano alkaloids appear not to be artifacts, but conclusive proof with fresh plant material has not been forthcoming. In this respect, the relatively recent structural revision of the kinamycins from N-cyanobenzo[b]carbazoles to diazo-substituted benzo[b]fluorenes is particularly relevant.127 The cyanoformamide 79 was obtained during bioassay-guided analysis of the marine sponge Pseudoceratina purpurea128 and Nat. Prod. Rep., 1999, 16, 597606 603

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NH2 CN N N Br O N H 74 CN MeO 75 NH2 CN HN N O HO MeO OH 76 HO 77 OH N N N O N CN OH N

Br

found to exhibit both antifouling activity (EC50 = 5.0 mg mL21 against B. amphitrite cyprids) and cytotoxicity against P388 murine leukemia cells (IC50 = 3.4 mg mL21). This bioactivity is believed to play a role in chemical defense and, in this sense, is perhaps somewhat similar to benzoyl cyanide (80) employed by millipedes (Pseudopolydesmus serratus, Apheloria corrugata and A. trimaculata) as a source of HCN.129
O R1 H R2 O N H H O N CN

H 78a R1 = R2 = H 78b R1 = H, R2 = OMe or R1 = OMe, R2 = H Br NH3 Br O N H CN 80 O CN

O 79

This survey of nitrile-containing natural products serves to underscore the vast structural diversity of these metabolites. The number of bioactive nitriles continues to increase as does the structural diversity of these metabolites. One pattern that emerges from this survey is that the medicinally active natural products tend to be those containing one or more ring systems and an a,b-unsaturated nitrile group. Marine sources have been a particularly rich source of medicinally active nitriles and the indications are that this trend will continue into the future. 6 References
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