Determinación de las condiciones de reacción

Yang, C.G. et al., Curr. Org. Chem., 2004, 8, 1691
1720 (rev, bisindole alkaloids from sponges) Kam, T.-S. et al., Alkaloids, 2006, 63, 181
337 (rev)

S

IMPLE TRYPTAMINE ALKALOIDS

(VX4040)

Tryptamine itself and some simple relatives have been isolated from marine tissues, and Bufotenine, long known as an amphibian product, has more recently been detected in a gorgonian. More highly elaborated marine alkaloids containing a (dehydro)tryptamine residue include the Kottamides. There are also some simple tryptamine dimers and oligomers such as the Gelliusines.

Somei, M. et al., Nat. Prod. Rep., 2004, 21, 278
311 (rev)

Kawasaki, T. et al., Nat. Prod. Rep., 2005, 22, 761
793 (rev)

Kam, T.-S. et al., Alkaloids, 2006, 63, 181
337 (rev)

C

YCLOTRYPTAMINE ALKALOIDS

(VX4100)

This group is formally derived from tryptophan by cyclisation and decarboxylation. (The presence of the cyclised form, cyclotryptophan, can be demonstrated in tryptophan solutions). Physostigmine, the prototype of this group of alkaloids, was first isolated from Physostigma venenosum and has also been produced by Streptomyces spp. The alkaloid is characterised by a urethane group which is readily hydrolysed with aqueous base to afford Eseroline. In addition to plant alkaloids with this skeleton, other representatives of this class have been isolated from marine organisms (e.g. the Flustramines) and from skin extracts of the Australian frog Pseudophryne coriacea (e.g.

Pseudophrynamine A, where there is evidence for de novo biosynthesis by the amphibian rather than a dietary source). A number of interesting oligomers of this class occur in plants, e.g. Chimonanthine, a dimer, Hodgkinsine (a trimeric species), the Quadrigemines (tetramers) and higher.

N N

HMe Me MeNHCOO

Physostigmine

Anthoni, U. et al., Alkaloids Chem. Biol. Perspect., 1999, 13, 163
236 (rev) Kam, T.-S. et al., Alkaloids, 2006, 63, 181
337 (rev)

C

HAETOCIN ALKALOIDS

(VX4110)

Also called Epipolythiodioxopiperazines, although some members of the series lack the polysulfur bridge. These are microbial products, but a considerable number, including the extensive series of Leptosins, have been isolated from marine sources. The prototype is Echinulin, from Aspergillus echinulatus. They are biosynthesised from diketopiperazines, which are cyclic amino acid anhydrides.

NH N NMe HN N

NMe

O O H

H

O

O S S

S S

Chaetocin HO

OH

Williams, R.M. et al., Top. Curr. Chem., 2000, 209, 97
173 (prenylated tryptophans, biosynth) Somei, M. et al., Nat. Prod. Rep., 2004, 21, 278
311(rev)

Gardiner, D.M. et al., Microbiology (Reading, U.K.), 2005, 151, 1021
1032 (biosynth) Kawasaki, T. et al., Nat. Prod. Rep., 2005, 22, 761
793 (rev)

E

UODIA (QUINAZOLINOCARBAZOLE) ALKALOIDS

(VX4120)

These alkaloids are characteristic of the Rutaceae. The most studied is Rutaecarpine, which has useful hypotensive activity. They arise by incorporation of a C

1

unit into a b-carboline precursor.

NH N N

O

Rutaecarpine

Bergmann, J., Alkaloids, 1983, 21, 29
55 (rev)

I

NDOLACTAM ALKALOIDS

(VX4200)

The indolactam group contains an unusual nine-membered lactam ring derived from tryptophan and valine, via N-Methyl-

L

-isoleucyl-

L

-tryptophanol. The grouping occurs in the tumour-promoting Teleocidins and Lyngbyatoxins, which are microbial products. These contain a monoterpenoid portion which is derived from glucose, not mevalonate.

NH HN N

O

Me OH

Lyngbyatoxin A

Irie, K et al., Tet. Lett., 1990, 31, 7337
7340; 1998, 39, 7929
7930 (biosynth)

b-C

ARBOLINE ALKALOIDS

(VX4240)

A large number of relatively simple carboline (pyrido[3,4-b]indole) derivatives occur naturally. These include b-carbolines unsubstituted at C-1, e.g. 1,2,3,4-Tetrahydro-6-methoxy-2-methyl-b-carboline, those containing a methyl group at C-1, i.e. the Harman group, and several which contain a substituent at C-1 and/or C-3. The substituents at position 1 may be acyl, carboxyl, or they may be more complex, as in Perlolyrine

NH N

Harman

Long known as terrestrial alkaloids, these are also widespread in marine organisms. b-Carboline (Norharman) itself has been found in an ascidian and in dinoflagellates, and examples of simple brominated analogues include the Eudistomins and some of the Arborescidines. Another group of b-carboline derivatives, presumably derived from tryptophan and cysteine, have been isolated from Eudistoma olivaceum, a Caribbean tunicate. The b-Carboline nucleus is also found in some of the Manzamines and other more complex alkaloids.

Husson, H.-P., Alkaloids, 1985, 26, 1
51 (rev)

Baker, B.J. et al., Alkaloids Chem. Biol. Perspect., 1997, 10, 357
407 (rev, marine b-carbolines) Somei, M. et al., Nat. Prod. Rep., 2004, 21, 278
311 (rev)

Fresneda, P.M. et al., Synlett, 2004, 1
17 (rev, synth) Kawasaki, T. et al., Nat. Prod. Rep., 2005, 22, 761
793 (rev)

C

ARBAZOLE ALKALOIDS

(VX4300)

Nearly all carbazole alkaloids have a substituent at C-3, although Carbazole itself and one or two simple marine halogenated derivatives have also been characterised. The main source of carbazole alkaloids are the plants of the Rutaceae subfamily Aurantioideae, especially the genera Clausenia, Murraya and Glycosmis. They are also found in some other higher plants, as well as streptomycetes and cyanobacteria. 3-Methylcarbazole appears to be the key biosynthetic intermediate, although there is little direct experimental evidence. Elaboration into prenylcarbazoles (e.g. Ekeberginine) and dimerisation occurs. They have been well-reviewed.

NH

OMe CHO

Ekeberginine

Husson, H.-P., Alkaloids, 1985, 26, 1
51 (rev)

Chakraborty, D.P., Alkaloids, 1993, 44, 257
364 (rev) Kno¨lker, H.-J. et al., Chem. Rev., 2002, 102, 4303
4428 (rev) Kno¨lker, H.-J., Curr. Org. Synth., 2004, 1, 309
331 (rev, synth) Somei, M. et al., Nat. Prod. Rep., 2004, 21, 278
311 (rev) Kawasaki, T. et al., Nat. Prod. Rep., 2005, 22, 761
793 (rev)

Kno¨lker, H.-J. et al.,, Alkaloids, 2008, 65, 3
158; 159
180; 189
194; 195
384 (occurrence, biosynth, biochem, chemistry)

I

NDOLO[2,3-A]CARBAZOLE ALKALOIDS

(VX4350)

These are a class of alkaloids exemplified by Staurosporine, which was first isolated in 1977 from a terrestrial microorganism, and which has since been found to be widely distributed. They are essentially microbial metabolites from a variety of organisms (field-collected or cultured), and show a wide range of biological activities. Others are the Tjipanazoles (from the blue-green alga Tolypothrix tjipanasensis) and several metabolites from slime moulds of the genus Arcyria (e.g. the Arcyriarubins and Arcyriaflavins). The isolation of 4?-N,O-Didemethylstaurosporine from a flatworm Pseudoceros sp. is noteworthy. Their biosynthesis has been intensively studied; they are produced from bisindolyl precursors resembling Violacein; the indolyl residues are derived from tryptophan via 7-chlorotryptophan followed by an oxidative ring closure.

HN

N N

O

NHMe MeO

O

Staurosporine

Gribble, G.W. et al., Studies in Natural Product Chemistry, (ed. Atta-ur-Rahman), Elsevier, 1993, 12, 365 (rev) Walsh, C.T. et al., Nat. Prod. Rep., 2006, 23, 517
531 (rev, biosynth)

Sanchez, C. et al., Nat. Prod. Rep., 2006, 23, 1007
1045 (rev, biosynth)

I

NDOLONAPHTHYRIDINE ALKALOIDS

(VX4400)

These are the canthinones, a numerous and relatively straightforward subgroup of the b-carbolines, e.g. Canthin-6-one, in which an additional C

3

unit is attached between C-1 and the indole nitrogen to form an additional ring.

The C-3 unit appears to be derived from ketoglutarate. The group includes a few dimeric examples, e.g.

Haplophytine. They occur especially in the Simaroubaceae and Rutaceae, and some representatives have been

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