npr2005-22-196

REVIEW

NPR

Zhong Jin* Institute and State Key Laboratory of Elemento-organic Chemistry, Nankai University, Tianjin, 300071, P. R. China. E-mail: jinzhong2000@eyou.com

www.rsc.org/npr

Muscarine, imidazole, oxazole and thiazole alkaloids

Received (in Cambridge, UK) 6th January 2005 First published as an Advance Article on the web 4th March 2005

Covering: January 2003 to June 2004. Previous review: Nat. Prod. Rep. 2003, 20, 584 Novel and structurally diverse natural products containing imidazole-, oxazole-, or thiazole-unit(s) display a wide variety of biological activities. The isolation, biological activity and total synthesis of naturally occurring muscarine, imidazole, oxazole and thiazole alkaloids have been reviewed. The literature covers from January 2003 to June 2004, and 168 references are cited.

1 2 3 3.1 3.2 3.3 3.4 3.5 4 4.1 4.2 4.3 4.4 4.5 4.6 5 5.1 5.2 5.3 5.4 5.5 5.6 6

Introduction Muscarine alkaloids Imidazole alkaloids Alkaloids from marine sponges Alkaloids from other marine origins Imidazolyl cyclic peptides Alkaloids from plants Alkaloids from microorganisms Oxazole and isoxazole alkaloids Macrolides Bisoxazole alkaloids Terpenes Oxazolyl cyclic peptides Miscellaneous Isoxazole alkaloids Thiazole alkaloids Epothilones Thiopeptides Other thiazolyl alkaloids from microorganisms Thiazolyl cyclic peptides Alkaloids from marine sponges Miscellaneous References

DOI: 10.1039/b316104h

Born in Nanjin, P. R. China in 1973, Zhong Jin started to study chemistry at Nankai University in 1991. After obtaining his B. Sc., M. Sc. and Ph. D. degrees in organic chemistry from Nankai University, he joined the faculty of Nankai University in 2002.

His research interests focus on the discovery of novel natural and unnatural biological molecules, the development of new selective and efficient synthetic methods, and the total syntheses of natural products, especially alkaloids.

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1

Introduction

Over the past two decades, natural products have demonstrated, in a clear manner, their prominent importance and potential in pharmaceutical development. Although natural products are diversely distributed, the best known sources of natural products are plants, fungi, bacteria, marine animals, and microorganisms.

More recently, mammals, vertebrates, parasitic organisms, and insects have served as sources of new natural products, and their characterization has substantially expanded the rich chemical diversity of established natural product structures. Amongst them, novel and structurally diverse natural products containing imidazole-, oxazole-, or thiazole-unit(s) have displayed a wide variety of biological activities. In addition, the complicated structures and biological importance of these secondary metabolites has provided a challenge to modern synthetic methodology.

2

Muscarine alkaloids

Muscarine alkaloids, including (+)-(2S,3R,5S)-muscarine 1, (−)-(2S,3R,5R)-allo-muscarine 2, (+)-(2S,3S,5S)-epi-muscarine 3, and (+)-(2S,3S,5R)-epiallo-muscarine 4, have been isolated from many species of the genus Amanita mushroom, such as A. muscaria, A. phalloides, along with many Inocybes and Clitocybes species. Their biological effect resembles the action of acetylcholine upon smooth muscle and they interact directly with cholinergic receptors in the peripheral nervous system.

With many subtypes of muscarinic receptor subsequently identified, the acetylcholine agonistic activity of these alkaloids has potential applications in a variety of medicinal therapies, notably neurodegenerative conditions such as Parkinson’s and Alzheimer’s diseases. These potent biological activities, together with their relatively simple but challenging structures, have resulted in a number of synthetic methodologies or strategies.

Employing a 5-endo-trig cyclization strategy of substituted (Z)-homoallyl alcohols, two contrasting asymmetric approaches to muscarine alkaloids have been developed recently.1 Alkylation of the epoxybutanoate 5, readily obtained from (S)-malic acid, by lithiopropyne under Yamaguchi–Hirao conditions delivered the hydroxyheptynoate 6. Lindlar reduction proceeded smoothly to give the necessary (Z)-hydroxyalkenoate 7. The key iodocyclization step then gave the desired hydroxytetrahydrofuran 8.

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The Royal Society of Chemistry 2005

Scheme 1 Reagents and conditions: a) lithiopropyne, BF3 .OEt2 , THF, −78 ◦ C; b) H2 , 5% Pd–BaSO4 , quinoline, EtOAc; c) I2 , NaHCO3 , MeCN, 0–5 ◦ C; d) TIPSOTf, 6-lutidine, 0 ◦ C; e) KOH, MeOH–H2 O, 20 ◦ C; f) (i) (COCl)2 , DMF, pyridine, 0 ◦ C; (ii) 2-mercaptopyridine N-oxide sodium salt, DMAP, CHI3 ; g) TBAF, THF, 20 ◦ C; h) NMe3 , MeOH, 70 ◦ C.

Scheme 2 Reagents and conditions: a) LiC≡CCH2 OTBDPS, 12-crown-4, THF, −78 ◦ C to 0 ◦ C; b) H2 , 5% Pd–CaCO3 , quinoline, MeOH, 20 ◦ C; c) IBr, NaHCO3 , MeCN, −10 ◦ C; d) H2 , 10% Pd–C, Et3 N, EtOAc, 20 ◦ C; e) NH4 F, MeOH, 20 ◦ C.

Sequential protection of the hydroxyl group in 8 and saponification of resulting derivative 9 provided the corresponding carboxylic acid 10. To complete the synthesis, a Barton– Hunsdiecker reaction sequence was carried out to afford the known hydroxyl iodide 11 via the corresponding acid chloride intermediate. Finally, exposure to trimethylamine in ethanol delivered the (−)-muscarine iodide 13 (Scheme 1). In the alternative strategy, the initial O-silyl lactaldehyde 14 was prepared from methyl (S)-lactate in two efficient steps. Crucially, non-chelation controlled addition of lithiated O-TBDPS propargyl alcohol in the presence of 12-crown-4 gave the anti-adduct 15. Subsequent Lindlar reduction then gave the corresponding (Z)-alkene 16.

The desired iodotetrahydrofuran 17 was obtained by direct treatment of 16 with two equivalents of iodine monobromide in acetonitrile. Hydrogenolysis provided an excellent yield of the de-iodinated tetrahydrofuran 18, desilylation of which gave the diol 19 (Scheme 2). The latter compound was converted into (+)muscarine 1 in two straightforward steps, following a previously described route.

3 Imidazole alkaloids 3.1 Alkaloids from marine sponges The bromopyrrole-imidazole alkaloids comprise a large, structurally diverse family of marine secondary metabolites based on a common key metabolite, oroidin 20. These alkaloids, which include non-cyclized members: oroidin 20, clathramide A 21 and hymenidin 22, cyclized ones: cyclooroidin 23, hymenialdisine 24, agelastatin B 25, dibromophakellin 26, dibromoagelaspongin 27, dibromoisophakellin 28, palau’amines 29 and styloguanidines 30, and dimerized ones: mauritiamine 31, sceptrin 32, ageliferin 33 and axinellamine A 34, are extensively distributed in marine sponges, mainly the Agelasidae, Axinellidae, and Halichondridae families. Over the past decades, much attention has been paid to the biogenesis, biological profiles, and total synthesis of bromopyrrole-imidazole alkaloids because of their fascinating biological activities together with unprecedented molecular architecture. A recent comprehensive review on Nat. Prod. Rep., 2005, 22, 196–229

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the pyrrole-imidazole alkaloids describes both biomimetic and non-biomimetic total syntheses of non-cyclized, cyclized, and dimerized-alkaloids.2 A short synthesis of non-cyclized bromopyrrole-imidazole alkaloid sventrin 35, isolated from the marine sponge Agelas sventres, has been stereoselectively achieved via an alkynylimidazole intermediate.3 The pathway featured a chemo- and stereoselective reduction of a 2-azido-4-alkynylimidazole to the corresponding amino alkene using NaAlH2 (OCH2 CH2 OMe)2 (Red-Al).

During the course of studies towards the synthesis of the non-cyclized bromopyrrole-imidazole marine alkaloids midpacamide 36 and dispacamide 37, isolated from Agelas mauritiana and Agelas dispar respectively, an analogue 38 of midpacamide has been synthesized involving a Staudinger reaction of tertiary phosphines with azides.4 Novel bromopyrrole-imidazole alkaloids slagenins A–C 39– 41 with a unique tetrahydrofuro[2,3-d]imidazolidin-2-one moiety, obtained from the Okinawan sponge Agelas nakamurai, have been enantioselectively synthesized utilizing an efficient condensation of dihydrofuran-3-one 49 with urea to construct the

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slagenin bicyclic core as the key step.5 The preparation of 49 from L-xylose 42 is outlined in Scheme 3. Ketalization of L-xylose 42 followed by selective hydrolysis afforded 1,2-O-isopropylidenea-L-xylofuranose 43. Selective protection of the 5-OH with BzCl gave compound 44. The 3-hydroxy group was deoxygenated by conversion into the xanthate followed by treatment with tributyltin hydride and AIBN to give compound 45. Removal of the benzyl protecting group afforded primary alcohol 46 and treatment with TsCl and pyridine gave the corresponding tosylate, which was transformed into azide 47. Methanolysis with refluxing 1% I2 –MeOH, followed by Dess–Martin oxidation of

the b-anomer of compound 48, afforded the key intermediate 49. Subsequently, a direct condensation between dihydrofuran-

3-one 49 and urea under acidic conditions afforded the mixture 50. Hydrogenation of the mixture in methanol and acylation with 4-bromo-2-(trichloroacetyl)pyrrole in DMF yielded only slagenin A 39.

A systematic experimental study on the chiroptical properties of bicyclic bromopyrrolopyrazinones, which always occur as the core in a variety of cyclized marine bromopyrrole-imidazole alkaloids, has been conducted. On the basis of a chiral-pool synthesis of conformationally fixed dipyrrolopyrazinones, the CD spectrum of (−)-dibromophakellin 26 as well as the influence of bromination of the pyrrole ring has become predictable.6 The tumor and GSK-3b inhibiting alkaloid, (–)-agelastatin A 51, from a collection of the axinellid sponge Agelas dendromorpha, has been enantiospecifically synthesized from the aziridine 52.7 The synthetic sequence included a highly regioselective trans-diaxial ring-opening of aziridine 52 with azide ion to install the vicinal diamido functionality present within 66 and a Grubbs–Hoveyda ring-closing metathesis (RCM) reaction to construct the cyclopentene core of 66 (Scheme 4).

The first enantioselective total synthesis of cyclized alkaloids (+)-phakellstatin and (+)-dibromophakellstatin 67,

Scheme 3 Reagents and conditions: a) CuSO4 , H2 SO4 , acetone, rt, then HCl, rt; b) BzCl, py; c) NaH, CS2 , rt then MeI, THF, rt, then Bu3 SnH, AIBN, reflux; d) NaOMe, MeOH; e) TsCl, py, CHCl3 , then NaN3 , DMF; f) 1% I2 –MeOH, reflux; g) Dess–Martin oxidation; h) 0.1 M HCl, THF, reflux, then urea, rt; i) H2 , Pd/C, methanol, then 4-bromo-2-(trichloroacetyl)pyrrole, DMF, rt.

Scheme 4 Reagents and conditions: a) MeO2 CCl, py, 0 ◦ C to rt; b) NaN3 , DMF, 140 ◦ C; c) H2 , Pd(OH)2 , MeOH; d) SESCl, AgCN, benzene, 75 ◦ C; e) AcCl, MeOH, 0 ◦ C to rt; f) TsCl, Et3 N, DMAP, 0 ◦ C to rt; g) Et3 SiCl, DMAP, py; h) NaI, acetone, heat; i) Zn, THF; j) 1-phenyltetrazolyl methyl sulfone, KN(SiMe3 )2 , THF, toluene; k) Hoveyda–Grubbs catalyst, heat; l) K2 CO3 , MeOH, heat; m) (Boc)2 O, DMAP; n) 5-trimethylsilylpyrrole-2-carbonyl chloride, DMAP, Et3 N, rt.

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Scheme 5 Reagents and conditions: a) Ref. b) KHMDS, THF, −78 ◦ C; PhSeBr; DMDO, −78 ◦ C to 0 ◦ C; SeO2 , dioxane reflux; c) NaBH4 , MeOH, −40 ◦ C; KOBut , But OH; d) Ac2 O, py; e) H2 , 10%, Pd/C, EtOAc; f) (COCl)2 , DMF; CbzNHOH, DMAP; g) NH3 , MeOH; h) DIAD, PPh3 , THF, reflux, NH3 , MeOH; i) TiCl3 , KOAc, THF, H2 O; j) PhI(OCOCF3 )2 , py, MeCN; k) H2 , 10% Pd/C, MeOH; l) NBS, THF.

isolated from the Indian Ocean sponge Phakellia mauritiana, has been achieved from C 2 -symmetric diketopiperazine 68.8 The synthetic strategy featured a diastereoselective acylation, an intramolecular Mitsunobu reaction to introduce the C6 aminal, and a tandem Hoffmann rearrangement/cyclization to simultaneously introduce the C10 quaternary aminal center and deliver the cyclic urea (Scheme 5).

Both the palau’amines 29 and the regioisomeric styloguanidines 30 belong to the guanidine-containing derivatives of cyclized marine bromopyrrole-imidazole alkaloids. A stereoselective strategy to the deschloro cyclopentyl core 80 of the palau’amines and styloguanidines has been developed by an intramolecular Pauson–Khand cyclization reaction of an enyne with a transient N-O linkage.9 A concise and efficient synthesis of the protein kinase inhibitor debromohymenialdisine 81 has been described, which allowed multi-gram preparation of the desired compound.10 The preparation of other cyclized bromopyrrole-imidazole alkaloids such as hymenialdisine 24 and 3-bromohymenialdisine 82 could also be envisaged using this synthetic strategy.

In the course of the continuing search for drug leads from marine invertebrates, the organic extract of the marine sponge Stylissa aff. Massa, collected in the Gulf of Sagami, was found to show Candida GGTase I inhibitory activity with an IC50 value of 3.9 lM. Bioassay-guided fractionation afforded a novel dimerized bromopyrrole-imidazole alkaloid, named massadine 83.11 Despite its potent activity as an antiviral, antimuscarinic, antibacterial, and antihistaminic agent, sceptrin 32 has remained an unanswered synthetic challenge since its isolation from Agelas sceptrum and characterization in 1981. Recently sceptrin 32 has been synthesised by a concise sequence that proceeds in approximately 24% overall yield, can be conducted on a preparative scale, and does not necessitate chromatography.12 Noteworthy features of this total synthesis included: (a) the first application of an oxaquadricyclane rearrangement in natural product synthesis; (b) a new chemo- and regioselective halogenation method; and (c) a mild 2-aminoimidazole forming reaction (Scheme 6). Ageliferin 33, isolated from Agelas conifera in 1986, was derived from sceptrin 32 under thermal conditions.13 Hence, an alternative biogenetic hypothesis (Scheme 7) has been presented commencing from sceptrin 32 rather than hymenidin 22 for other complex dimeric bromopyrrole-imidazole alkaloids, including the axinellamines 34 and palau’amines.

Calcarea class sponges of the genera Leucetta and Clathrina are well-known to be rich in 2-aminoimidazole alkaloids. To 200

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date, five structural frameworks of 2-aminoimidazole alkaloids have been established from the two genera. The lead alkaloids in each category are: (a) dorimidazole A 91 and preclathridine A 92, (b) naamine A 93, (c) isonaamine A 94, (d) leucettamine C 95, and (e) 2-amino-2-deoxykealiiquinone 96.

Chemical investigation of the sponge Leucetta chagosensis collected in Indonesia yielded five new 2-aminoimidazole alkaloids: naamine F 97, naamine G 98, kealiinine A 99, kealiinine B 100, and kealiinine C 101, together with the known compound naamine A 93.14 Amongst them, naamine G 98 exhibited strong antifungal activity against the phytopathogenic fungus Cladosporium herbarum and also showed mild cytotoxicity against mouse lymphoma (L5178Y) and human cervix carcinoma (HeLa) cell lines. The structures of the new compounds were unambiguously characterized by 1D and 2D NMR and MS data.

From the MeOH extract of the calcareous sponge Leucetta sp. collected at Vitu Levu, Fiji, three novel 2-aminoimidazole alkaloids, named calcaridine A 104, spirocalcaridine A 105, and spirocalcaridine B 106, were obtained.15 They represent two

Scheme 6 Reagents and conditions: a) H2 SO4 , MeOH; b) MeOH, CH(OMe)3 , TsOH; DIBAL-H; AcOH, H2 O c) MsCl, py; NaN3 ; d) MeOH, CH(OMe)3 , TsOH; H2 /Lindlar catalyst; 4-bromo-2-trichloroacetylpyrrole; e) PhCH2 NMe3 ICl2 ; H2 O; f) (OHC)2 NNa; g) HCl, MeOH; NH2 CN, H2 O.

unprecedented skeletons and are the first chiral aminoimidazoles isolated from the calcareous sponges (other than compounds that derive their chirality through complexation to Zn2+ ).

Nine different Indo-Pacific collections of calcareous Leucetta sp. sponges have been investigated for variation in their alkaloid

constituents.16 A Fijian collection of the sponge Leucetta avocado afforded three 2-aminoimidazole alkaloids consisting of the known alkaloid naamine A 93 and two new structures Nat. Prod. Rep., 2005, 22, 196–229

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Scheme 7

Possible biosynthetic relationships among the bromopyrrole-imidazole alkaloids.

N,N-dimethyl naamine D 107 and leucettamine C 95. Among the nine Leucetta species investigated, six specimens contained a polyunsaturated fatty amino alcohol, leucettamol A 108, while the other three contained imidazole alkaloid, dorimidazole A 91, and these two alkaloids did not occur in the same sponge sample.

Using 1-methyl-3-trimethylsilylparabanic acid 119 as a key reagent, an efficient total synthesis of 2-aminoimidazole alkaloids, isonaamidine A 109, isonaamidine C 110 and isonaamine A 94 has been accomplished (Scheme 8).17 Lithiation of the sulfide 111 with n-BuLi followed by addition of p-anisaldehyde gave the alcohol 112, the hydroxyl group of which was removed by reduction with triethylsilane in the presence of trifluoroacetic acid (TFA) to give the benzylimidazole 113. The sulfide was desulfurized with a combination of NaBH4 and NiCl2 to give 114, which was alkylated to deliver the corresponding imidazolium salt 115. Hydrolysis of the resulting quaternary salt gave 1,4-di-(4-methoxybenzyl)imidazole 116. Bromination with NBS gave the 2-bromimidazole 117, lithiation of which with tert-BuLi followed by treatment with trisyl azide and then by hydrogenation over Pd/C afforded the key precursor, 2amino-1,4-bis(4-methoxybenzyl)imidazole 118. Demethylation of 118 with boron tribromide gave isomaamine A 94. Finally, isonaamidine A 109 and isonaamidine C 110 respectively were obtained by refluxing solutions of 94 and 118 in CHCl3 with 1-methyl-3-trimethylsilylparabanic acid 119 followed by desilylation.

On the basis of a combination of HRMS, high-field (500 MHz, HMBC, and GOESY experiments) 15 N, 1 H, and 13 C NMR, and X-ray crystal structure analyses, a new imidazole alkaloid, isolated from the marine sponge Cribrochalina sp. collected from the Republic of Maldives, has been designated as cribrostatin 6 120. It exhibited dark blue cancer cell growth inhibitory activity (P388 ED50 0.3 lg mL−1 ).18 202

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Fractionation of the EtOH extract of the marine sponge Cribrochalina olemda has afforded three new cyclic peptide compounds, named kapakahines E–G 121–123.19 Their structures have been elucidated by NMR techniques accompanying FAB-MS/MS analyses. Kapakahine E 121 showed cytotoxicity against P388 murine leukemia cells with an IC50 value of 5.0 lg mL−1 .

Eleven manzamine type alkaloids, two b-carbolines, and five nucleosides have been isolated from an Indonesian sponge.

Among them, an imidazole-containing manzamine-type alkaloid, assigned as des-N-methylxestomanzamine A 124, was characterized on the basis of NMR and X-ray analysis data.20 In a continuing search for naturally occurring antimitotic agents, two novel antimitotic heterocyclic alkaloids, ceratamines A 125 and B 126, have been isolated from the marine sponge Pseudoceratina sp., collected in Papua New Guinea.21 A bioassay-guided fractionation led to isolation of two new aaptamine class alkaloids 127 and 128 from an Indonesian marine sponge of the genus Xestospongia.22 Two new asmarine alkaloids, asmarines G 130 and H 131 have been isolated from the Kenyan sponge Raspailia sp. along with two known asmarines, A 129 and F 132, and four known diterpenes.23 The 15 N chemical shifts of the heterocycles of the asmarines have been measured from 15 N HMBC experiments, and the influence of various structural features on the d N values has also been studied.

3.2

Alkaloids from other marine origins

The alkaloids such as aplysinopsin 133, N 3 -methylaplysinopsin 134, 6-bromoaplysinopsin 135 and 3 -deimino-3oxoaplysinopsin 136, isolated from the scleractinian corals of the family Dendrophylliidae and also found in the dictyoceratid and astrophorid sponges, belong to a class of the indole-imidazole alkaloids. From a stony coral, Tubastraea sp., collected in the Odomari area, Kagoshima Prefecture, three novel dimeric aplysinopsin type alkaloids, named tubastrindoles A–C 137– 139, have been isolated.24 Two further dimeric aplysinopsin type alkaloids, cycloaplysinopsin A 140 and cycloaplysinopsin B 141, which are epimeric to the tubastrindoles at one of the spiro centers, have been obtained from an unidentified dendrophylliid coral from the Comora islands and also from a Tubastraea sp. from the Philippines.25 Both alkaloids were isolated as a mixture of enantiomers in a ca. 65 : 35 ratio. Biogenetic involvement of

Scheme 8 Reagents and conditions: a) n-BuLi, p-anisaldehyde, THF; b) Et3 SiH, TFA; c) NaBH4 , NiCl2 .6H2 O, THF, MeOH; d) 4-MeOC6 H4 CH2 Br, AcOEt; e) aq. HCl; f) NBS, THF; g) tert-BuLi, THF; trisyl azide; H2 , 10% Pd/C, EtOH; h) 119, CHCl3 ; CsF, THF; i) BBr3 .

an enantiodefective Diels–Alderase-catalyzed reaction of two molecules of aplysinopsin 133 has been postulated.

Bioassay-guided isolation from the soft coral Bellonella albiflora from southern Japan has yielded a new cytotoxic diterpene, (Z)-sarcodictyin A 142 along with five known compounds, sarcodictyins A 143 and B 144, eleutherobin 145, (Z)-eleutherobin 146, and eleutherobin aglycon 147.26 Two approaches toward construction of the central ring system of eleutherobin 145 have been reported and both used a ring-closing metathesis (RCM) as the key step.27–29 Granulatimide 148, isogranulatimide 149, and isogranulatimides A–C 150–152 are natural indole-imidazole alkaloids isolated from the ascidian Didemnum granulatum. Their biological activity is related to their capacity to inhibit the G2 checkpoint, which represents a promising target for the development of new chemotherapeutic anticancer agents. Several granulatimide and isogranulatimide analogues, possessing a pyrrole, maleimide, or azaindole moiety instead of imidazole heterocycle and indole moiety, have been synthesized in the search for novel antitumor compounds.30–32 First isolated from the red ascidian Botryllus leachi, imidazole alkaloid 153 has been synthesized by a straightforward route.33 The analysis of spectroscopic data of 153 was discussed and compared with the original literature.

Chartellines A–C 154–156, isolated from the marine bryozoan, Chartella papyracea, belong to a class of imidazole alkaloids containing a 10-membered ring fused with b-lactam, indoline and imidazole rings. Due to their unusual chemical architecture, few synthetic studies have been reported. The synthesis of a model compound containing an indole spiro-blactam moiety bearing a vinyl chloride group as found in the chartellines has been described.34 The marine cyanobacterial toxin cylindrospermopsin 157 and its congener 7-epicylindrospermopsin 158 have been isolated as the principal hepatotoxins from Cylindrospermopsis raciborskii and Aphazinomenon ovalisporum. These highly polar compounds have posed a significant synthetic challenge as they contain almost as many heteroatoms as carbon atoms, and their structures include a zwitterionic guani-

dinium sulfate, a rare tetrasubstituted tricyclic guanidine, and a uracil moiety. Recently, an asymmetric total synthesis of 7-epicyclindrospermopsin 158 has been reported in eighteen steps.35 3.3

Imidazolyl cyclic peptides

During the continuing search for potent inhibitors of tubulin polymerization, a series of novel antimitotic bicyclic peptides, designated as celogentins D–H 159–163 and J 164, and a monocyclic peptide, celogentin K 165, has been isolated from the seeds of Celosia argentea (Amaranthaceae).36,37 Their structures including absolute stereochemistry were elucidated by extensive use of NMR and chemical means. A structure–activity relationship study indicated that the ring size of the bicyclic ring system including the unusual crosslinked Leu, Trp, and His residues would be important for their tubulin polymerization inhibitory activity. The stereostructure of a known closely related bicyclic peptide, moroidin 166, has been established by single crystal X-ray diffraction analysis.37 The right-hand Trp-His-Gly-Arg derived macrocycle 167 of moroidin 166 containing the unusual tryptophan C-2 histidine N-1 link has been synthesized in protected form.38 The synthetic sequence featured displacement of the chlorine of a 2-chloroindole with a histidine derived nucleophile, a Horner–Wadsworth–Emmons reaction followed by asymmetric hydrogenation to establish the tryptophan side chain, and incorporation of the Gly-Arg dipeptide by peptide coupling.

In the course of a screening program for potent antifungal substances, a novel cyclic tetrapeptide antibiotic named glomecidin 168 was isolated from the fermentation broth of Streptomyces sp. H698 SY2.39 The structure of 168 was deduced on the basis of 1D, 2D NMR experiments in CD3 OD. 3.4

Alkaloids from plants

From a root lipidic extract of Lepidium meyenii Walp (with the common name Maca) of the Solanaceae family from the Andean Mountains in Peru, two new imidazole alkaloids, assigned as lepidiline A 169 and lepidiline B 170, have been Nat. Prod. Rep., 2005, 22, 196–229

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identiďŹ ed as 1,3-dibenzyl-4,5-dimethylimidazolium chloride and 1,3-dibenzyl-2,4,5-trimethylimidazolium chloride, respectively.

The structures of these two new alkaloids were established by spectroscopic methods, as well as single crystal X-ray diffraction performed on lepidiline A 169.40,41 Jaborandi leaves (the Pilocarpus genus) are the only known source of pilocarpine 171, an imidazole alkaloid probably derived from histidine, which was employed for the treatment of glaucoma in reducing intraocular pressure and also used as a 204

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salivation and perspiration stimulant for the treatment of xerostomia. In order to study the induction of alkaloid pilocarpine

in the jaborandi leaves, jaborandi seedlings were subjected to different treatments. Salicylic acid and methyl jasmonate were found to induce a 4-fold increase in pilocarpine concentration, but this increase was dependent on the concentration and time after exposure as well as extraction methods.42 3.5

Alkaloids from microorganisms

From the strain Penicillium aureovirens VKM FW-766 from various permafrost regions of the Russian Federation, a new alkaloid 173, an N 16 -ethoxycarbonyl derivative of the known compound 3,12-dihydroroquefortin 172, has been isolated.43 The structure of the new alkaloid has been determined on the basis of MS, 1D and 2D NMR spectroscopy.

Cytotoxic alkaloids of the fumiquinazoline family such as fumiquinazolines A–C 174–176, E–I 177–181, and fiscalins A– C 182–184 have been isolated from different fungi including a strain of the fungus Aspergillus fumigatus, the fungus Acremonium sp. from the surface of the Caribbean tunicate Ecteinascidia

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of Troc-protected tryptophan methyl ester 185 with N-Cbz-Lalanine nitrophenyl ester in the presence of KF, 18-crown-6, and (i-Pr)2 NEt afforded N-acylindole 186. 2-Mercuration of 186 followed by work-up with iodine provided iodoindole 187, which was subjected to the Buchwald palladium-catalyzed condensation to give the desired imidazoindolone 188. Cyclization to the spiro ring system 189 was effected by oxidation of the indole double bond, followed by NaBH4 reduction and SiO2 catalyzed lactonisation. Deprotection of the Troc group of 189 with Zn in AcOH provided the free amine, which was coupled with anthranilic acid using 1-(3-dimethylaminopropyl)-3ethylcarbodiimide hydrochloride (EDAC). Further coupling of the aniline group with Fmoc-L-NHCH(CH2 SePh)CO2 H, again using EDAC, afforded diamide 190. Dehydrative cyclization of 190 with Ph3 P, Br2 and (i-Pr)2 NEt provided iminobenzoxazine 191. Treatment of 191 with excess piperidine in EtOAc cleaved the Fmoc group and opened the iminobenzoxazine to give amidine 192, which still contained the phenylselenyl group.

Prolonged refluxing 192 in acetonitrile containing excess acetic acid gave Cbz-fumiquinazoline C 193, which was deprotected with Pd/C and H2 to afford the (−)-fumiquinazoline C 176 (Scheme 9). Other alkaloids of this family were synthesized in a similar manner.

4 4.1

turbinate, and the broth extracts of the fungus Neosartorya fischeri. The first total synthesis of (−)-fumiquinazolines A 174, B 175, C 176, E 177, H 180, and I 181, has been described in a fully asymmetric fashion from protected tryptophan, anthranilic acid, leucine, and alanine in excellent overall yield.44 Amidation 206

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Oxazole and isoxazole alkaloids Macrolides

During the past two decades, myxobacteria have proven to be a rich source of structurally diverse secondary metabolites with significantly biological activities. In a screening of Sorangium cellulosum strains for new secondary metabolites, six novel compounds named leupyrrins A1 194, A2 195, B1 196, B2 197, C 198, and D 199 have been isolated as major metabolites from the strains So ce705 and So ce690.45 Among them, leupyrrin A1 194 showed good biological activity against the fungus Rhodotorula glutinis (MIC50 0.25 lg mL−1 ) and eukaryotic cells (IC50 1.0 lg mL−1 for mouse fibroblast cells L929).

Ulapualide A 200, as well as mycalolide A 201, kabiramide C 202, halichondramide 203, and jaspisamide A 204, are macrocyclic lactones belonging to a unique family of trisoxazole containing marine metabolites. On the basis of Xray crystallography analysis of ulapualide A 200 in a complex

Scheme 9 Reagents and conditions: a) Cbz-L-AlaOpNP, KF, 18-crown-6, iPr2 Net, MeCN; b) Hg(OTFA)2 , KI; I2 ; c) Pd2 (dba)3 , P(o-Tol)3 , K2 CO3 , toluene, reflux; d) 7b-butyl-7bH-oxazirino[2,3-b][1,2]benzoisothiazole 3,3-dioxide; NaBH4 , AcOH; SiO2 , CH2 Cl2 ; Zn, AcOH; anthranilic acid, EDAC, MeCN; e) Fmoc-L-NHCH(CH2 SePh)CO2 H, EDAC, MeCN; f) PPh3 , Br2 , iPr2 NEt; g) piperidine, EtOAc, rt; h) MeCN, AcOH, reflux; Pd/C, H2 .

with G-actin, its absolute stereochemistry has been definitely established as 3S,9S,22S,23R,24S,26S,27S,31R,32R,33R.46 Callipeltosides A–C, 14-membered macrolides containing a six-membered hemiacetal ring, have previously been isolated

from extracts of the shallow water lithistid sponge Callipelta sp. and represent a class of novel cytotoxic glycoside macrolides.

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207

Recently, a fully stereoselective total synthesis of (–)-callipeltoside A 205 has been achieved in 23 steps with an overall yield of 4.8%. The synthetic strategy highlighted a novel asymmetric vinylogous aldol reaction to install the C13 stereocenter and (E)-trisubstituted alkene, an anti-selective aldol addition, a Sonogashira coupling, and a Schmidt-type glycosylation to attach the sugar unit.47 Utilizing a highly diastereoselective formal [4 + 2] annulation and a Cr(VI)-catalyzed oxidative C–C bond cleavage as key steps, methyl L-callipeltoside 206, the sixmembered sugar unit of callipeltoside A has been synthesized in eight steps.48

Phorboxazole A 207 as well as its C13-epi congener phorboxazole B 208 is a unique tetrahydropyran-oxazole-based sixring 21-membered macrolide structure isolated from the Indian Ocean sponge Phorbas sp. The unprecedented structural features and remarkable antitumor activity against the 60 tumor cell lines of the U. S. National Cancer Institute (NCI) with a mean GI50 208

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value of < 1.6 × 10−9 M have made them attractive synthetic targets.49 Recently, two formal total syntheses of phorboxazole A 207 have been reported. After successful synthesis of four nonracemic components C3–C19, C20–C26, C28–C41 and C42–C46, of phorboxazole A, the convergent assembly of the target macrolide has been achieved (Scheme 10).50 The strategy featured the union of components C20–C27 221 and C28–C41 220 by a Horner–Wadsworth–Emmons reaction, incorporation of the intact bispyran component C3–C19 225 utilizing a Wittig reaction to construct the (E)-C19–C20 alkene, a Julia olefination for attachment of the labile C42–C46 segment, and finally, a late-stage macrocyclization by a Horner–Wadsworth–Emmons reaction creating the (Z)-C2–C3 enoate.

The other synthetic route was based on the assembly of three key fragments C3–C19, C20–C27, C33–C46 described previously in phorboxazole A.51,52 The C28–C46 side chain was first attached to the tetrahydropyran C20–C27 using Horner– Wadsworth–Emmons reaction, then the bispyran C3–C19 was added by a Wittig reaction, and finally the macrolide C2–C3 double bond was elaborated in a last step. In addition, during the course of studies toward the total syntheses of phorboxazoles, several elaborated segments, C3–C19 230,53 C21–C27 231,54 C28–C46 232,55 C20–C28 233,56 and C4–C32 234,57 have been accomplished.

The disorazoles such as disorazole A1 235 and disorazole D1 236 comprise a family of 29 closely related macrodiolides which were first isolated from the myxobacterium Sorangium cellulosum in 1994. In view of their interesting biological profile and challenging structural features, the protected northern moiety of 235 and 236 has been stereoselectively synthesized in a study directed towards their total synthesis.58,59 Marine organisms produce many structurally diverse secondary metabolites, which often possess unprecedented molecular architecture and various significant biological activities.

Leucascandrolide A 237 is a doubly O-bridged 18-membered macrolide which was isolated from the calcareous sponge Leucascandra caveolata Borojevic and Klautau, collected in 1989 from the east coast of New Caledonia, Coral Sea. Assays of 237 exhibited strong in vitro anticancer properties with IC50 values of 0.05 and 0.25 lg mL−1 against KB tumor and P338 murine leukemia cell lines, respectively. For extensive structure– activity investigations, an enantiocontrolled second generation synthetic route to the macrolactone of leucascandrolide A,

Scheme 10 Reagents and conditions: a) CH2 Cl2 , −78 ◦ C to rt; b) OsO4 , K3 Fe(CN)6 , K2 CO3 , DABCO; NaIO4 ; Me4 NBH(OAc)3 , HOAc–MeCN; c) 2,2-dimethoxypropane, CSA, rt; d) HF, py; e) (COCl)2 , DMSO, TEA; f) SmI2 , THF; g) TFAA, DMSO, acetylacetone, TEA; h) CSA, MeOH; i) MeI, CaSO4 , Ag2 O; j) TBAF, THF, 0 ◦ C; Dess–Martin periodinane, py; k) NaH, THF; NaBH4 , CeCl3 , MeOH; l) Tf2 O, py; m) DDQ, rt; Dess–Martin periodinane, py. rt; n) 225, PBu3 , rt, then 224, DBU, THF, −78 ◦ C; o) DIBAL-H; Dess–Martin periodinane, py; p) 5-bromo-2R-methoxypent-4-enyl 2-benzothiazolyl sulfone, NaHMDS, THF; DCM–MeOH–HOAc; dimethylphosphonoacetic acid, DCC, DCM; q) CSA, MeOH; Dess–Martin periodinane, DCM; r) K2 CO3 , 18-crown-6, toluene; TBAF, THF; 6% HCl, THF.

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209

the C3–C7 tetrahydropyran ring, a 1,5-anti aldol coupling to set up the correct configuration of the C11 hydroxy center, and two sequential Mitsunobu reactions to close the 18membered macrolactone and append the oxazole-containing side chain respectively.62,63 Another convergent synthetic strategy for leucascandrolide A has been described based on a diastereoselective addition of a zinc alkynylide to (R)-isopropylidene glyceraldehydes, an enantioselective copper(I) fluoride catalyzed aldol addition of a TMS-dienolate to crotonaldehyde, and the formation of a 2,6-trans-substituted tetrahydropyran by selenium-mediated intramolecular cyclization.64 In addition, using a formal [4 + 2] annulation of a chiral organosilane, the C9– C22 segment of leucascandrolide A has been stereoselectively constructed.65 Sequential diastereoselective Mukaiyama aldol reactions introduced the C9 stereocenter and finally completed the assembly of the macrocycle’s carbon skeleton.

Rhizoxin 238 and its congeners 239–245 are a family of 16membered macrolides first isolated from the plant pathogenic fungus Rhizopus chinensis in 1984. The unique structure of rhizoxin 238 contains 11 stereogenic centers, two epoxides, a d-lactone, a 16-membered macrocyclic lactone, and an oxazoleterminated side chain. Due to their complicated molecular structures and promising biological activities, especially their potential as chemotherapeutic antitumor agents, the rhizoxins have become the target for several total syntheses.66 Recently, an enantioselective total synthesis of rhizoxin D 240 has been completed.67 The C1–C9 fragment of the molecule was synthesized utilizing a threefold pseudosymmetric intermediate derived from c-butyrolactone. The central macrocyclic core of rhizoxin D was cyclized via a chiral resolution/asymmetric

which was readily amenable to the production of analogues, has been achieved in 21 steps with 7% overall yield.60,61 An asymmetric allylation methodology and Terashima reduction for the stereocontrolled generation of 1,3-polyol derivatives were highlights of the strategy. A fully stereoselective total synthesis of leucascandrolide A 237 has been completed, featuring a Jacobsen asymmetric hetero Diels–Alder reaction to construct 210

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diazonamides, another flexible synthetic route to diazonamide A 246 has been reported involving an SmI2 -mediated heteropinacol coupling cascade to construct the 12-membered heterocyclic core (Scheme 12).70

During studies towards the total synthesis of the diazonamides, a heteroaromatic biaryl macrocycle/hemiaminal core 262 has been synthesised by Stille coupling of an arylstannane aminal 263 with the palladium complex 264 and sequential macrocyclization strategy.71 In addition, as an approach to diazonamide A, a C3 disubstituted oxindole 265 was furnished via a rhodium-catalyzed two-step sequence.72 In ongoing work directed toward the synthesis of oxazolecontaining natural products, a mild method for iterative oxazole construction, based on the repeatable cyclization of N-acyl propargylamines, has been developed.73 Accordingly, a concise total synthesis of (−)-muscoride A 266, a secondary metabolite of the freshwater cyanobacterium Nostoc muscorum, has been achieved in a fully asymmetric fashion (Scheme 13).

4.3

aldol sequence. The assembly of the left and right moieties of the molecule was achieved using a Julia olefination protocol to install the C9–C10 (E)-alkene, and the macrocyclization was accomplished using a Horner–Emmons (E)-olefination at C2–C3. More recently, another stereoselective total synthesis of rhizoxin D 240 has also been reported involving a (+)chlorodiisopinocamphenylborane-promoted asymmetric aldol reaction to create the correct configuration of the C15 hydroxy group stereocenter, Evans–Tishchenko 1,3-anti-diol synthesis between C13 and C15, a modified Julia coupling process to install (E)-alkene of C9–C10, and an intramolecular Horner– Wadsworth–Emmons reaction to complete the 16-membered macrocyclic core.68

4.2 Bisoxazole alkaloids The diazonamides A 246 and B 247 were first isolated from the colonial ascidian Diazona angulata, collected from the ceilings of caves along the northwest coast of Siquijor Island, Philippines in 1991. The unprecedented and challenging molecular structure, as well as significant biological activity, has stimulated much interest directed toward its total synthesis. After the originally proposed structure was found to be incorrect by synthesis, a new total synthesis of diazonamide A 246, possibly relevant to its biosynthesis, has been described recently.69 Highlights of the synthetic pathway were an oxidative cycloaddition using PhI(OAc)2 and a photo-induced biaryl coupling (Scheme 11).

For investigation of the structure–activity relationships of the

Terpenes

Naturally occurring diterpene alkaloids in soft corals are rare.

Two diterpenes containing an oxazole ring in their structures have been reported, pseudopteroxazole 275 and secopseudopteroxazole 276, from a marine soft coral Pseudopterogorgia elisabethae.

Chemical investigations on the methanolic extract of the marine soft corals Cladiella species, collected from Andaman Island, India, has led to isolation of a novel sesquiterpene containing an oxazoline ring, cladioxazole 277.74 This is the first reported isolation of a nitrogenous sesquiterpene from Cladiella sp., a genus, that until now has yielded predominantly eunicellane- and cembrane-type diterpenes.

In search of novel antimycobacterial secondary metabolites from Caribbean gorgonian octocorals, a diterpene alkaloid, namely, homopseudopteroxazole 278, which showed strong growth inhibitory activity against Mycobacterium tuberculosis H37 RV, has been obtained as a minor constituent of hexane extract from the sea plume Pseudopterogorgia elisabethae.75 Its structure was established by extensive 1D and 2D NMR analysis and comparisons with known amphilectane models.

A concise and enantiospecific synthesis of the antitubercular agent, pseudopteroxazole 275, has been accomplished starting from S-(−)-limonene.76 On the basis of the total synthesis, the originally proposed stereochemistry has been revised. The known cyclohexanone 279 was first converted in five steps to the a,b-enone 282 by a modified Robinson annulation.

Transformation of 282 to the orthogonally protected amino phenol 285 was accomplished by a new modification of the Wolff–Semmler rearrangement. The synthesis was completed by cationic cyclization of 287 to form 288 diastereoselectively and final generation of the oxazole ring (Scheme 14). Additionally, a tricyclic benzothiazine 290, a potential precursor to pseudopteroxazole 275, has been prepared utilizing a completely stereoselective intramolecular Friedel–Crafts alkylation as key step.77 The strategy also involved a completely selective Nat. Prod. Rep., 2005, 22, 196–229

211

Scheme 11 Reagents and conditions: a) TBTU, i-Pr2 NEt, DMF, rt; b) PhI(OAc)2 , LiOAc, trifluoroethanol; c) PhSH, Na2 CO3 , DMF; TeocCl, DCM, aq. K2 CO3 ; d) LiOH, MeOH, H2 O; TBTU, i-Pr2 NEt, DMF; Ac2 O, py, DCM–THF; e) DDQ, THF–water; PPh3 , (CCl3 )2 , TEA; f) hv, MeCN, H2 O, LiOH; TfOpNP, K2 CO3 , DMF; Pd(OH)2 /C, H2 ; g) diallyldicarbonate, Et3 N; TeocCl, Et3 N; Pd(PPh3 )4 , morpholine; 2,2,4,5,6,6-hexachloro-2,4-cyclohexadien-1-one, DMF, rt; (Me3 N)3 S.Me3 SiF2 ; (S)-Me2 CHCH(OH)CO2 H, (EtO)2 P(O)CN, N-methylmorpholine.

Scheme 12 Reagents and conditions: a) Pd(dppf)Cl2 , DCM, DME, K2 CO3 ; b) TBAF; SO3 .py, MeONH2 .HCl; c) SmI2 , DMA; aq. NH4 Cl; FmocValOH, EDC, HOBt; d) TPAP; POCl3 , py; aq. HF; IBX; NaClO2 ; Et2 NH.

intramolecular addition of a sulfoximine-stabilized carbanion to an a,b-unsaturated ester.

4.4 Oxazolyl cyclic peptides Chemical investigation of the strain Lyngbya majuscula, collected from a shoreline growth of coral in Wewak Bay, Papua New Guinea, led to the isolation of a novel cyclic dodecapeptide containing six five-membered heterocycles, namely, wewakazole 291.78 212

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From the Philippines marine sponge Myriastra clavosa, three new cyclic octapeptides have been isolated and their structures were assigned as myriastramides A–C 292–294 based on extensive NMR spectroscopic analyses and chemical studies.79 The first total synthesis of marine bioactive cyclic heptapeptide leucamide A 295, recently isolated from the dichloromethane extract of the Australian marine sponge Leucetta microraphis, has been accomplished.80 During the synthetic sequence, a simple method for the construction of the bisheterocyclic ring system 297 has been developed employing a

Scheme 13 Reagents and conditions: a) OHCCOOEt, THF, reflux; b) SOCl2 ; c) Me2 AlC≡CSiMe3 , Et2 O–THF; LiOH, THF; d) EtOCOCl, TEA, DCM; NH3 ; e) repeat steps a) to c); f) prenyl alcohol, BOP, TEA, DCM, rt; g) Cd/Pb couple, THF, aq. NH4 OAc, rt; h) (S)-CH2 =CHC(Me2 )NHCH(CHMe2 )CO2 C6 F5 , DMAP, chloroform, reflux.

pristinamycin IIA 304 have been prepared via different strategies and allowed for constructing novel cycle peptide derivatives.82,83 A wide variety of structurally diverse cyclopeptide alkaloids have been isolated from marine sources over the past two decades. The Lissoclinum family of cyclic peptides, such as westiellamide 305 and ascidiacyclamide 306, is characterized by an alternating sequence of oxazole, thiazole, oxazoline, and thiazoline moieties. However, no cyclopeptides containing imidazole units in the scaffold have been isolated from this family yet. Some imidazole analogues of cyclic peptides of the Lissoclinum family have been synthesized for further investigation on their structures.84 4.5

diethylaminosulfur trifluoride (DAST)-mediated cyclization of b-hydroxy amide 296.

Bistratamide G 298, one of many bistratamide-type polyheterocyclic cyclopeptides, recently isolated from the southern Philippines ascidian Lissoclinum bistratum, showed potent inhibitory activity in the human colon tumor HCT-116 cell line.

A short total synthesis of bistratamide G has been achieved by assembling two elaborated fragments 299 and 300.81 Pristinamycins are naturally occurring antibiotics of the Streptogramin class. Pristinamycin IIA 301 and pristinamycin IIB 302, as the most abundant components, are peptidic macrolactones. 17-Diazo pristinamycin IIB 303 and 14,36-didehydro

Miscellaneous

In the course of a search for small-molecule inhibitors of 5hydroxytryptamine receptors (5-HT), a novel ergoline alkaloid 307 has been identified from the fungal culture of Dicyma sp.85 The compound showed a high affinity for 5-HT1A receptors (a pK i of 10.2 versus the 5-HT1A ).

Investigation of myxobacteria species for new biologically active derivatives has led to the isolation of two novel isochromanone derivatives, named ajudazol A 308 and ajudazol B 309, from the Chondromyces crocatus species.86 Experiments on their mechanism of action showed that the ajudazols selectively inhibit electron transport in beef heart submitochondrial particles (SMP) at the site of complex I, i.e. NADH:ubiquinoneoxidoreductase.

Tolerance to nutrient deprivation as well as angiogenesis is essential for malignant tumor progression and elimination of the tolerance might serve as a new strategy for cancer therapy.

From the culture broth of Amycolatopsis sp. ML 630-mF1, five Nat. Prod. Rep., 2005, 22, 196–229

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Scheme 14 Reagents and conditions: a) TBDPSCl, imidazole, DMF; b) LDA, TMSCl; 1-benzyloxy-3-methylbut-3-en-2-one, SnCl4 , DCM; c) KOH, EtOH; SOCl2 , py; d) NH2 OH.HCl, py; e) pivaloyl chloride, py; f) AcCl, toluene; g) H2 , Pd(OH)2 –C, EtOH; carbonyldiimidazole, TEA, then NaHCO3 aq.; h) HF, py; TPAP, NMO; Wittig olefination; i) MeSO3 H, AcOH; j) (Boc)2 O, DMAP; MeMgBr, then TFA, HC(OEt)3 .

novel antibiotics named kigamicins A 310, B 311, C 312, D 313, and E 314 have been found to possess selective inhibitory activity against PANC-1 cells only under nutrient deficient conditions.87,88 Kigamicins A, B, C, and D inhibited PANC-1 cell survival at a concentration 100 times lower than in normal culture. Kigamicin D also showed inhibitory activity against various mouse tumor cell lines with an IC50 value of 1lg mL−1 .

Zoanthamines, e.g. 315–317, are a family of marine alkaloids isolated from the zoanthid Zoanthus sp. and possess a unique array of skeletal and stereochemical complexities. To date, no total synthesis of zoanthamines has been reported. However, recently, several analogues of zoanthenol 317 have been synthesized for further biological investigation.89 Streptazolins 318–322, first isolated from a culture of the strain Streptomyces viridochromogenes, are lipophilic, neutral, 214

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tricyclic compounds possessing antibiotic and antifungal activities. Utilizing an intramolecular Pauson–Khand reaction of 2oxazolone derivative 324 as the key step, the first total synthesis of (±)-8a-hydroxystreptazolone 319 has been accomplished in a highly stereoselective manner (Scheme 15).90 Cytoxazone 329 is a microbial metabolite isolated from a soil sample of Streptomyces sp. in 1998, which has been identified as a selective modulator of TH 2 cytokine secretion. Due to its

potent biological activity and relatively simple structure, the development of an efficient synthetic pathway to cytoxazone as well as its congeners has been accomplished independently by different groups.91–96 Nat. Prod. Rep., 2005, 22, 196–229

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4.6 Isoxazole alkaloids Pyrinodemin A 330, recently isolated in 1999 from the marine sponge Amphimedon sp. collected off Nakijin, Okinawa, is a structurally novel cis-cyclopent[c]isoxazolidine alkaloid which showed potent cytotoxicity against murine leukemia L1210 and KB epidermoid carcinoma cells with an IC50 value of 0.058 lg mL−1 and 0.5 lg mL−1 , respectively. Upon total synthesis of the originally proposed structure, the spectroscopic data of the synthetic material did not match those of the natural product. Recently, revision of the absolute stereochemistry of pyrinodemin A 330 has been independently provided by two groups through organic synthesis.97,98 The double bond was assigned at C14 –C15 and the full configurations are C15 S, C16 S, C20 R. 5 Thiazole alkaloids 5.1 Epothilones Epothilones, such as epothilones A–F 331–336, a class of macrolides originally isolated from the soil bacterium So216

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rangium cellulosum, are mictotubule polymerization promoters.

Although structurally dissimilar, the mechanism of action of the epothilone family is similar to the cancer drug paclitaxel (Taxol R ) but with somewhat higher potencies, involving induction of tubulin polymerization and stabilization of microtubule assembly. Particularly, they display dramatically improved potency against multiple drug resistant (MDR) tumor cell lines that are highly resistant to Taxol R and other anticancer drugs.

The fact that kilogram quantities are available by fermentation, the higher solubility in water than paclitaxel, and the improved potency against MDR, have made the epothilones the most promising of antitumor agents. Among the epothilone family, epothilone B is the most potent antiproliferative agent among the naturally occurring tubulin polymerization promoters, with an activity from 2- to 10-fold greater than that of paclitaxel, and it is less susceptible than paclitaxel to Pgp-mediated MDR. Epothilone B is in phase II trials by Novartis, and its lactam analogue BMS-247550 is in phase II/III trials

by Bristol-Myers Squibb. 12,13-Deoxyepothilone B (SloanKettering/Kosan/Roche) and C21-amino epothilone B (BMS) have also entered clinical trials.99 A fundamental study on the interactions of the epothilones with the paclitaxel binding site of microtubules has been conducted comprehensively.100 By determining the correlation between binding, microtubule stabilization, and cytotoxicity of the epothilones, the structure–affinity relationships were well characterized allowing further structural modification. In agreement with previous results, the S configurations at C13 and C15 are crucial (see structure 337 for numbering), while that at C12 can be either R or S. Replacement of the epoxide with a cyclopropane ring enhances binding affinity, as does replacement of the C21 methyl group with a thiomethyl group.

This method of correlating binding affinity with cytotoxicity has demonstrated a useful tool for new drug design.101 To provide in-depth understanding of the biologically active conformation of the epothilones, several analogues of C1– C8 and C11–C15 of the epothilones A 331 and B 332 have been synthesized and the conformation–activity relationships determined as an important complement to classic structure– activity data.102 As nonribosomal-peptide-polyketide natural products, the epothilones are constructed by mixed enzymic assembly lines

Scheme 15 Reagents and conditions: a) NaHMDS, MeCHO, THF; b) Co2 (CO)8 , Et2 O, r.t; Me3 NO, toluene; c) TBDMSCl, imid. DMF; NaBH4 , CeCl3 , MeOH; d) p-NO2 C6 H4 CO2 H, DEAD, PPh3 , benzene; e) 10% HCl, MeOH, rt; Dess–Martin periodinane, DCM, rt; f) K2 CO3 , MeOH, rt; TBAF, THF, rt.

composed of nonribosomal-peptide synthetases (NRPS) and polyketide synthases (PKS). These proteins catalyze the formation of the epothilone’s carbon–carbon backbone in a linear fashion starting with the heteroaromatic side chain. In an early step of the epothilone biosynthetic pathway, acetyl transfer from

the PKS subunit EpoA to the cysteine residue of the NRPS subunit EpoB occurs. Subsequent cyclization, dehydration, and oxidation by cyclization (Cy) and oxidase (Ox) domains of EpoB result in the methylthiazolyl species, which is then transferred from EpoB to the downstream PKS acceptor subunit EpoC by the ketosynthase (KS) domain of EpoC (Scheme 16). It has been demonstrated that EpoA or EpoB proteins can be replaced in vitro with proteins from rapamycin, yersiniabactin, and enterobactin biosynthetic pathways.103 The final step in the biosynthetic pathway of the epothilones is the thioesterase (TE)catalyzed cyclorelease of the epothilone from the EpoF protein, which occurs first by transacylation of the linear epothilone-acyl carrier protein (ACP) thioester to the active site serine residue of the TE domain, followed by intramolecular nucleophilic attack of the C15 hydroxyl group, and final release of the product from the enzyme (Scheme 16).104 Precursor-directed biosynthesis has provided a powerful method to introduce non-native starting materials into biosynthetic pathways. To express the last half of the epothilone biosynthetic pathway, exogenous transformation from synthetic substrate into epothilone C by an engineered Escherichia coli strain has been achieved at levels comparable to the native host (Scheme 17).105 A combination of chemical and enzymatic approaches to complex molecules has proven to be an efficient way to provide access to analogues with improved pharmacological properties in quantities sufficient for clinical development. The great potential of the epothilones in cancer therapy has excited strong interest in more novel epothilone analogues. Eight novel analogues 338–345 of epothilone D and 10,11-dehydroepothilone D (Epo490) have been biogenetically produced by using the Amycolata autotrophica strain to alter the oxidation state of the parent epothilone D and Epo490.106 To produce additional epothilone analogues, two deactivated mutants of the enoyl reductase domain ER5 in the epothilone B- and the epothilone D-producing Myxococcus xanthus strains and one deactivated mutant of the ketoreductase domain KR6 of the epothilone D-producing strain have been generated. From these mutants, Nat. Prod. Rep., 2005, 22, 196–229

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Scheme 16 Biosynthetic pathway of the epothilones.

Scheme 17 Mechanism for the precursor-directed biosynthesis of epothilone C a) Acylation of EpoD-M6; b) Acyl-enzyme intermediate was transferred to epoE; c) Acyl-enzyme intermediate was transferred to epoF; d) EpoF catalyzes the final round of elongation and cyclorelease.

nine novel analogues 346–353 of the epothilones were produced together with the known major epothilone product.107 A number of synthetic studies have been focused on novel analogues of the epothilones.108–112 Utilizing commercially available immobilized reagents and scavengers, epothilone A 331 and C 333 have been efficiently prepared by a solid-phase synthetic strategy via a multi-step sequence which avoided frequent use of conventional workup and purification procedures.113–114 Additionally, the C7–C21 fragment 354 of epothilone A has been stereoselectively synthesized via a-pinene-derived asymmetric alkoxyallyl- and crotylboration processes.115 A fluoro-containing derivative 355 of epothilone B has been efficiently synthesized by early introduction of the synthetically demanding fluoromethyl epoxide functional group.116 218

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Based on aldol condensation of a b-methallyloxy aldehyde derived from methyl 3-hydroxy-2S-methyl propionate followed by ring-closing metathesis (RCM), a short synthesis of 10-oxa epothilone analogue 356 has been described.117 Epothilone D has been degraded via an oxidative cleavage sequence to produce acid intermediate 357, from which a variety of epothilone analogues were smoothly derived using ring-closing metathesis to construct the trisubstituted C12–C13 double bond in the macrocycle.118 Two fluorescently labeled epothilone analogues 358 and 359 have been synthesized using a modification of Nicolaou’s macrolactonization and Stille coupling strategy.119 By incorporating an alkyne group into epothilone C for replacement of the C13–C15 segment, several C16–C17-alkyne analogues, i.e.

360, have been prepared.120

5.2 Thiopeptides The thiopeptide family of antibiotics is a class of sulfurcontaining, highly modified cyclic peptides isolated from microorganisms characterized by several common structural features such as the presence of thiazole and, in some cases, oxazole rings, unusual and dehydro amino acids, and a heterocyclic centerpiece of a tri- or tetra-substituted pyridine, all in a macrocyclic array.

In the course of screening for novel antibiotics against a multi-drug resistant Enterococcus faecium strain, a new group of thiazolyl thiopeptide antibiotics, designated as nocathiacins

I, II, and III 361–363, has been isolated from the culture broth of Nocardia sp. WW-12651 (ATCC-202099).121,122 They exhibit potent in vitro inhibitory activity against a wide spectrum of Gram-positive bacteria, including multi-drug resistant pathogens such as methicillin-resistant Staphylococcus aureus (MRSA), multi-drug resistant Enterococcus faecium (MREF) and fully penicillin-resistant Streptococcus pneumoniae (PRSP), and also demonstrate excellent in vivo efficacy in a systemic Staphylococcus aureus infection of mice.

Two new thiopeptide antibiotics, named YM-266183 364 and YM-266184 365, have been identified from the culture broth of Bacillus cereus QN03323, which was isolated from a marine sponge Halichondria japonica, along with two known thiopeptides, thiocillins I 366 and II 367.123,124 Both of the new antibiotics Nat. Prod. Rep., 2005, 22, 196–229

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exhibited potent antibacterial activities against Staphylococci and Enterococci multi-drug resistant strains, whereas they were inactive against Gram-negative bacteria.

The amythiamicins, such as amythiamicin A 368 and D 369, first isolated from a strain of Amycolatopsis sp. MI481-42F4, were originally reported to inhibit the growth of Gram-positive bacteria including MRSA, but more recently, in common with other thiopeptides, they have been shown to exhibit antimalarial activity against Plasmodium falciparum. Recently, the first total synthesis of one of the amythiamicins, amythiamicin D 369 has been reported using a biomimetic thermal Diels–Alder reaction between 370 and 371 to establish the pyridine core of the antibiotic as the key step.125 Another method of constructing the pyridine-containing central domain 372 was achieved from thiazole-4-carboxylic acid 373 via 2-(2-thiazolyl)enamine 374 and intermolecular Michael addition–cyclodehydration with 1(2-thiazolyl)propynone 375.126 220

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During studies towards the total synthesis of thiostrepton 376, two analogues 379 and 380, which lack only the quinaldic acid macrocyle and differ from thiostrepton at the imine-containing ring core, have been accomplished.127 The dihydroxyisoleucine-, thiazoline- and dehydroamino acid-containing pentapeptide segment 381 of the thiostrepton family has been prepared via a sequence including b-lactone opening by phenylselenide, vinylzinc addition to a chiral sulfinimine, the Wipf oxazolinethiazoline conversion method and oxidative syn-elimination of the phenylseleno group.128 Sulfomycin I 382, another member of the thiopeptide family, was originally isolated from a culture of Streptomyces viridchromogenes MCRL-0368. The tridehydropentapeptide segment 383 of the central macrocycle of the antibiotic has been synthesized by fragment condensation.129 After successful isolation of nocathiacin-type thiopeptides from the fermentation broth of Nocardia sp., in order to improve their aqueous solubility while maintaining their intrinsic biological activity, a structural modification by Michael addition of amine and thiol nucleophiles to the dehydroalanine moiety of nocathiacins has been achieved in frozen water.130

5.3

Other thiazolyl alkaloids from microorganisms

Chemical investigation of the marine cyanobacterium Lyngbya sp. (Oscillatoriaceae), collected in Guam during the Spring

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221

of 2002, has led to isolation of two more members of the lyngbyapeptin and lyngbyabellin families, 15-norlyngbyapeptin A 384 and lyngbyabellin D 385, while lyngbyabellin D showed an IC50 value of 0.1 lM against the KB cell line.131 Their structures were elucidated through standard 2D NMR and chemical degradation.

From the marine cyanobacterium Symploca sp. collected in Guam, two new cytotoxins named micromide 386 and guamamide 387 have been isolated along with three known lipopeptides, apramides A 388, B 389, and G 390.132 Micromide and guamamide displayed IC50 values against KB cells line at 0.26 and 1.2 lM, respectively.

The lipopeptide kalkitoxin 391 was first isolated from an extract of the marine cyanobacterium Lyngbya majuscula collected in the Caribbean and possessed potent neurotoxicity in a primary cell culture of rat neurons (LC50 3.86 nM). A short 222

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total synthesis of kalkitoxin has been completed by a route which employed asymmetric organocopper conjugate addition followed by in situ enolate alkylation to install the anti,anti-1,2,4trimethyl portion of the toxin.133 Apratoxins A–C 392–394 are secondary metabolites of the marine cyanobacterial Lyngbya sp. collected in Guam and Palau. They belong to cyclodepsipeptides bearing both peptide and polyketide moieties in the macrocyclic core. A concise total synthesis of apratoxin A 392, featuring stereocontrolled access to the novel polyketide portion and late-stage installation of the sensitive 2,4-disubstituted thiazoline moiety using an intramolecular Staudinger reduction/aza-Wittig process, has been described.134 Studies toward the total synthesis of apratoxin A have resulted in the synthesis of the polyketide segment 395 of apratoxin A.135 Additionally, an oxazoline analogue 396 of apratoxin A has been synthesised.136 Myxobacteria have been increasingly recognized as a valuable source of novel bioactive compounds and have attracted considerable attention in recent years after the discovery of promising antitumor agents, the epothilones. The cystothiazoles A–F 397– 402, and myxothiazole 403, characterized as bisthiazole and b-methoxyacrylate structures, have recently been isolated from the myxobacterium Cystobacter fuscus strain AJ-13278. Further investigation of a large-scale culture of the strain resulted in the isolation of an additional cystothiazole analogue, cystothiazole G 404. On the basis of total synthesis, its stereochemistry has now been characterized as 4R,5S,6(E).137 By comparison of the spectral data with that of a synthetic sample, the stereochemistry of naturally occurring cystothiazole B 398 has also been identified to be 4R,5S,6(E).138 Recently, three enantioselective total syntheses of (+)-cystothiazole A 397 have been described.139–141 The biosynthetic pathway to cystothiazole A 397 has been investigated by feeding the producing organism, Cystobacter fuscus, with stable-isotope-labeled compounds including [213 C]acetate, [1,2-13 C2 ]acetate, [1-13 C]propionate, L-[1-13 C]serine, L-[methyl-13 C]methionine, and DL-valine-d 8 .142 The polyketide moiety of cystothiazole A was confirmed to be derived from acetate and propionate, the bisthiazole moiety from L-serine, the O-methyl groups from the S-methyl group of L-methionine, and the isopropyl moiety from L-valine, which should be the metabolic precursor of isobutyryl CoA. During screening for new biologically active metabolites from the myxobacteria Archangium gephyra and Cystobacter sp., two novel cytotoxic macrolides, archazolid A 405 and B 406 were identified from the culture broth of both myxobacteria.143 They consist of a macrocyclic lactone ring with a thiazole ring side chain and exhibited high inhibitory activity with IC50 values ranging from 0.1 to 1 ng mL−1 against different cell lines.

Leinamycin 407, a potent antitumor antibiotic, was originally isolated from the fermentation broth of a Streptomyces sp. in 1989. The unique structural features include the 1-oxo1,2-dithiolan-3-one moiety fused in a spiro fashion to an 18membered lactam with an extensively conjugated thiazole ring.

The bleomycins (BLMs), such as A2 408, B2 409, and A5 410, are a family of glycopeptide-derived antitumor antibiotics that were originally isolated from a culture broth of Streptomyces verticillus as copper chelates. They can mediate sequence selective DNA and RNA cleavage in the presence of a metal ion and have been applied clinically for the treatment of a variety of malignancies, including those of the testes

In addition to total synthetic studies, the preparation of various dithiolanone type compounds has also been studied in order to develop simple analogues of the parent antibiotic.144â&#x20AC;&#x201C;146 Nat. Prod. Rep., 2005, 22, 196â&#x20AC;&#x201C;229

223

and lymph nodes.147 108 unique deglycobleomycin analogues have been prepared through parallel solid-phase synthesis.148 Sufficient quantities of each analogue were provided by the synthesis to permit characterization by 1 H NMR and highresolution mass spectrometry. Using this procedure, a number of conformationally constrained methylvalerate analogues were incorporated into deglycobleomycin A5 .149 WS75624 A 411 and B 412 are two related secondary metabolites of microorganisms first isolated from the fermentation broth of Saccharothrix sp. No. 75624. A short total synthesis of WS75624 B 412 has been accomplished via the Stille coupling of appropriately functionalized pyridine 414 and thiazole components 413.150 The stereochemistry of the natural product was assigned as S-configuration at the carbon bearing the secondary alcohol based on the total synthesis.

A novel algaecide, bacillamide 415, produced by a marine bacterium, Bacillus sp. SY-1, has been isolated which showed high inhibitory activity against harmful dinoflagellate, Cochlodinium polykrikoides.151 This is the first report of an algaecide against this type of dinoflagellate, which is frequently responsible for large-scale red tides and mass mortalities of cultured fishes and bivalves.

Bioassay-guided fractionation of the MeOH extract of the sponge Haliclona sp. collected from Palau in 1997 has yielded a known hexapeptide, waiakeamide 417, together with a new sulfone derivative 418.153 The structures of both hexapeptides have been established by extensive NMR analyses and the advanced Marfey’s method with LC/MS.

Ascidians (sea squirt) of the genera Lissoclinum and Didemnum have been shown to be a rich source of cyclic peptides.

Two new cyclohexapeptides, didmolamides A 419 and B 420 have been isolated from the ascidian Didemnum molle, collected in Madagascar.154 The absolute configuration of all amino acid units was determined to be L using Marfey’s method for HPLC. A total synthesis of mollamide 421, a prenylated cyclic peptide isolated from the ascidian Didemnum molle, has been completed.155

5.4 Thiazolyl cyclic peptides Numerous cyclic peptides, many of which incorporate modified amino acid residues containing thiazole, oxazole, thiazoline, or oxazoline rings, are secondary metabolites from a variety of marine sources including sponges, ascidians, marine cyanobacteria, and others.

A new cyclic peptide with a polyketide-derived moiety in the macrocycle core, designated as scleritodermin A 416, has been isolated from the sponge Scleritoderma nodosum Thiele 1900 (Scleritodermidae).152 The structure was determined on the basis of an extensive combination of spectroscopic techniques.

Six novel cyclic hexapeptides, bistratamides E–J 422–427, have been identified from the ascidian Lissoclinum bistratum, collected from Tablas Island in the Philippines, along with two known metabolites bistratamides C 428 and D 429.156 Their 224

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showed multi-drug resistance (MDR) inhibitory activity by acting as a P-glycoprotein and MRP1 antagonist at noncytotoxic doses. The oxazole and thiazoline units have been prepared from a b-ketodipeptide and protected cysteine-containing dipeptides respectively utilizing bis(triphenyl)oxodiphosphonium trifluoromethanesulfonate as the key agent. On the basis of this, a formal total synthesis of dendroamide A 433 has been achieved.161

structures have been verified by highly efficient total syntheses.157 In addition, a synthesis of bistratamide G 424 (≡ 298) was described in Section 4.4.

With the aim of further investigating the capacity of Lissoclinum-type cyclic peptides to bind metal ions, trunkamide A 430 has been synthesized158 as have other cyclic peptide analogues of the Lissoclinum family using a concise and efficient cyclooligomerisation procedure.159

5.5

Alkaloids from marine sponges

Latrunculeic acid 434, a novel thiazolidinone-devoid analogue of latrunculin B 435, has been identified from the Red Sea sponge Negombata magnifica along with several known compounds including latrunculin B 435, 15-methoxylatrunculin B 436, 16epi-latrunculin B 437, and latrunculin C 438.162

Marine cyanobacteria of the genus Lyngbya abound with structurally diverse secondary metabolites with significant pharmaceutical potential. Six novel cyclic depsipeptides, guineamides A–F, have recently been isolated and characterized from a Papua New Guinea collection of the marine cyanobacterium Lyngbya majuscula.160 Amongst them, guineamides A 431 and B 432 incorporate a thiazole moiety in the macrocyclic core.

Dendroamide A 433, first isolated from the terrestrial blue-green alga (cyanobacterium) Stigonema dendroideium fremy in 1996, Nat. Prod. Rep., 2005, 22, 196–229

225

Scheme 18 Reagents and conditions: a) TiCl4 , i-Pr2 NEt, DCM, −78 ◦ C; b) aq. HCl, THF; CSA, MeOH; c) Tf2 O, py, DCM; 439 Na salt, 15-crown-5, THF; d) Mo[N(But )(3,5-Me2 C6 H3 )]3 , toluene, DCM, 80 ◦ C; e) H2 /Lindlar catalyst, DCM; CAN, MeCN–water.

By convergent combination of three elaborated building blocks, a concise total synthesis of latrunculin B 435 has been completed involving Fe(acac)3 -catalyzed cross-coupling reactions and Mo-mediated alkyne metathesis as the key steps.163 The required acid component 439 was readily prepared from ethyl acetoacetate via the corresponding triflate under Fe(acac)3 catalysis. The synthesis of cysteine-derived ketone 440 also took advantage of iron catalysis. The third building block aldehyde 441 was derived from (+)-citronellene. Reaction of aldehyde 441 with the titanium enolate derived from ketone 440 gave aldol 442 as a mixture of diastereomers. Acid-catalyzed cleavage of the TBS group delivered hemiacetal 443. After acetal formation with MeOH, conversion of 444 into the corresponding triflate, and reaction with the sodium salt of acid 439 furnished diyne 445.

The ring-closing metathesis of diyne 445 under Mo[NBut (3,5Me2 C6 H3 )]3 catalysis smoothly afforded the cycloalkyne 446, which, by a Lindlar reduction, was converted to latrunculin B 435 in protected form (Scheme 18).

Halipeptins A 447, B 448 and C 449, originally presumed to have an oxazetidine ring incorporated in the macrocyclic core, are cyclic D2 -thiazoline-containing depsipeptides from a marine sponge belonging to the genus Haliclona. To develop a stereochemically flexible synthetic strategy for the elaboration of its polyketide fragment, the 3-hydroxy-7-methoxy-2,2,4-trimethyldecanoid acid 450 has been prepared in a fully asymmetric fashion.164 After publication of a preliminary account of the total synthesis of mycothiazole 451, first isolated from a marine sponge Spongia mycofijiensis collected from Vanuatu in 1988, the full details of the synthesis have been reported.165 The synthesis clearly showed the absolute configuration of natural mycothiazole to be R. 226

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5.6

Miscellaneous

A practical synthesis of the cancer cell growth inhibitor dolastatin 18 452, originally isolated from the marine shell-less mollusc Dolabella auricularia, has been completed starting from dolaphenine 453, a previously synthesized unit of dolastatin 10 454.166

In order to investigate the stereochemistry of representative cruciferous phytoalexin, S-(−)-spirobrassinin 455 and its related metabolites, (−)-dioxibrassinin 456 and (−)-3-cyanomethyl3-hydroxyoxindole 457 have been prepared from isatin and resolved. The configurations of both have been determined by the new chiroptical technique, vibrational circular dichroism (VCD), as well as by the more conventional electronic circular dichroism (ECD), and concluded to be S.167 A concise synthesis of an arylhydrocarbon receptor (AHR) endogenous ligand, methyl 2-(1 H-indol-3 -carbonyl)thiazole4-carboxylate 458, recently isolated from porcine lung, has been accomplished via TiCl4 -mediated cyclization to a D2 thiazoline, followed by dehydrogenation to the final indole thiazole ketone.168

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