Simple indole alkaloids and those with a non-rearranged monoterpenoid unit

Contents

• 1 Introduction

• 2 Simple indole alkaloids
  • 2.1 Non-tryptamines
  • 2.1.1 Indole auxins and phytoalexins
  • 2.1.2 Carbazoles and indolocarbazoles
  • 2.2 Non-isoprenoid tryptamines
  • 2.2.1 Piperazinediones
  • 2.2.2 Physostigmine and related compounds
  • 2.2.3 Pyrrolo[3,2-e]indoles and pyrrolo[2,3-f]indoles
  • 2.2.4 Indoloiminoquinones
  • 2.2.5 β- and γ-Carbolines

• 3 Isoprenoid tryptamines
  • 3.1 Ergot alkaloids

• 4 Bisindole alkaloids

• 5 Peptide alkaloids containing a tryptophan residue

• References

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Abstract

Covering: January 2003 to December 2003. Previous review: Nat. Prod. Rep., 2004, 21, 211

This review covers newly isolated simple indole alkaloids, structure determinations, total syntheses and biological activities reported in the literature in 2003.

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Masanori Somei

Masanori Somei was born in 1941 in Chiba, Japan. He attended Tokyo University (1961–1970) and obtained his Ph.D. degree (1970) under the supervision of Professor Toshihiko Okamoto. He then moved to ITSUU Laboratory (1970–1976). After postdoctoral work (1975–1976) with Professor William G. Dauben (University of California, Berkeley), he was promoted to associate professor in 1976 and full professor in 1984, his current position. He received the Pharmaceutical Science of Japan Award for Young Scientists (1971) and the Kametani award (2001). His main research interests are verification of his 1-hydroxyindole hypotheses, their synthetic applications and creation of suitable new reactions for realising syntheses of indole alkaloids as simply as possible. He proposed the originality rate, the intellectual property factor, and the application potential factor for evaluating the effectiveness of organic synthesis.

Fumio Yamada

Fumio Yamada is an associate professor of Kanazawa University. He was born in 1955 in Toyama, Japan and received his Batchelor of Pharmaceutical Science (1978) from Kanazawa University and his Ph.D. degree (1988) from Tokyo University. He joined the Faculty of Pharmaceutical Sciences, Kanazawa University in 1980 and was promoted to his current position in 1997. He worked as a postdoctoral fellow with Professor Alan. P. Kozikowski at University of Pittsburgh and Mayo Clinic Jacksonville from 1990 to 1991. He received the award of encouragement in 1999 from the Hokuriku branch of Japan Pharmaceutical Society. His current research interests are the synthesis of biologically active indole alkaloids as simply as possible and creation of new reactions suitable for attaining simple syntheses of the target molecules.

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1 Introduction

This review covers the literature on simple indole alkaloids and those with a non-rearranged monoterpenoid unit from the beginning of 2003 up to the end of 2003. In this series, marine natural products and peptide alkaloids have also been surveyed. As a result, there will be some overlap with the marine alkaloids and the peptide alkaloids containing the indole moiety. Reviews on the synthesis of melatonin¹ and betalains² have appeared.

2 Simple indole alkaloids

2.1 Non-tryptamines

Extensive fractionation of the crude organic extract from a Puerto Rican collection of Lyngbya majuscula has led to the discovery of a new indole derivative (1).³ The structure was deduced by spectroscopic methods (¹H and ¹³C NMR, HSQC, TOCSY, and HMBC experiments).

Thiersindoles A–C (2–4), new 3-substituted indole diterpenoids, have been isolated from organic extracts of a new Penicillium species (P. thiersii).⁴ Their structures, including absolute stereochemistry, were determined by analysis of NMR data (¹H and ¹³C NMR, NOESY, DEPT, HMQC, and HMBC experiments) and application of Mosher's method. The [6,6,5] tricyclic diterpenoid skeleton in compounds 2 and 3 is unprecedented in any of the known members of this class.

A new indole alkaloid, galanthindole (5), has been isolated from Galanthus plicatus ssp. byzantinus (Amaryllidaceae), a plant native to northwestern Turkey.⁵ The structure was determined by spectral analysis (¹H and ¹³C NMR, COSY, HMQC, NOESY, and HMBC spectra).

Bioactivity-directed fractionation of the crude extract of Stemona tuberosa has led to the isolation and characterisation of four new alkaloids, tuberostemonine J (6a), tuberostemonine H (6b), neostenine (6c), and epi-bisdehydroneotuberostemonine J (7).⁶ Their structures were determined by spectroscopic analysis (¹H and ¹³C NMR, and DEPT spectra), and their absolute structures elucidated by X-ray crystallographic analysis. These alkaloids were examined for antitussive activity in the guinea pig after cough induction by citric acid aerosol stimulation; 6c showed significant antitussive activity. Studies of the structure–activity relationships for these alkaloids and synthetic analogues revealed that the saturated tricyclic pyrrolo[3,2,1-jk]benzazepine nucleus is the primary key structure contributing to the antitussive activity, and that the all-cis configurations at the three ring junctions are the optimal structure for the antitussive activity of stenine-type Stemona alkaloids.

The aquatic peptide aeruginosin EI461 was isolated from the cyanobacterium Microcyctis aeruginosa and structure 8a was proposed (Scheme 1).⁷ Valls' group had prepared a putative structure 8a for aeruginosin EI461 from O-methyl-D-tyrosine,⁸ but the synthetic material was not identical with the natural product. A corrected structure (8b) for aeruginosin EI461 was proposed and the structure proven by synthesis. O-Methyl-L-tyrosine was converted to the azabicyclic ketone 9. Successive couplings of the dipeptide 10 with L-Hpla and NH₄OH, and then a deprotection step gave aeruginosin EI461 (8b).

Scheme 1 Reagents and conditions: i, NaBH₄, MeOH; ii, Ac₂O, DMAP, PyBOP; iii, 1. TFA, CH₂Cl₂, 0 °C, 2. Boc-D-Leu, CH₂Cl₂, PyBOP, NMM, rt; iv, TFA, CH₂Cl₂, 0 °C; v, AcO-L-Hpla(Bn), CH₂Cl₂, PyBOP, NMM, rt; vi, 0.1 N LiOH, THF, rt; vii, HOBt·H₂O, EDC, NMM, THF, 0 °C then NH₄OH, rt; viii, H₂, 10% Pd/C, rt.

The first stereoselective total synthesis of (+)-benzastatin E (11), isolated from Streptomyces nitrosporeus 30643,⁹ has been accomplished in 11 steps from commercially available (S)-2-indolinecarboxylic acid (12) (Scheme 2).¹⁰ The key reaction is a diastereoselective Grignard addition to 2-acylindole 13 leading to 14, which was further converted into (+)-benzastatin E (11). The previously unknown absolute stereochemistry of (+)-11 was determined as (9S,10R).

Scheme 2 Reagents and conditions: i, MeOH, H₂SO₄, 80 °C; ii, Boc₂O, CH₂Cl₂, rt; iii, NBS, DMF, 0 °C; iv, i-PrMgBr, Me(MeO)NH·HCl, THF, −20 to −10 °C; v, MeOCH₂Sn(n-Bu)₃, n-BuLi, THF; vi, 15, THF, −78 °C; vii, HCO₂H, CH₂Cl₂, 40 °C; viii, Me₂C(OMe)₂, PPTS, CH₂Cl₂, rt; ix, t-BuLi, CO₂, Et₂O, −78 to 0 °C; x, CDI, 28% aq. NH₃, THF, rt; xi, PPTS, MeOH, rt.

Stereoselective synthesis of (−)-monatin (16), isolated from the bark of the roots of Schlerochiton ilicifolius,¹¹ has been achieved by chelation-controlled cycloaddition of the nitrone 17 with the allyl alcohol 18 in the presence of MgBr₂·OEt₂ to produce 19 (Scheme 3).¹² Cycloadduct 19 was converted into (−)-monatin (16) through the lactone 20.

Scheme 3 Reagents and conditions: i, MgBr₂·OEt₂, CH₂Cl₂, rt; ii, TBSCl, imidazole, DMF; iii, Boc₂O, DMAP, MeCN; iv, HF·pyridine, THF; v, H₂, Pd(OH)₂/C, MeOH; vi, Boc₂O, MeCN; vii, PDC, DMF; viii, HCl, HCO₂H; ix, NaOH, MeOH then Amberlite^® IR-120-H⁺ form, aq. NH₃.

The total synthesis of (±)-alantrypinone (21), isolated from the extracts of the fungus Penicillium thymicola,¹³ has been accomplished employing a novel aza-Diels–Alder reaction of 3-methyleneoxindole (22) and the azadiene 23 as the key step (Scheme 4).¹⁴ The reaction sequence comprises 8 steps starting from anthranilic acid. Mild acid hydrolysis of the adduct 24 afforded (±)-alantrypinone (21).

Scheme 4 Reagents and conditions: i, glycine ethyl ester, EDCI, CH₂Cl₂, rt; ii, Fmoc-L-Ala–OH, EDCI, MeCN, rt; iii, PPh₃, Br₂, Et₃N, CH₂Cl₂, rt; iv, piperidine, CH₂Cl₂, rt; v, Na₂CO₃, Et₃O⁺BF₄⁻, CH₂Cl₂, rt; vi, DDQ, PhH, reflux; vii, 22, CHCl₃, rt; viii, 1 N HCl, AcOEt, rt.

A total synthesis of (±)-epiuleine (25), isolated from Aspidosperma subincanum,¹⁵ has been achieved starting from 4-methoxypyridine and indolyl magnesium bromide (Scheme 5).¹⁶ The key finding is the isolation of the thermodynamic enolate as the vinyl triflate 26 in the 1,4-reduction of dihydropyridone (27). Heck vinylation of 26 followed by reductive methylation afforded 28, which was then converted into (±)-epiuleine (25) according to the reported procedure.^17,18

Scheme 5 Reagents and conditions: i, CbzCl, THF; ii, Boc₂O, DMAP; iii, L-Selectride, N-(5-chloro-2-pyridyl)triflimide, 0 °C; iv, n-butyl vinyl ether, Pd(OAc)₂, dppf, THF, 40 °C; v, 1,4-cyclohexadiene, Pd/C; vi, CH₂O, NaBH₃CN; vii, TFA; viii, EtMgBr, CuCl, 0 °C; ix, p-TsOH, 40 °C.

The first total synthesis of the inhibitor of 3α-hydroxysteroid dehydrogenase, 0231B (29), isolated from a fermentation broth of Streptomyces sp. HKI0231,¹⁹ has been achieved starting from 6-methylindole (30) (Scheme 6).²⁰ Introduction of an acyl group into the 3-position of 30, cyclisation of the side chain at the 3-position of 31 to the 4-position and subsequent elimination of the phenyl group, and conjugate addition of the salicylamide derivative afforded 32. Compound 32 was then converted into 0231B (29).

Scheme 6 Reagents and conditions: i, trimethylacetyl chloride, DMAP, Et₃N, CH₂Cl₂; ii, trans-p-methylcinnamoyl chloride, AlCl₃, CH₂Cl₂; iii, 1 N NaOH, MeOH; iv, AlCl₃, CHCl₂CHCl₂, 80 °C; v, TsCl, pyridine; vi, N,N-dimethyl-O-methylsalicylamide, s-BuLi, TMEDA, THF; vii, O₂, KOH, CuCl, MeOH; viii, PhMe, reflux; ix, LiAlH₄, THF, −40 °C; x, CSA, MeOH, reflux.

The total synthesis of anhydrolycorinone (33) and hippadine (34), isolated from Amaryllidaceae plants,²¹ has been accomplished by an iron-mediated construction of the indole nucleus (Scheme 7).²² Nucleophilic addition of the lithium ester enolate 35 to the iron complex 36, followed by an iron-mediated oxidative alkylamine cyclisation, afforded the iron complex 37. This complex was converted into anhydrolycorinone (33) by an intramolecular palladium-mediated biaryl coupling. The oxidation of 33 with DDQ provided hippadine (34).

Scheme 7 Reagents and conditions: i, THF, −78 °C; ii, DIBAL-H, PhMe, −78 °C; iii, iodopiperonylamine·HCl, MeOH, NaBH₃CN, 4 Å MS; iv, Cp₂FePF₆, Na₂CO₃, CH₂Cl₂, 25 °C; v, Me₃NO, Me₂CO, reflux; vi, Pd(PPh₃)₄, DMF, 100 °C, air; vii, DDQ, CH₂Cl₂, reflux.

The first total synthesis of (−)-21-isopentenylpaxilline (38), isolated from the sclerotioid ascostromata of Eupenicillium shearii (NRRL3324),²³ has been achieved starting from 39 and 40 (Scheme 8).^24,25 Key elements of the synthesis include the stereocontrolled construction of the eastern fragment (41), a highly efficient union of the eastern and western fragments (41 and 42, respectively), and the construction of 43, entailing mesylation followed by treatment with a Grignard reagent. Compound 43 was further converted into (−)-21-isopentenylpaxilline (38).

Scheme 8 Reagents and conditions: i, 42, MeLi, Et₂O, TMSCl, 0 °C, then s-BuLi, 0 °C to rt, then 0 °C quench with 41, 0 °C to rt; ii, PhMe, 110 °C; iii, MsCl, DMAP, CH₂Cl₂; iv, t-BuMgCl, PhMe, 110 °C; v, TBAF, THF; vi, Ph₃BiCO₃, PhH; vii, 10% Pd/C, 1-methyl-1,4-cyclohexadiene, MeOH, 65 °C.

The first total synthesis of (−)-penitrem D (44), isolated from Penicillium crustosum,²⁶ has been accomplished in a similar convergent and stereocontrolled manner (Scheme 9).²⁷ Union of the western hemisphere (45) and the eastern hemisphere (46) was achieved employing the 2-substituted indole synthesis. After oxidation of 47 and subsequent selective removal of the TMS and TES groups, a Sc(OTf)₃-promoted cationic cascade reaction completed construction of the nonacyclic system 48, which was then converted into (−)-penitrem D (44).

Scheme 9 Reagents and conditions: i, n-BuLi, THF, −78 °C to rt, then TMSCl, 0 °C, then s-BuLi, 0 °C, then 46, THF–Et₂O (1 : 1), 0 °C; ii, SiO₂, CHCl₃; iii, SO₃·pyridine, DMSO–Et₃N (4 : 1); iv, 1 N HCl, THF–H₂O (5 : 1); v, Sc(OTf)₃, PhH; vi, Ac₂O, DMAP, Et₃N, CH₂Cl₂; vii, TBAF, THF, 0 °C to rt; viii, o-nitrophenylselenocyanide, P(n-Bu)₃, THF; ix, m-CPBA, NaHCO₃, CH₂Cl₂, 0 °C to rt; x, K₂CO₃, MeOH, 0 °C to rt.

2.1.1 Indole auxins and phytoalexins

Three new cytotoxic 3,6-disubstituted indoles (49a–c) have been isolated from the mycelium of a strain identified as Streptomyces sp. (BL-49-58-005), which was separated from a Mexican marine invertebrate.²⁸ Their structures were established by analysis of spectral data (¹H and ¹³C NMR, COSY, HMQC, and HMBC experiments). Cytotoxic assays for these compounds were performed against a panel of 14 different tumor cell lines. Compound 49a showed the best activity against K-562 (leukemia), with a GI₅₀ value of 8.46 µM.

Hinckdentine A (50a) is an alkaloid isolated from the bryozoan Hincksinoflustra denticulate.²⁹ The first synthesis of unnatural 8-desbromohinckdentine A (50b) was achieved using a 20-step reaction sequence from readily available starting materials 51 and 52 (Scheme 10).³⁰ The quaternary center of hinckdentine A was formed using an uncommon pinacol-like rearrangement of 53 to produce key intermediate 54. The lactam 56 was synthesised by employing a seven-membered ring-forming intramolecular aldol condensation of 55 and subsequent reduction with complete stereocontrol. The dihydropyrimidine ring of 57 was prepared by means of a reaction sequence in which the Pd-catalysed amination of 56 is the key step. Bromination of 57 in HCO₂H afforded 8-desbromohinckdentine A (50b).

Scheme 10 Reagents and conditions: i, polyphosphoric acid, 120 °C; ii, NaNO₂, AcOH, rt; iii, Na₂S₂O₄, NaOH, H₂O, EtOH, reflux; iv, PbO₂, PhH, reflux; v, 1 N HCl, PhMe, rt, then reduced pressure, 105 °C; vi, allylmagnesium bromide, THF, rt; vii, 88% HCO₂H, PhMe, reflux; viii, Boc₂O, DMAP, MeCN, rt; ix, O₃, MeOH, −78 °C to rt; x, 2,4-dimethoxybenzylamine, AcOH, NaBH₃CN, MeOH, THF, rt; xi, Ac₂O, pyridine, 0 °C to rt; xii, LDA, THF, −78 °C, then AcOH, THF, −78 °C to rt; xiii, MsCl, pyridine, 0 °C to rt; xiv, Mg turnings, MeOH, rt; xv, Ph₂C=NH, NaOt-Bu, Pd(DPPF)₂Cl₂, DPPF, PhMe, 140 °C; xvi, 2 N HCl, THF, rt; xvii, 20% TFA, CH₂Cl₂, 0 °C to rt; xviii, 96% HCO₂H–2-propanol (1 : 1), 75 °C; xix, 96% HCO₂H, 100 °C; xx, Br₂, 96% HCO₂H, rt.

Wasalexin A (58) and desmethyl analogue 59 have been prepared starting from phenylacetyl chloride (Scheme 11).³¹ Following formylation of the key intermediate³²60, the resulting enol was converted to the enamine 61. Treatment of 61 with carbon disulfide, followed by methylation, afforded 58 or 59 depending on the conditions. The Z configuration of the double bond of 59 was determined on the basis of NOE experiments. A synthesis of arvelexin³³ (62) from 4-methoxyindole (63) employing a Grignard reagent has also been developed.³¹

Scheme 11 Reagents and conditions: i, MeONH₂·HCl, Na₂CO₃; ii, t-BuOCl; iii, Ag₂CO₃, TFA; iv, HCO₂Et, NaH; v, SOCl₂; vi, NH₄OH, MeOH; vii, NaH (1.1 eq.), CS₂, then MeI (1.1 eq.); viii, NaH (2.1 eq.), CS₂, then MeI (2.1 eq.); ix, MeI, Mg, Et₂O; x. BrCH₂CN.

2.1.2 Carbazoles and indolocarbazoles

Two new carbazole alkaloids, murrayanine (64) and 8,8″-biskoenigine (65) have been isolated from Murraya koenigii.³⁴ Their structures were elucidated by spectral data (¹H and ¹³C NMR, ROESY, and HMBC experiments). Compound 65 showed antiosteoporotic activity in the CAT-B model with IC₅₀ 1.3 µg ml⁻¹. The synthesis of 65 from koenigine (66) was carried out through oxidative coupling using a solid-state reaction (Scheme 12).

Scheme 12 Reagents and conditions: i, FeCl₃·6H₂O in the solid state.

Two novel quasi-racemic bisindole alkaloids, cycloaplysinopsin A (67a) and B (67b) have been isolated from tropical Indo-Pacific scleractinian corals of the family Dendrophylliidae.³⁵ Their structures were elucidated by spectroscopic analysis (ESIMS, ¹H and ¹³C NMR, COSY, and NOE experiments).

Three novel indole alkaloids named tubastrindoles A (68), B (69a), and C (69b) have been isolated from a stony coral, Tubastraea sp.³⁶ Their structures were elucidated on the basis of spectral data (¹H and ¹³C NMR, COSY, and HMBC experiments). Neither compound exhibited antibacterial, antifungal or cytotoxic activity.

A direct total synthesis of 9-methoxycarbazole-3-carbaldehyde (70), isolated from Murraya euchrestifolia Hayata,³⁷ has been achieved based on a novel methodology for the preparation of 1-methoxyindoles (Scheme 13).^38,39 Compound 71 was converted into the aldehyde 72 in 4 steps. Allylation of 72 followed by ring closing metathesis and DDQ oxidation afforded 9-methoxycarbazole-3-carbaldehyde (70).³⁹

Scheme 13 Reagents and conditions: i, methyl cyanoacetate, NaH, THF, 0 to 60 °C; ii, NaH, DMF, CH₂=CHCH₂Br, 0 °C to rt; iii, NaCl, DMSO, 155 °C; iv, DIBAL-H, dry PhMe, −78 °C; v, allyltributyltin, n-BuLi, THF, −78 °C; vi, Grubbs' catalyst, CH₂Cl₂, rt to reflux; vii, DDQ, AcOH, rt.

Mukonine (73a) has been isolated from the Indian curry-leaf tree, Murraya koenigii.⁴⁰ Mukonidine (73b) has been independently isolated from the stem bark of Murraya koenigii⁴¹ and from the root bark of Clausena excavata.⁴² The iron-mediated total synthesis of these alkaloids has been achieved by oxidative cyclisation with air as the oxidising agent (Scheme 14).⁴³ Electrophilic substitution of the methyl esters 74a and 74b with the iron-complex salt 36 led to the iron complexes 75a and 75b. The oxidative cyclisation of 75a and 75b by air in protic medium followed by demetalation provided mukonine (73a) and mukonidine (73b), respectively.

Scheme 14 Reagents and conditions: i, 36, MeCN, heat; ii, air, PhH, TFA, 25 °C; iii, Cp₂FePF₆, Na₂CO₃, ClCH₂CH₂Cl, 83 °C; iv, PhH, p-chloranil, 110 °C.

The neuronal cell protecting carbazole alkaloid, carbazomadurin A (76), isolated from the microorganism Actinomadura madurae 2808-SV1,⁴⁴ has been synthesised in 9 steps and 11% overall yield from isovanillic acid (77) (Scheme 15).⁴⁵ The key steps in the synthesis are the following palladium-catalysed reactions: Buchwald–Hartwig amination of 78 with 79, oxidative cyclisation of 80, and Stille coupling of 81 with 82. The resulting compound 83 was converted into carbazomadurin A (76).

Scheme 15 Reagents and conditions: i, MeOH, H₂SO₄, 65 °C; ii, 2,6-lutidine, Tf₂O, CH₂Cl₂, −10 °C to rt; iii, Pd(OAc)₂, BINAP, Cs₂CO₃, PhMe, 100 °C; iv, Pd(OAc)₂, dioxane, AcOH, 100 °C; v, BBr₃, CH₂Cl₂, −78 °C to rt; vi, t-BuPh₂SiCl, imidazole, DMF, 70 °C; vii, 82, Pd(PPh₃)₄, PhMe, 110 °C; viii, DIBAL-H, PhMe, 0 °C; ix, TBAF, THF, rt.

A formal total synthesis of murrayaquinone A (84), isolated from the root bark of Murraya eucrestifolia,⁴⁶ has been achieved using two sequential palladium-catalysed reactions as the key steps in a novel synthetic route to 1,2-dihydro-4(3H)-carbazolones (Scheme 16).⁴⁷ An intermolecular Stille cross-coupling of 85 with arylstannane 86 followed by a reductive N-heteroannulation of the resulting compound 87 afforded the carbazolone 88, which was converted into murrayaquinone A (84) according to the literature procedures.^48,49,50

Scheme 16 Reagents and conditions: i, I₂, CCl₄, pyridine; ii, PdCl₂(PhCN)₂, AsPh₃, CuI, NMP, 80 °C; iii, Pd(dba)₂, dppp, 1,10-phenanthroline, CO, DMF, 80 °C; iv, Pd/C. Ph₂O, 230 °C, 1,2,4-trimethylbenzene; v, Fremy's salt.

Koeniginequinones A (89a) and B (89b) have been isolated from the stem bark of Murraya koenigii.⁵¹ The total syntheses of these two compounds, and of murrayaquinone A (84) have been achieved employing regioselective addition of the arylamines 90a–c to 2-methyl-1,4-benzoquinone (91) followed by a palladium(II)-catalysed oxidative cyclisation (Scheme 17).⁵²

Scheme 17 Reagents and conditions: i, AcOH, MeOH, H₂O; ii, Pd(OAc)₂, Cu(OAc)₂, AcOH, heat.

The total synthesis of the carbazole-1,4-quinol alkaloids carbazomycins G (92a) and H (92b), isolated from Streptoverticillium ehimense,⁵³ has been achieved by a convergent iron-mediated construction of the carbazole framework (Scheme 18).⁵⁴ Electrophilic substitution of the arylamine 93 using the iron-complex salts 36 and 94, followed by oxidative iron-mediated arylamine cyclisation, afforded the carbazole derivatives 95a and 95b, respectively. These carbazoles were transformed to the corresponding carbazole-1,4-quinones 96a and 96b by oxidation with cerium(IV) ammonium nitrate. Finally, regioselective addition of methyllithium at C-1 provided carbazomycins G (92a) and H (92b).

Scheme 18 Reagents and conditions: i, MeCN; ii, Ac₂O, Et₃N, DMAP, CH₂Cl₂; iii, activated MnO₂, CH₂Cl₂; iv, (NH₄)₂Ce(NO₃)₆, MeCN, H₂O; v, MeLi, THF, −78 °C.

The total syntheses of calothrixins A (97) and B (98b), isolated from Calothrix cyanobacteria,⁵⁵ have been accomplished starting from quinoline-3,4-dicarboxylic anhydride (Scheme 19).⁵⁶ The key steps employed in the construction of the pentacyclic ring system are Friedel–Crafts acylation of indole with 99 and metalation of the N–MOM derivative 100. Deprotection of 98a with BBr₃ afforded calothrixin B (98b), which was further converted into calothrixin A (97) by Kelly's procedure.⁵⁷

Scheme 19 Reagents and conditions: i, dry MeOH, reflux; ii, SOCl₂, reflux; iii, indole, MeMgCl, ZnCl₂, CH₂Cl₂, rt; iv, NaH, MOMCl, THF, rt; v, LHMDS, TMEDA, THF, −78 °C to rt; vi, BBr₃, CH₂Cl₂, 0 °C to rt; vii, m-CPBA.

The total syntheses of tjipanazoles B (101a), D (102a), E (101b), and I (102b), isolated from Tolypothrix tjipanasensis,⁵⁸ have been achieved starting from TMS-nitro compound 103 and indole-2-carbaldehyde derivatives 104a and 104b (Scheme 20).⁵⁹ The key step is a condensation of 2,2′-biindoles 105a and 105b with (dimethylamino)acetaldehyde diethyl acetal to afford tjipanazoles D (102a) and I (102b). Tjipanazole D (102a) was further converted into tjipanazoles B (101a) and E (101b) by glycosidation with 106a and 106b, respectively.

Scheme 20 Reagents and conditions: i, cat. TBAF, 103, 104a or 104b; ii, TFAA, then DBU; iii, P(OEt)₃ or Pd(OAc)₂, PPh₃; iv, (dimethylamino)acetaldehyde diethyl acetal, AcOH; v, 45% KOH, Aliquat 336, 106a or 106b; vi, Pd(OH)₂, H₂.

2.2 Non-isoprenoid tryptamines

Bacillamide (107) has been isolated as a new algicide from the marine bacterium Bacillus sp SY-1.⁶⁰ The structure was elucidated by spectroscopic analysis (¹H, ¹³C, and ¹⁵N NMR, HMBC, and HSQC experiments). Compound 107 showed algicidal activity against the harmful dinoflagellate, Cochlodinium polykrikoides, with an LC₅₀ of 3.2 µg ml⁻¹.

Kottamide E (108), a novel indole alkaloid containing dibrominated indole enamide, oxalic acid diamide, and 4-amino-1,2-dithiolane-4-carboxamide moieties, has been isolated from the New Zealand ascidian Pycnoclavella kottae.⁶¹ The structure was established by spectroscopic analysis (¹H, ¹³C, and ¹⁵N NMR, HMBC, and HSQC experiments).

Aciculosporium take (Ascomycota; Clavicipitaceae), causes the witches' broom disease in bamboo, particularly Phyllostachys bambusoides. N-p-Coumaroylserotonin (109a) and N-feruloylserotonin (109b) have been found to accumulate in the diseased twigs.⁶² Compound 109a possesses antifungal activity, and A. take was unable to grow at concentrations of 109a higher than 100 µg ml⁻¹. However, A. take grew at 100 µg ml⁻¹ of 109b.

The structure of gelsemoxonine,⁶³ isolated from Gelsemium elegans Benth., has been revised to a novel oxindole alkaloid (110) having an azetidine unit, based on the reinvestigation of its spectral data and the result of X-ray single crystallographic analysis.⁶⁴ A new alkaloid, 14,15-dihydroxygelsenicine (111), which was presumed to be a biosynthetic precursor of 110, has also been isolated.

Three new gelsedine-type oxindole alkaloids, GS-1 (112a), GS-2 (112b), and GS-3 (113), have been isolated from the stems and leaves of cultivated Carolina jasmine (Gelsemium sempervirens Ait. f.).⁶⁵ Their structures were determined by spectroscopic analysis (¹H and ¹³C NMR, and HMBC experiments). The absolute configuration of these alkaloids was determined by comparison of their CD spectra with that of gelsemicine.

Ipobscurines B–D (114–116) have been isolated from the methanolic seed extract of Ipomoea obscura.⁶⁶ Their structures were established on the basis of spectral data (HR-EIMS, ¹H and ¹³C NMR, and NOESY spectra). Moreover, total synthesis of the racemic erythro- and threo-ipobscurine B 4′,4″-dimethyl ethers and comparison with the corresponding derivative of natural (−)-ipobscurine B proved the erythro configuration of the latter.

The synthesis of coscinamide B (117), isolated from Coscinoderma sp.,⁶⁷ has been achieved starting from tryptamine, which was condensed with 3-indolylglyoxyl chloride to give 118a (Scheme 21).⁶⁸ After sulfonylation of 118a, one-pot benzylic bromination of the resulting 118b and subsequent in situ dehydrobromination in the absence of an added base produced 119. Alkaline hydrolysis of 119 furnished coscinamide B (117).

Scheme 21 Reagents and conditions: i, MeCN, rt; ii, PhSO₂Cl, BnEt₃NCl, NaOH, CH₂Cl₂, rt; iii, NBS, (PhCO₂)₂O, CCl₄, reflux; iv, K₂CO₃, MeOH, H₂O, reflux.

Terpentin (120a) is a novel peptide recently isolated from Aspergillus terreus which inhibits the cell cycle at G2/M phase (Scheme 22).⁶⁹ The related aspergillamide A (120b) and the corresponding E-enamide stereoisomer, aspergillamide B (121), have been isolated from the genus Aspergillus and they showed modest in vitro cyctotoxicity toward the human carcinoma cell line HCT-116.⁷⁰ The total syntheses of these natural products have been achieved starting from tryptophan derivatives 122a and 122b.⁷¹ As a key reaction, an oxidative decarboxylation–elimination of the carboxylic acids 123a and 123b was employed to construct the indolic enamide moiety of 124a and 124b. Compound 124a was converted into (−)-terpentin (120a). Deprotection of 124b gave (−)-aspergillamide A (120b). Isomerisation of 124b to the E-isomer followed by deprotection afforded (−)-aspergillamide B (121).

Scheme 22 Reagents and conditions: i, 1. 10% HF, MeCN, 2. HOBT, EDC, DIEA, DMF, 0–25 °C, Boc–NMe-L-Val–OH, 3. 10% HF, MeCN, 4. HATU, DIEA, DMF, 0–25 °C, Boc-L-Val–OH, 5. TMSOTf, 2,6-lutidine, 6. MeOH; ii, 1. TFA, CH₂Cl₂, 2. HOBT, EDC, DIEA, DMF, 0–25 °C, Boc-L-NMePhe–OH, 3. TFA, CH₂Cl₂, 4. HATU, DIEA, DMF, 0–25 °C, Boc-L-Leu–OH, 5. TFA, CH₂Cl₂; iii, Et₃N, Ac₂O, CH₂Cl₂; iv, LiOH, THF, H₂O; v, Pb(OAc)₄, Cu(OAc)₂, pyridine, THF, 0 °C to rt; vi, PS-TBD, CH₂Cl₂, 0 °C; vii, Mg, MeOH, rt, 0 °C to rt; viii, KI, AcOH.

A synthesis of psilocin (125), reported to enter the central nervous system and cause powerful psychotomimetic effects,⁷² has been achieved (Scheme 23).⁷³ The key step is the preparation of 126 by the palladium-catalysed cyclisation of the protected aniline derivative 127 and the silyl acetylene 128. Removal of the protecting groups of 126 afforded psilocin (125).⁷⁴

Scheme 23 Reagents and conditions: i, TsCl, Et₃N, CH₂Cl₂; ii, Me₂NH, rt; iii, n-BuLi, Et₂O, −10 °C, then TMSCl; iv, Pd(OAc)₂, PPh₃, NEt₄Cl, i-Pr₂EtN, DMF, 80 °C; v, TFA, 25 °C; vi, BBr₃, CH₂Cl₂, −78 to 25 °C.

The large-scale syntheses of psilocin (125) and psilocybin (129), the principal hallucinogenic constituents of magic mushroom, have been achieved without chromatographic purification (Scheme 24).⁷⁵ The key step in the synthesis of 129 is the isolation of the dibenzyl-protected zwitterionic derivative 130.

Scheme 24 Reagents and conditions: i, Ac₂O, pyridine; ii, (COCl)₂; iii, Me₂NH; iv, LiAlH₄; v, [(BnO)₂PO]₂O, n-BuLi, THF, −78 °C to 0 °C; vi, Pd/C, H₂.

The total synthesis of (+)-hapalindole Q (131), isolated from the terrestrial blue-green alga Hapalosiphon fontinalis,⁷⁶ has been achieved in 12 steps starting from the indole-3-carbaldehyde derivative 132 (Scheme 25).⁷⁷ The key step is a Diels–Alder reaction mediated by the organocatalyst 133 to provide the critical intermediate 134 with high enantioselectivity. The intermediate then underwent a series of functional group transformation to converge with 135, which was further converted into (+)-hapalindole Q (131).

Scheme 25 Reagents and conditions: i, malonic acid, pyridine, pyrrolidine, reflux; ii, EtOH, cat. H₂SO₄, reflux, Dean–Stark; iii, DIBAL-H, CH₂Cl₂, −10 to 0 °C; iv, Dess–Martin periodinane, CH₂Cl₂, 0 °C or DMSO, (COCl)₂, CH₂Cl₂, −78 °C, Et₃N; v, DMF–MeOH (1 : 1) (5% H₂O); vi, NaClO₂, NaH₂PO₄, 2-methyl-2-butene, t-BuOH; vii, 1. DPPA, Et₃N, PhMe, reflux, 2. MeOH, sealed tube, 150 °C. viii, K₂OsO₂(OH)₄, DABCO, MeSO₂NH₂, K₂CO₃, K₃Fe(CN)₆, THF, H₂O; ix, NaIO₄/SiO₂, CH₂Cl₂; x, KOt-Bu, Ph₃PCH₃I, THF; xi, KOt-Bu, Ph₃PCH₃I, PhMe, 60 °C; xii, TBAF, THF, reflux; xiii, TCDI, CH₂Cl₂, 0 °C.

A formal synthesis of (−)-peduncularine (136), isolated from the Tasmanian shrub Aristotelia peduncularis,⁷⁸ has been completed by preparing the key intermediate (−)-137 in 5 steps from imide 138 (Scheme 26).⁷⁹ The key reaction is a ring-closing metathesis of 139 to form 137 using Grubbs′ catalyst (140). Compound 137 has been previously converted into (−)-peduncularine (136).⁸⁰

Scheme 26 Reagents and conditions: i, NaBH₄, HCl, EtOH; ii, PhSO₂H, CaCl₂, CH₂Cl₂, rt; iii, CH₂=CHMgBr, ZnCl₂, THF, rt, then, H₂SO₄; iv, LDA, THF, 0 °C, then CH₂=CHCH₂Br, −78 °C to −20 °C; v, 140, 40 °C.

A brief synthesis of the spiropyrrolidinyloxindoles (±)-horsfiline (141a) and (±)-coerulescine (141b) has been achieved, starting from itaconic acid and (respectively) p-anisidine or o-iodoaniline (Scheme 27).⁸¹ Tandem radical cyclisation of iodoaryl alkenyl azides 142 is the key step in both syntheses.

Scheme 27 Reagents and conditions: i, t-BuLi, Et₂O then ICH₂CH₂I; ii, TFA, CH₂Cl₂; iii, ZnCl₂, PhCHO, MeOH, NaBH₃CN; iv, Et₃N, 143, PhH; v, PhSH, DBU, THF; vi, DIBAL-H, PhMe; vii, m-CPBA, CH₂Cl₂, then PhMe, heat; viii, LiCl, NaBH₄, EtOH, THF; ix, PPh₃, (PhO)₂P(O)N₃, DEAD, THF; x, (Me₃Si)₃SiH, AIBN, PhH; xi, CH₂O, NaBH₃CN, MeCN; xii, Na, NH₃.

The structures of D-seco Corynanthe-type oxindoles Us-7 and Us-8, isolated from a Rubiaceous plant, Uncaria attenuata Korth,⁸² were proposed as 144 and 145, respectively (Scheme 28). Aimi's group has succeeded in the syntheses of 145 and 146 starting from (S)-glycidol through 147 and 148.⁸³ The synthetic 145 and 146 are completely identical in all respects (chromatographic behavior, mass, IR, UV, CD, ¹H and ¹³C NMR, [α]_D) with natural Us-8 and Us-7, respectively. Therefore, the structure of Us-7 was revised from 144 (with the (3R,7S) configuration), to 146 (with the (3S,7R) configuration), and the absolute stereochemistry at C-15 of both alkaloids was established.

Scheme 28 Reagents and conditions: i, tryptamine, AlMe₃ in hexane, CH₂Cl₂, rt; ii, Cbz₂O, CeCl₃, THF, 60 °C; iii, POCl₃, PhH, reflux; iv, NaBH₄, MeOH, 0 °C; v, C₆H₅OCHO, CH₂Cl₂, rt; vi, t-BuOCl, Et₃N, CH₂Cl₂, −30 °C, then 1 drop AcOH, aq. MeOH, reflux; vii, H₂, 10% Pd/C, EtOH, rt, then Dess–Martin periodinane, rt.

2.2.1 Piperazinediones

Marine fungi producing antifungal compounds were screened against Pyricularia oryzae and a novel diketopiperazine (149) has been isolated from the fungus M-3 isolated from the marine alga Porphyra yezoensis.⁸⁴ The structure was elucidated by spectroscopic methods (¹H and ¹³C NMR, COSY, HMQC, and HMBC experiments). The MIC of 149 against Pyricularia oryzae was 0.36 µM.

A brief total synthesis of the cell cycle inhibitor tryprostatin B (150), isolated from a marine strain (BM939) of Aspergillus fumigatus,⁸⁵ has been achieved in 32% overall yield from the readily available cyclo-(L-Trp-L-Pro) (151) (Scheme 29).⁸⁶ Tandem C-3 prenylation/cyclisation of 151 gave the corresponding pentacyclic pyrroloindoles 152 and 153. These compounds were then submitted to acid-catalysed opening of the newly formed ring, with concomitant migration of the prenyl group to the indole C-2 position, giving trifluoroacetate ester 154 and tryprostatin B (150), respectively. Exposure of compound 154 to Et₃N gave tryprostatin B (150).

Scheme 29 Reagents and conditions: i, prenyl bromide, Mg(NO₃)₂·6H₂O, AcOH–NaOAc buffer, rt; ii, CF₃CO₂H–CH₂Cl₂ (1 : 10), rt; iii, Et₃N, MeOH, rt; iv, Yb(OTf)₃, MeNO₂, reflux.

An asymmetric total synthesis of spirotryprostatin A (155), isolated from Aspergillus fumigatus,⁸⁷ has been achieved utilising the asymmetric [1,3]-dipolar cycloaddition reaction of methylene indolinone 156 as the key step (Scheme 30).⁸⁸ Compound 157 was further converted into spirotryprostatin A (155) through 158.

Scheme 30 Reagents and conditions: i, TFA, PhMe, 0 °C, then 159, 160, 3 Å MS, PhMe, −15 ° to 0 °C; ii, H₂, Pd(OH)₂, THF, MeOH; iii, n-PrCHO, AcOH, 65 °C; iv, L-Pro–OBn·HCl, BOP, Et₃N, MeCN; v, H₂, Pd/C, EtOH, MeOH; vi, WSC, Et₃N, MeCN; vii, p-TsOH·H₂O, 3 Å MS, PhMe, 110 °C.

The total synthesis of spirotryprostatin B (161), isolated from the fermentation broth of Aspergillus fumigatus BM939,⁸⁹ has been accomplished by employing the MgI₂-catalysed ring-expansion reaction of spiro[oxindole-3,1′-vinylcyclopropane] (162) in the presence of alkynyl imine 163 as a key reaction (Scheme 31).⁹⁰ The resulting 164 was converted into 165 through the coupling of the L-proline fragment by a Kociensky–Julia reaction. From 165, the synthesis of spirotryprostatin B (161) was completed in 4 steps following the Danishefsky route.⁹¹

Scheme 31 Reagents and conditions: i, piperylene, [Rh(OAc)₂]₂, PhH, CH₂Cl₂, reflux; ii, 163, MgI₂, THF, sealed tube, 75 °C; iii, Pd(PPh₃)₄, 1,3-dimethylbarbituric acid, CH₂Cl₂, 30 °C; iv, Et₃N, Boc-L-ProCl, CH₂Cl₂, rt; v, NMO·H₂O, OsO₄, THF, t-BuOH, H₂O, rt; vi, Pb(OAc)₄, AcOEt, rt; vii, NaClO₂, 2-methyl-2-butene, t-BuOH, pH 3.6 buffer, rt; viii, CH₂N₂, Et₂O, rt; ix, TBAF, THF, rt; x, H₂, Pd/BaSO₄, quinoline, EtOH, rt; xi, 166, LHMDS, THF, −78 °C; xii, 1. PhSeCl, LHMDS, THF, 0 °C, 2. DMSO, THF, 0 °C; xiii, 1. TFA, CH₂Cl₂, rt, 2. Et₃N, CH₂Cl₂, rt.

The first total synthesis of paraherquamide A (167), isolated from cultures of Penicillium paraherquei,⁹² has been achieved (Scheme 32).⁹³ The key steps in this asymmetric, stereocontrolled synthesis include enantioselective synthesis of an α-alkylated-β-hydroxyproline derivative, coupling of the gramine derivative⁹⁴168 with the diketopiperazine 169, an intramolecular S_N2′ cyclisation of 170, and a palladium-mediated ring closure to produce 171. Following a sequence of reactions, 171 was converted to (−)-paraherquamide A (167).

Scheme 32 Reagents and conditions: i, P(n-Bu)₃, MeCN; ii, HMPA, H₂O, LiCl, 105 °C; iii, Me₃OBF₄, Cs₂CO₃, CH₂Cl₂; iv, DMAP, Et₃N, (Boc)₂O; v, TBAF, THF; vi, MsCl, collidine, CH₂Cl₂, 7 °C, then HMPA, n-Bu₃BnNCl; vii, TBSOTf, 2,6-lutidine, CH₂Cl₂; viii, NaH, THF, heat; ix, PdCl₂, AgBF₄, MeCN, then propylene oxide, then NaBH₄, EtOH; x, aq. HCl, THF; xi, 2-hydroxypyridine, PhMe, reflux; xii, DIBAL-H, CH₂Cl₂; xiii, NaH, MeI, DMF; xiv, bromocatecholborane, CH₂Cl₂; xv, Dess–Martin periodinane, CH₂Cl₂; xvi, TFA, CH₂Cl₂; xvii, t-BuOCl, pyridine; xviii, TsOH, THF, H₂O; xix, (PhO)₃PMeI, DMPU; xx, MeMgBr, THF.

A short enantioselective total synthesis of okaramine N (172), isolated from the fungus Penicillium simplicissum (ATCC 90288),^95,96 has been accomplished. Starting from (S)-tryptophan methyl ester, it was converted into 173 by reductive N-alkylation with 3-methyl-2-butenal, followed by acylation with 174 (Scheme 33).⁹⁷ The key reaction in the synthesis is a Pd-promoted conversion of 173 to the dihydroindoloazocine tricycle 175. Cyclisation of 175, followed by an ene reaction with N-methyltriazolinedione and photooxidation, produced okaramine N (172).

Scheme 33 Reagents and conditions: i, 3-methyl-2-butenal, CH₂Cl₂, then removal of CH₂Cl₂, then NaBH₄, MeOH, then BOPCl, 174; ii, Pd(OAc)₂, AcOH, dioxane, H₂O, O₂, 25 °C; iii, Et₂NH, THF; iv, N-methyltriazolinedione, CH₂Cl₂, −5 °C, then removal of CH₂Cl₂, then O₂, sunlamp, MeOH, methylene blue, −28 °C, then Me₂S, then 110 °C.

2.2.2 Physostigmine and related compounds

A new 16N-ethoxycarbonyl derivative (176) of 3,12-dihydroroquefortin has been isolated from the fermentation broth of Penicillium aureovirens VKM FW-766.⁹⁸ The structure was assigned on the basis of spectral analysis (HR-EIMS, ¹H and ¹³C NMR, DEPT, NOESY, HMQC, and HMBC experiments).

A formal total synthesis of (±)-physostigmine (177), isolated from calabar beans,⁹⁹ has been achieved (Scheme 34).¹⁰⁰ The key step in the synthesis is a new vicarious nucleophilic substitution reaction between p-nitroanisole and the C-silylated derivative of N-methylpyrrolidinone (178). Subsequent conversion of 179 to the tricyclic framework of physostigmine followed a well-established protocol and provided the key intermediate 180. The final 3 steps to obtain (±)-physostigmine (177) are efficient and well-established.¹⁰¹

Scheme 34 Reagents and conditions: i, TASF, THF, −78 °C, then DDQ; ii, MeI, CsOH·H₂O, PhMe, n-Bu₄NBr, rt; iii, H₂, 10% Pd/C, AcOEt, 50 psi; iv, LiAlH₄, THF.

A total synthesis of (−)-pseudophrynaminol (181), isolated from the skin of the Australian frog Pseudophryne coriacea, ¹⁰² has been achieved by a sequence involving 3-allylindol-2-one (182) as a key intermediate (Scheme 35).¹⁰³ The enantioselective construction of the quaternary carbon in 182 was performed through a tandem cascade reaction of 2-allyloxyindolin-3-one (183), olefination, isomerisation, and asymmetric Claisen rearrangement. Compound 182 was converted into (−)-pseudophrynaminol (181) through the reductive cyclisation of 184.

Scheme 35 Reagents and conditions: i, Br₂, CH₂Cl₂, 0 °C, then 185, MeCN, DMF, 4 Å MS, rt; ii, (EtO)₂POCH₂CN, KOt-Bu, DMF, −78 °C to rt; iii, 35% NaOH aq., MeOH, reflux; iv, HOC₆F₅, Et₃N, EDC, THF, then MeNH₂, rt; v, OsO₄, NMO, MeCN, rt, then NaIO₄, dioxane, H₂O; vi, Ph₃P=C(Me)CO₂Me, pyridine, MeCN, reflux; vii, LiAlH₄, THF, reflux.

A three-step total synthesis of debromoflustramine B (186), isolated from the marine byrozoan Flustra foliacea,¹⁰⁴ has been completed starting from tryptamine (Scheme 36).¹⁰⁵ The key step is the zinc triflate mediated alkylation of 187 to afford 188. Reduction of 188 with Red-Al gave debromoflustramine B (186).¹⁰⁶

Scheme 36 Reagents and conditions: i, ClCO₂Et, CH₂Cl₂, aq. NaHCO₃, 0 °C; ii, prenyl bromide, Zn(OTf)₂, n-Bu₄NI, i-Pr₂NEt, PhMe, rt; iii, Red-Al, PhMe, reflux.

The convergent total synthesis of (+)-okaramine J (189), isolated from fermentation extracts of Penicillium simplicissimum and Aspergillus aculeatus cultured on okara,⁹⁵ has been achieved in a linear sequence of 12 steps from L-tryptophan t-butyl ester (Scheme 37).¹⁰⁷ A key reaction is the acid-catalysed room-temperature aza-Claisen rearrangement of the N-reverse-prenylated hexahydro[2,3-b]pyrroloindole 190 to the C-prenylated derivative 191. Removal of the t-butyl ester of 191 followed by coupling with 192 afforded 193, which was converted into (+)-okaramine J (189) by removal of protecting group and subsequent cyclisation.

Scheme 37 Reagents and conditions: i, HC≡CC(Me)₂Br, CuCl, i-Pr₂NEt, THF; ii, H₂, Pd/Al₂O₃, AcOEt; iii, TFA, CH₂Cl₂; iv, TMSOTf, 2,6-lutidine, CH₂Cl₂; v, PyBop, Et₃N, 192, THF; vi, Al/Hg, THF, H₂O; vii, 10% KOH, MeOH, 1,4-dioxane; viii, HBTU, i-Pr₂NEt, CH₂Cl₂.

The enantioselective total synthesis of (−)-idiospermuline (194), isolated from the seed of Idiospermum australiense,¹⁰⁸ has been achieved starting from isatine in 6% overall yield (Scheme 38).^109,110 The first key step in the synthesis is stereocontrolled formation of the vicinal quaternary carbon centers of 195 by dialkylation of the lithium dienolate of dihydroisoindigo (196) with enantiopure ditriflate 197. The second key step is a catalyst-controlled diastereoselective Heck reaction of 198 to afford an inseparable 6 : 1 mixture of 199 and 200. Catalytic hydrogenation of this mixture, followed by reduction of the carbonyl group and treatment with Na in NH₃ provided (−)-idiospermuline (194) and isomer 201, which could be separated readily by preparative HPLC.

Scheme 38 Reagents and conditions: i, NaH, BnBr, DMF, rt; ii, oxindole, AcOH, HCl, 110 °C; iii, Cs₂CO₃, MeI, DMF, rt; iv, PtO₂, H₂, AcOEt, rt; v, LHMDS, THF, HMPA, 197, −40 °C; vi, Pd(OAc)₂, (S)-Tol-BINAP, PMP, MeCN, 80 °C; vii, Pd(OH)₂, 1500 psi H₂, 80 °C, EtOH; viii, 1. Red-Al, PhMe, rt, 2. Na, NH₃, THF, −78 °C.

Hodgkinsine (202) has been isolated from the leaves of Hodgkinsonia frutescens¹¹¹ and hodgkinsine B (203) from Amazon Psychotria species (Scheme 39).¹¹² The enantioselective total syntheses of these alkaloids from meso-chimonanthine (204) have been accomplished^113,114 by highly concise sequences.¹¹⁵ The key reaction in the synthesis is an asymmetric intramolecular Heck reaction of 205, prepared from 204 in 4 steps, to afford enantioenriched 206 and 207. Saturation of the alkene double bond of 206 and 207, followed by reductive deprotection–cyclisation, furnished hodgkinsine (202) and hodgkinsine B (203). The stereorational total synthesis of 203 established the relative and absolute configuration of this Psychotria natural product.

Scheme 39 Reagents and conditions: i, Boc₂O, NaHMDS, THF, rt; ii, 1. s-BuLi, TMEDA, THF, −78 °C, 2. diiodoethane, −78 °C to 0 °C; iii, TMSOTf, CH₂Cl₂; iv, 208, Pd₂(dba₃)·CHCl₃, P(2-furyl)₃, CuI, DMA, rt; v, Pd(OAc)₂, (R)-Tol-BINAP, PMP, MeCN, 80 °C; vi, Pd(OH)₂, 80 psi H₂, 80 °C, EtOH; vii, Na, NH₃, THF, −78 °C.

2.2.3 Pyrrolo[3,2-e]indoles and pyrrolo[2,3-f]indoles

A novel chiral dipyrrolobenzoquinone derivative, terreusinone (209a), has been isolated as a potent UV-A protectant from the marine algicolous fungus Aspergillus terreus.¹¹⁶ The structure was established by spectroscopic analysis (¹H and ¹³C NMR, COSY, TOCSY, DEPT, HMBC, and HSQC experiments) and the absolute stereochemistry was determined by Horeau's method¹¹⁷ and quantum calculations. 209a exhibited a UV-A absorbing activity with an ED₅₀ value of 70 µg ml⁻¹.

Preparative-scale fermentation of terreusinone (209a) with Streptomyces sp. has resulted in the isolation of a new oxidised metabolite, terreusinol (209b).¹¹⁸ The structure was determined by spectral analysis (¹H and ¹³C NMR, DEPT, HMQC, and HMBC experiments). Terreusinol (209b) showed UV-A protecting activity with an ED₅₀ value of 150 µM, making it more active than oxybenzone (ED₅₀ = 350 µM) currently being used as sunscreen.

Yatakemycin (210), a novel antibiotic belonging to the family of CC-1065 and the duocarmycins, known DNA alkylating reagents, has been found in the culture broth of Streptomyces sp. TP-A0356.¹¹⁹ The structure was elucidated by spectroscopic methods (CID-MS/MS, ¹H and ¹³C NMR, DOF-COSY, HMQC, and HMBC experiments). 210 inhibited the growth of pathogenic fungi such as Aspergillus fumigatus and Candida albicans with MIC values of 0.01–0.03 µg ml⁻¹, lower than amphotericin B (MIC = 0.1–0.5 µg ml⁻¹) and itraconazole (MIC = 0.03–0.2 µg ml⁻¹). 210 also showed potent cytotoxicity against cancer cell lines with an IC₅₀ of 0.01–0.03 µg ml⁻¹.

Five new alkaloids, dictyodendrins A–E (211, 212, 213a, 213b and 214, respectively), have been isolated from the Japanese marine sponge Dictyodendrilla verongiformis as telomerase inhibitors.¹²⁰ Their structures were elucidated by spectroscopic (HR-FABMS, ¹H and ¹³C NMR, ROESY, and HMBC experiments) and chemical methods. Dictyodendrins are tyramine-based pyrrolocarbazole derivatives containing three or four p-hydroxyphenyl groups. They inhibited telomerase completely at a concentration of 50 µg ml⁻¹.

A total synthesis of seco-duocarmycin SA (215), a highly potent cytostatic agent, has been achieved (Scheme 40).¹²¹ Starting from 2-methoxy-4-nitroaniline (216) the synthetic protocol contains a Fischer indole synthesis using phenylhydrazone 217 to introduce the heterocyclic scaffold, and a radical 5-exo-trig-cyclisation of 218 to furnish the chloromethylindoline derivative 219 as key reactions.

Scheme 40 Reagents and conditions: i, NaNO₂, HCl, then SnCl₂; ii, NaOAc, methyl pyruvate, MeOH; iii, PPA, xylene; iv, AlCl₃, CH₂Cl₂; v, BnBr, K₂CO₃; vi, Boc₂O, DMAP; vii, Lindlar catalyst, quinoline, AcOEt, H₂; viii, Boc₂O, THF; ix, NBS, THF; x, NaH, DMF, then (E/Z)-1,3-dichloropropene; xi, (Me₃Si)₃SiH, AIBN, PhH; xii, 4 M HCl–AcOEt, then TMI-CO₂H, EDC, DMF; xiii, NH₄HCO₂, Pd/C, THF.

(+)-Duocarmycins A (220) and SA (221) are prominent members of the potent antitumor antibiotics isolated from Streptomyces species (Scheme 41).¹²² A convergent synthesis of (+)-duocarmycin A (220) has been achieved starting from 222 through 223, whose flexible strategy also enabled a straightforward synthesis of (+)-duocarmycin SA (221).¹²³ The key reaction is the copper-mediated aryl amination reaction which has been used for forming all of the aryl–nitrogen bonds present in the duocarmycins. The intermediates 224 and 225 obtained by the aryl amination were converted into 220 and 221, respectively.

Scheme 41 Reagents and conditions: i, n-BuLi, THF, −78 °C; then 226 in PhMe, −78 °C; ii, NBS, DMF, 23 °C; iii, CuI, CsOAc, DMSO, 23 °C; iv, TrocCl, NaHCO₃, MeCN, 70 °C; v, Zn, KH₂PO₄, THF–H₂O (5 : 1), 23 °C; vi, 227, pyridine, CH₂Cl₂, 0 °C; vii, TBAF, THF, 23 °C; viii, MsCl, pyridine, 0 °C; ix, H₂, Pd/C, AcOEt, EtOH, 23 °C; x, CsCO₃, MeCN, 23 °C; xi, n-BuLi, THF, −78 °C, then I₂; xii, 228, Pd(OAc)₂, P(O-tolyl)₃, Et₃N, MeCN, 90 °C.

2.2.4 Indoloiminoquinones

Discorhabdins S (229), T (230), and U (231), three new discorhabdin analogues, have been isolated from a deep-water marine sponge of the genus Batzella.¹²⁴ Their structures were elucidated based on spectroscopic methods (HR-ESIMS, ¹H and ¹³C NMR, DEPT, HMQC, and HMBC experiments). 229, 230, and 231 showed in vitro cytotoxicity against murine P-388 tumor cells, with IC₅₀ values of 3.08, >5, and 0.17 µM, respectively. Cytotoxicity was also observed for A-549 human lung adenocarcinoma cells (IC₅₀ values of >5, >5, and 0.17 µM, respectively), and for PANC-1 human pancreatic cells (IC₅₀ values of 2.6, 0.7, and 0.069 µM, respectively).

The synthesis of the marine alkaloid sebastianine A (232), isolated from the ascidian Cystodytes dellechiajei,¹²⁵ has been accomplished via hetero-Diels–Alder reaction of indole-4,7-dione (233), prepared from 4,7-dimethoxyindole (234) in 3 steps, with trifluoroacetamidocinnamaldehyde dimethylhydrazone (235) (Scheme 42).¹²⁶ Subsequent cyclisation of 236 under alkaline conditions gave sebastianine A (232).

Scheme 42 Reagents and conditions: i, NaH, Boc₂O, THF, rt; ii, CAN, MeCN–H₂O (4 : 1), rt; iii, TFA, CH₂Cl₂, rt; iv, PhMe, reflux then MnO₂; v, 1 N NaOH, CH₂Cl₂.

The first total synthesis of (+)-discorhabdin A (237), isolated from marine sponges such as New Zealand sponges of the genus Latrunculia¹²⁷ and the Okinawa sponge Prianos melanos,¹²⁸ has been achieved starting from L-tyrosine methyl ester hydrochloride (Scheme 43).¹²⁹ The key step of the synthesis involves both a diastereoselective oxidative spirocyclisation of 238 using a hypervalent iodine(III) reagent and an efficient construction of the labile and highly strained N,S-acetal core (239). Removal of the tosyl group of 239 gave discorhabdin A (237) in an optically pure form. Discorhabdin A shows potent antitumor activity.

Scheme 43 Reagents and conditions: i, TrCl, Et₃N, DMF; ii, NBS, DMF; iii, DIBAL-H, CH₂Cl₂, −78 °C to rt; iv, TBSCl, DBU, CH₂Cl₂, 0 °C; v, TBAF, THF, 0 °C; vi, 0.1 N HCl, MeOH, then 240, MeOH; vii, PIFA-MK10, CF₃CH₂OH; viii, BF₃·Et₂O, CH₂Cl₂, 0 °C to rt; ix, Pb(OAc)₄, CH₂Cl₂–MeOH (2 : 1), 0 °C; x, p-MeOC₆H₄CH₂SH, 30% HBr–AcOH, −78 to 4 °C then aq. MeNH₂; xi, NaOMe, THF, MeOH, 0 °C.

2.2.5 β- and γ-Carbolines

Five new manzamine type alkaloids, 32,33-dihydro-31-hydroxymanzamine A (241), 32,33-dihydro-6-hydroxymanzamine A-35-one (242), 32,33-dihydro-6,31-dihydroxymanzamine A (243), des-N-methylxestomanzamine A (244), and 1,2,3,4-tetrahydronorharman-1-one (245), have been isolated from an Indonesian sponge.¹³⁰ Their structures have been assigned on the basis of spectral data (HR-ESIMS, ¹H and ¹³C NMR, COSY, HMQC, and HMBC experiments). The structure of 241 was confirmed by X-ray crystallographic analysis. The bioactivity and SAR of the manzamines against malaria, TB, and leishmania are also presented.

Two new compounds, taraxacines A (246a) and B (246b), have been isolated and characterised from the fresh aerial parts of Taraxacum formosanum.¹³¹ Structures of 246a and 246b were determined by spectral analysis (¹H and ¹³C NMR, HMQC, and HMBC experiments).

Chemical investigation of the Micronesian ascidian Eudistoma sp. has afforded two new eudistomins, W (247) and X (248).¹³² Their structures were established on the basis of spectroscopic analysis (¹H and ¹³C NMR, COSY, and HMBC experiments). 248 exhibited antibiotic activity toward Bacillus subtilis, Staphyloccocus aureus, and Escherichia coli, and was also found to be fungicidal against Candida albicans in an agar diffusion assay. 247 was selectively active against C. albicans but showed no antibacterial activity.

Three novel enediyne antitumor antibiotics, shishijimicins A (249a), B (249b), and C (249c), have been isolated from a lipophilic extract of the thin encrusting orange ascidian Didemnum proliferum collected in southern Japan.¹³³ Their structures were determined by spectral analysis (¹H and ¹³C NMR, COSY, HOHAHA, HMBC, NOESY, and HMQC experiments). Shishijimicins show extremely potent cytotoxicity. The IC₅₀ values of shishijimicins A, B, and C against P388 cells are 0.47, 2.0, and 1.7 pg ml⁻¹, respectively.

Three new β-carboline alkaloids, n-pentyl β-carboline-1-propionate (250), 5-hydroxymethyl-9-methoxycanthin-6-one (251), and 1-hydroxy-9-methoxycanthin-6-one (252), have been isolated from the roots of Eurycoma longifolia.¹³⁴ Their structures were determined by spectral data (HR-FABMS, ¹H and ¹³C NMR, COSY, NOESY, HMQC, and HMBC experiments) and by chemical transformation.

Investigation of the extract of the sponge Cymbastela (order Halichondrida, family Axinellidae), screened against Caco-2 and A-431 cell lines, has led to the isolation of cytotoxic milnamide D (253).¹³⁵ The structure was assigned on the basis of spectral analysis (¹H and ¹³C NMR, COSY, HMQC, and HMBC experiments). In an assay for inhibition of tubulin polymerisation, the IC₅₀ value was 16.90 µM. In an HCT-116 cytotoxicity assay, the IC₅₀ value was 66.8 nM.

From the stem of Strychnos vanprukii, a new vincosan-type gluco-indole alkaloid, 3,4-dehydropalicoside (254) has been isolated.¹³⁶ The structure was elucidated based on spectroscopic evidence (ES-MS/MS, ¹H and ¹³C NMR, and HMBC spectra).

Indole alkaloid glycosides linked with a second secoiridoid glucoside unit have been isolated from the dried roots of Neonauclea sessilifolia and named as neonaucleosides A (255a), B (256), and C (257).¹³⁷ Their structures were determined by spectroscopic analysis (HR-ESIMS, ¹H and ¹³C NMR, ROESY, and HMBC experiments). The stereochemistry at C-3 of 255a was confirmed by the synthesis of 255a and its C-3 epimer (255b). Independently, the same alkaloids, 255b (major) and 255a (minor), have been isolated from the aerial parts of Psychotria bahiensis collected in Trinidad, West Indies¹³⁸ and named as bahienosides B and A, respectively.

Extraction of the leaves of Chimarrhis turbinata has led to the isolation of a new Corynanthean-type indole alkaloid, turbinatine (258).¹³⁹ The structure was elucidated based on spectroscopic data (¹H and ¹³C NMR, NOESY, HMQC, TOCSY, and HMBC experiments). An evaluation of the DNA-damaging activities was performed by means of a bioassay using mutant strains of Saccharomyces cerevisiae; 258 was weakly active.

Henrycinols A (259a) and B (259b) have been isolated from the roots of Melodinus henryi Craib.¹⁴⁰ Their structures were established on the basis of spectral analysis (HR-FABMS, ¹H and ¹³C NMR, NOESY, and HMBC experiments). The relative configuration of 259a and 259b was determined by NOESY analysis.

Three new alkaloids, 3-bromofascaplysin (260a), 14-bromoreticulatine (261), and 14-bromoreticulatate (262a), have been isolated along with the known reticulatate 262b from four organisms: two collections of the sponge Fascaplysinopsis reticulata and two collections of the tunicate Didemnum sp.¹⁴¹ Their structures were determined by spectral analysis (¹H and ¹³C NMR, HMBC, and NOESY spectra). These compounds were less cytotoxic than fascaplysin (260b).

Three new indoloquinazolidine-type alkaloids, 263a, 263b, and 264, have been isolated from Araliopsis tabouensis.¹⁴² Their structures were determined by spectral analysis (¹H and ¹³C NMR, COSY, HOHAHA, HMQC, and HMBC experiments). The antimalarial activities of compounds 263a, 263b, and 264 were evaluated against Plasmodium falciparum D6 and W2 clones. The IC₅₀ values in an antimalarial bioassay for 263b and 264 against D6 are 1.8 and 3.3 µg ml⁻¹. The corresponding IC₅₀ values against W2 are both >4.7 µg ml⁻¹. 263a is not active.

Two new alkaloids, 1,2-dihydroxyrutaecarpine (265) and 2-(2-[3-formylindolyl])-(3H)-quinazolin-4-one (bouchardatine, 266), have been isolated from the aerial parts of Bouchardatia neurococca (Rutaceae).¹⁴³ Their structures were determined by spectroscopic evidence (API-ESMS, ¹H and ¹³C NMR, COSY, and HMBC spectra).

A novel indole alkaloid, macrodasine A (267), incorporating fused spirocyclic tetrahydrofuran rings onto a macroline-like moiety, has been isolated from a Malayan Alstonia spcies.¹⁴⁴ The structure is also notable for the presence of a spiroacetal moiety in the alkaloid. The structure was established by spectroscopic analysis (¹H and ¹³C NMR, COSY, and HMBC experiments).

Two novel alkaloids, manadomanzamines A (268a) and B (268b), have been isolated from an Indonesian sponge Acanthostrongylophora sp. (Haplosclerida: Petrosiidae).¹⁴⁵ The structures were elucidated based on spectroscopic data (¹H and ¹³C NMR, COSY, HMQC, and HMBC experiments). Their absolute configuration and conformation were determined by CD, NOESY, and molecular modeling analysis. Manadomanzamines exhibited strong activity against Mycobacterium tuberculosis with MIC values of 1.9 and 1.5 µg ml⁻¹, respectively. They also exhibit activities against human immunodeficiency virus and AIDS opportunistic fungal infections.

8-Hydroxymanzamine A (269) has been isolated from sponges of the genera Amphimedon, Xestospongia, and Pachypellina.¹⁴⁶ The stereoselective dehydroxylation of 269 to form manzamine A (270), isolated from sponges of the genera Haliclona and Pellina,¹⁴⁷ has been completed by fermentation with Fusarium solani or Streptomyces seokies.¹⁴⁸ This unique biocatalytic conversion is important due to the fact that manzamine A (270) has more desirable biological activity when assayed in a murine model against malaria.

6-Methoxy-2-methyl-1,2,3,4-tetrahydro-β-carboline (271a) has been isolated from a variety of plant sources, such as Phalaris tuberosa¹⁴⁹ and Horsfieldia superba (Scheme 44).¹⁵⁰ Bauerine A (272) has been isolated from the blue–green alga Dichotrix baueriana.¹⁵¹ These β-carbolines have been prepared¹⁵² using a Stille cross-coupling of 273a and 273b with arylstannanes 274a and 274b, prepared from nitroanilines 275a and 275b, to give 276a and 276b, respectively. Subsequent palladium-catalysed N-heteroannulation of 276a and 276b afforded 6-methoxy-2-methyl-1,2,3,4-tetrahydro-β-carboline (271a) and 271b, respectively. N-Methylation of 271b followed by deprotection and oxidation using MnO₂ provided bauerine A (272).

Scheme 44 Reagents and conditions: i, NaNO₂, KI, H₂SO₄; ii, (n-Bu₃Sn)₂, PhMe, (PPh₃)₂PdCl₂, PPh₃, 80 °C; iii, 273a or 273b Pd(dba)₂, CuI, AsPh₃, NMP; iv, Pd(dba)₂, dppp, DMF, 1,10-phenanthroline, CO, 80 °C; v, NaH, MeI, THF, 0 °C; vi, 3 N HCl, AcOEt; vii, MnO₂, PhMe.

Harman (277a) and harmine (277b) were found to inhibit HIV replication in H9 lymphocyte cells.¹⁵³ These compounds also showed significant antitumor activity (Scheme 45).¹⁵⁴ Kusurkar's group has synthesised 277a and 277b starting from the indole-3-carbaldehyde derivatives 278a and 278b.¹⁵⁵ The key step is electrocyclic cyclisation of 279a and 279b leading to harman (277a) and harmine (277b), respectively.

Scheme 45 Reagents and conditions: i, Ph₃PMeI, KOt-Bu, THF; ii, LDA, THF, N,N-dimethylacetamide; iii, NH₂OH·HCl, NaOAc, o-dichlorobenzene, heat.

The first synthesis of marine alkaloid (±)-bengacarboline (280) has been achieved in 9 steps from indole-3-carboxylic acid (281) and tryptamine (Scheme 46).¹⁵⁶ The main features of this synthesis are the use of a microwave irradiation procedure for the formation of ketimine 282 and of trifluoroacetic anhydride to produce the tetrahydro-β-carboline derivative 283.

Scheme 46 Reagents and conditions: i, n-BuLi, THF; ii, PhSO₂Cl; iii, SOCl₂, neat; iv, tryptamine, K₂CO₃, AcOEt, H₂O; v, POCl₃, neat; vi, CbzCl, Na₂CO₃; vii, tryptamine, ZnCl₂, 1,4-Me₂C₆H₄, microwaves; viii, TFAA, CH₂Cl₂, reflux; ix, H₂, Pd/C, MeOH; x, K₂CO₃, MeOH, H₂O.

A synthesis of (+)-geissoschizine (284), a biosynthetic precursor of a variety of monoterpenoid indole alkaloids, has been performed starting from D-tryptophan (Scheme 47).¹⁵⁷ The key steps in the synthesis involve a vinylogous Mannich reaction to prepare the carboline 285, and an intramolecular Michael addition that leads to the tetracyclic Corynantheane derivative 286. Compound 286 was then transformed into 287 by a sequence that allowed the stereospecific introduction of the E-ethylidene moiety. Selective reduction of the lactam in 287 followed by removal of the carboxy group by radical decarbonylation gave 288. Formylation of 288 afforded (+)-geissoschizine (284).

Scheme 47 Reagents and conditions: i, HCO₂H, Ac₂O, HCl; ii, 289; iii, isobutylene, H₂SO₄; iv, diketene, DMAP, PhMe, then KOt-Bu; v, NaBH₄, MeOH; vi, NaOMe, MeOH, 50 °C, then AcCl; vii, Me₃OBF₄, 2,6-t-Bu₂Py, then NaBH₄; viii, TFA, PhSMe; ix, i-BuOCOCl, NaSePh; x, n-Bu₃SnH, AIBN, heat; xi, LDA, HCO₂Me.

The first total synthesis of racemic tangutorine (290), isolated from the leaves of Nitraria tangutorum,¹⁵⁸ has been performed in 7 steps starting from 291 (Scheme 48).¹⁵⁹ The key reactions in the synthesis are dithionite reduction of 292 to 293 and acidic cyclisation of 293 to 294. This was then converted into tangutorine (290) by reduction, dehydration of the resulting alcohol, and reduction of the ester group. The separation of the enantiomers of tangutorine was successfully performed by chiral HPLC.

Scheme 48 Reagents and conditions: i, tryptophyl bromide, 100 °C; ii, Na₂S₂O₄, NaHCO₃, MeOH, H₂O, rt; iii, HCl, MeOH, rt; iv, NaBH₄, AcOH, rt; v, MsCl, Et₃N, CH₂Cl₂, 0 °C; vi, DBU, 100 °C; vii, LiAlH₄, THF.

A stereoselective total synthesis of (±)-tangutorine (290) has been achieved in 19 steps starting from tryptamine (Scheme 49).¹⁶⁰ The key reactions are Heck coupling of 295 with methyl acrylate to give 296 and a formal intramolecular aza-[3+3] cycloaddition of 297 to afford 298. Compound 298 was further converted into (±)-tangutorine (290) in 9 steps.

Scheme 49 Reagents and conditions: i, phthalic anhydride, Et₃N, PhMe; ii, pyridine·HBr·Br₂, CHCl₃, THF, −10 °C; iii, Boc₂O, DMAP, CH₂Cl₂, rt; iv, methyl acrylate, Pd(PPh₃)₄, Cy₂NMe, PhMe, 95 °C; v, DIBAL-H, CH₂Cl₂, −78 °C; vi, NaBH₄, i-PrOH, H₂O, rt; vii, AcOH, i-PrOH, H₂O, 85 °C; viii, 1,3-cyclohexanedione, PhMe, reflux; ix, MnO₂, CH₂Cl₂, rt; x, cyclohexylamine, AcOH, EtOH–PhMe (2 : 3), Na₂SO₄, 95 °C; xi, 20% Pd(OH)₂, H₂, AcOEt; xii, Na, i-PrOH, THF, rt; xiii, pyridine–SO₃, DMSO, Et₃N; xiv, Boc₂O, DMAP, CH₂Cl₂; xv, NaH, (EtO)₂CO, THF, reflux; xvi, NaBH₄, MeOH, rt; xvii, MsCl, Et₃N, CH₂Cl₂, −78 °C; xviii, DBU, THF, reflux; xix, LiAlH₄, THF, 0 °C.

The total synthesis of (−)-raumacline (299), isolated from plant cell cultures of Rauwolfia serpentina Benth.,¹⁶¹ has been achieved. Starting from L-tryptophan, it was converted into the aminonitrile (300) (Scheme 50).¹⁶² The key steps are a cis-specific Pictet–Spengler reaction of 300 to yield 301 and a stereoselective Dieckmann cyclisation of 302 to give 303. Reduction of the ester group followed by the formation of lactone and reduction afforded (−)-raumacline (299).

Scheme 50 Reagents and conditions: i, TBSOCH₂CH₂CHO, 3 Å MS; ii, CH₂Cl₂, TFA, −78 °C to rt; iii, BnBr, 70 °C; iv, MeI, NaH, 0 °C; v, TBAF; vi, Swern oxidation; vii, (EtO)₂POCHEtCO₂Et, NaH; viii, LiNEt₂, THF, −78 °C; ix, LiBH₄; x, TsOH·H₂O, THF, reflux; xi, DIBAL-H; xii, H₂, Pd/C.

Isocryptolepine (304), isolated from the root of the West African plant Cryptolepis sanguinolenta,¹⁶³ has been synthesised in 3 steps (Scheme 51).¹⁶⁴ A selective Buchwald–Hartwig amination of 4-chloroquinoline (305) with 2-chloroaniline (306) afforded 307. Subsequent intramolecular arylation of 307, followed by methylation of 308, produced 304.

Scheme 51 Reagents and conditions: i, Pd₂(dba)₃, XANTPHOS, Cs₂CO₃, dioxane, reflux; ii, Pd₂(dba)₃, P(t-Bu)₃, K₃PO₄, dioxane, pressure tube, 120 °C; iii, MeI, DMF, 80 °C, then Na₂CO₃.

3 Isoprenoid tryptamines

Efforts directed towards the total synthesis of communesins A (309a) and B (309b) have been reported,¹⁶⁵ starting from the ergot alkaloid aurantioclavine¹⁶⁶ (310) (Scheme 52). The key step is the preparation of the intermediate 311 by a [4+2] cycloaddition reaction. Based on the ¹H and ¹³C NMR chemical shift data of 311 and 312, the authors suggest that the structure of the recently isolated microfilament-disrupting alkaloid nomofungin¹⁶⁷ (313), should be revised to 309b.

Scheme 52 Reagents and conditions: i, (Boc)₂O; ii, NaH, MeI; iii, Cs₂CO₃, CH₂Cl₂; iv, Mg, NH₄Cl, MeOH; v, TLC separation.

3.1 Ergot alkaloids

A new pentacyclic oxindole alkaloid, speradine A (314), has been isolated from the culture broth of the fungus Aspergillus tamarii.¹⁶⁸ The structure and relative stereochemistry were determined on the basis of spectral data (¹H, ¹³C, and ¹⁵N NMR, HMBC, and NOESY experiments) and a single crystal X-ray diffraction analysis.

4 Bisindole alkaloids

1,1,3-Tris(3-indolyl)butane (315) has been isolated from a North Sea bacterium that is closely related to Vibrio parahaemolyticus (98% homology).¹⁶⁹ The structure was established on the basis of spectral data (¹H and ¹³C NMR, COSY, and HMQC experiments). 315 was inactive against a range of bacteria and fungi.

A novel cyclopentenedione, asterredione (316) has been isolated from Aspergillus terreus occurring in the rhizosphere of Opuntia versicolor, using bioassay-guided fractionation.¹⁷⁰ The structure of 316 was elucidated by spectroscopic analysis (HR-FABMS, ¹H and ¹³C NMR, and HMBC experiments). 316 was evaluated for cytotoxicity in a panel of three sentinel cancer cell lines, NCI–H460 (non-small cell lung cancer), MCF-7 (breast cancer), and SF-268 (CNS glioma), and was found to be moderately active. A pathway for the biosynthetic origin of 316 from asterriquinone D is proposed.

The biomimetically divergent synthesis of hamacanthins A (317b) and B (318b), isolated from a deep-water marine sponge Hamacantha sp.,¹⁷¹ has been demonstrated through intramolecular transamidation–cyclisation (Scheme 53).¹⁷² Removal of the Boc group in 2-oxoethanamide (319), obtained in 7 steps from 320, followed by heating in ClCH₂CH₂Cl provided 317a and 318a. When 319 was reacted in ethanol, the cyclisation proceeded regioselectively to yield only 318a. Deacetylation of 317a and 318a afforded hamacanthins A (317b) and B (318b), respectively.

Scheme 53 Reagents and conditions: i, 10% LiOH, THF–MeOH (1 : 1), rt; ii, i-BuOCOCl, N-methylmorpholine, DME, −15 °C, then NaBH₄, rt; iii, TsCl, DMAP, Et₃N, CH₂Cl₂, −20 °C; iv, NaN₃, DMF, 80 °C; v, PPh₃, H₂O, THF, reflux, then 321, Et₃N, THF, 0 °C to rt; vi, 10% KOH, EtOH, reflux; vii, Ac₂O, DMAP, Na₂CO₃, THF, rt; viii, HCO₂H, CH₂Cl₂, rt, then ClCH₂CH₂Cl, pH 4, reflux; ix, HCO₂H, CH₂Cl₂, rt, then EtOH, pH 4, reflux; x, NH₄OH, THF, MeOH.

5 Peptide alkaloids containing a tryptophan residue

The cytotoxic hemiasterlins (322a–d) have been isolated from the marine sponges Hemiasterella minor,¹⁷³Cymbastella sp.,¹⁷⁴Auletta sp.,¹⁷⁵ and Siphonochalina sp.¹⁷⁶322a and a number of structural analogues have been synthesised and evaluated in cell-based assays for both cytotoxic and antimitotic activity in order to explore the SAR for this promising anticancer drug lead.¹⁷⁷ The synthesis of 322a, the analogues, and a discussion of how their biological activities vary with their structures are also presented.¹⁷⁷

Three novel iodine-containing tryprophan betaines, plakohypaphorine A (323a), B (323b), and C (323c), have been isolated from the organic extract of the Caribbean marine sponge Plakortis simplex.¹⁷⁸ Their structures were determined on the basis of spectral data (HR-ESIMS, ¹H and ¹³C NMR, ROESY, HMQC, and HMBC experiments). This is the first report of iodoindole compounds from either marine or terrestrial sources.

A new cyclic heptapeptide, phakellistatin 13 (324) has been isolated from the sponge Phakellia fusca Thiele, collected from Yongxing Island (China).¹⁷⁹ The structure was elucidated on the basis of spectral data (¹H and ¹³C NMR, TOCSY, DQFCOSY, HMQC, NOESY, and HMBC experiments). 324 showed strong cytotoxicity against the human hepatoma BEL-7404 cell line with an ED₅₀ of <10⁻² µg ml⁻¹, but it was not active against the HL-60 cell line.

Chemical investigation of the Philippines marine sponge Myriastra clavosa has resulted in the isolation of a new cyclic octapeptide, myriastamide C (325).¹⁸⁰ The structure was determined on the basis of spectral data (¹H and ¹³C NMR, COSY, and NOESY experiments) and a series of degradation and derivatisation studies.

Thiazolyl peptide antibiotics, nocathiacin I (326a), II (326b), and III (326c), have been identified in a culture of Nocardia sp. WW-12651 (ATCC 202099).¹⁸¹ Their structures were elucidated by spectroscopic methods (HR-ESIMS, ¹H, ¹³C, and ¹⁵N NMR, COSY, HMQC, and HMBC experiments). They exhibit potent in vitro activity (ng ml⁻¹) against a wide spectrum of Gram-positive bacteria, including multiple-drug resistant pathogens such as methicillin-resistant Staphylococcus aureus (MRSA), multi-drug resistant Enterococcus faecium (MREF) and fully penicillin-resistant Streptococcus pneumoniae (PRSP), and demonstrate excellent in vivo efficacy in a systemic Staphylococcus aureus mouse infection model.¹⁸²

Six new bicyclic peptides, celogentins D–H (327, 328a,b, 329a,b) and J (329c) have been isolated from the seeds of Celosia argentea.¹⁸³ Their structures, including absolute stereochemistry, were determined on the basis of spectral data (¹H and ¹³C NMR, COSY, HOHAHA, HMQC, and HMBC experiments) and chemical means. 328a,b and 329a–c showed potent inhibition of tubulin polymerisation, while the inhibitory activity of 327 was modest. The structure–activity relationship indicates that the ring size of the bicyclic ring system including the unusual crosslinked Leu, Trp, and His residues is be important for their biological activity. IC₅₀ values for celogentins D–H (327, 328a,b, 329a,b) and J (329c) are 20, 2.5, 3.0, 4.0, 2.0, and 3.0.µg ml⁻¹, respectively.

Three new kapakahines, E–G (330–332) have been isolated from the marine sponge Cribrochalina olemda.¹⁸⁴ Their structures were elucidated by spectroscopic methods (FAB-MS/MS, ¹H and ¹³C NMR, HMQC, NOE, and HMBC experiments). 330 showed cytotoxicity against P388 murine leukemia cells with an IC₅₀ of 5.0 µg ml⁻¹; 331 and 332 showed only weak cytotoxicity at this concentration.

The synthesis of the octacyclopeptide phakellistatin 10 (333), isolated from marine sponges of genus Phakellia,¹⁸⁵ has been accomplished using a combination of solid and solution-phase techniques (Scheme 54).¹⁸⁶ Starting from 334, obtained by anchoring Fmoc-protected valine to 2-chlorotrityl chloride resin as a solid support, stepwise elongation of the linear sequence was carried out in seven cycles up to the desired length using Fmoc-amino acids, resulting in the formation of 335. Removal of the Fmoc group from the N-terminal residue followed by cleavage from the resin afforded the linear peptide 336. After the cyclisation reaction of 336, removal of the side-chain protecting groups gave phakellistatin 10 (333).

Scheme 54 Reagents and conditions: i, Fmoc–Val–OH, DIEA, CH₂Cl₂; ii, 20% piperidine, DMF; iii, HOBt, HBTU, Fmoc-amino acid, NMM, DMF; iv, seven cycles of ii and iii; v, AcOH, CF₃CH₂OH, CH₂Cl₂; vi, HATU, DIEA, CH₂Cl₂; vii, TFA, TIS, H₂O.

The total synthesis of microsclerodermin E (337), isolated from the sponge Microscleroderma sp.,¹⁸⁷ has been achieved using the methods for assembling four unusual amino acid units, which include 3-amino-10-(p-ethoxyphenyl)-2,4,5-trihydroxydeca-7,9-dienoic acid (AETD), 4-amino-3-hydroxybutanoic acid (GABOB), (R)-Trp-2-carboxylic acid, and a pyrrolidinone fragment (Scheme 55).¹⁸⁸ Starting from the AETD unit 338 obtained from δ-gluconolactone in 17 steps, dipeptide fragment 339 was prepared by coupling with the GABOB unit 340. (R)-Trp-2-carboxylic acid derivative 341, prepared from the D-tryptophan derivative 342, was coupled with the pyrrolidinone fragment 343 and then with the dipeptide fragment 339 to produce 344. This was converted into microsclerodermin E (337) in 4 steps.

Scheme 55 Reagents and conditions: i, 340, AcOEt, reflux; ii, Dess–Martin periodinane, then NaClO₂, resorcinol, NaH₂PO₄; iii, HOSu, EDCI; iv, t-BuOCl, Et₃N, −78 °C, then TMSCN, BF₃·Et₂O; v, aq. KOH, MeOH, then MeI, KHCO₃, DMF; vi, Pd(OH)₂, H₂, MeOH; vii, BocN(Me)CH₂CO₂H, EDCl, HOBt, DIEA; viii, aq. LiOH, MeOH, then NH₂CH₂CO₂TMSE, EDCI, HOBt, DIEA; ix, TFA, then 343, NaHCO₃, DMF, 45 °C; x, TFA, then 339, NaHCO₃, MeCN; xi, TBAF, THF, xii, PMe₃, THF; xiii, DPPA, DMF; xiv, LiOH, MeOH, THF.

The first stereoselective total synthesis of anti-HIV agent chloropeptin I (345), isolated from Streptomyces sp. WK-3419,¹⁸⁹ has been completed from boronic ester 346,¹⁹⁰ which was prepared from the corresponding Boc-protected amino acid (Scheme 56).¹⁹¹ The key steps in the synthesis are the Cu-mediated formation of biaryl ether 347 and the Pd-mediated intramolecular cross coupling of 348 leading to chloropeptin I (345). Chloropeptin I exhibits notable activity against HIV-1-induced cytopathicity and syncyctium formation in CD-4⁺ lymphocytes.

Scheme 56 Reagents and conditions: i, 349a, DEPBT, NaHCO₃, THF, 0 to 22 °C; ii, TMSCHN₂, CH₂Cl₂, MeOH, 22 °C; iii, HCl(g), MeOH, −78 to 22 °C; iv, 1-hydroxy-7-azabenzotriazole, EDC, NaHCO₃, 349b, THF, DMF, 0 to 22 °C; v, NaIO₄, NH₄OAc, acetone, H₂O, 22 °C; vi, Cu(OAc)₂, Et₃N, 4 Å MS, MeOH, CH₂Cl₂, 22 °C; vii, HCl(g), MeOH, then NaHCO₃; viii, TFAA, 2,6-lutidine, CH₂Cl₂, 0 to 22 °C; ix, AlBr₃, EtSH, 0 °C; x, 349c, 1-hydroxy-7-azabenzotriazole, EDC, NaHCO₃, THF, 0 to 22 °C; xi, NIS, MeCN, 22 °C; xii, HCl, MeOH, 45 °C, then NaHCO₃; xiii, HATU, collidine, 349a, CH₂Cl₂, THF; xiv, HCl, MeOH, 22 °C; xv, 350, HATU, collidine, CH₂Cl₂, THF, 0 to 22 °C; xvi, Pd(Pt-Bu₃)₂, CsF, dioxane, 50 °C; xvii, 351, 1-hydroxy-7-azabenzotriazole, EDC, CH₂Cl₂, DMF, 0 to 22 °C; xviii, LiOH, H₂O, THF, 0 °C.

Diazonamide A is a potent antimitotic natural product, isolated from the colonial ascidian Diazona angulata.¹⁹² Harran's group revised its structure to 352 (Scheme 57).¹⁹³ Two novel syntheses of 352 have been reported. Nicolaou's group achieved the synthesis of (−)-352 using tyrosine methyl ester and 4-bromoindole as starting materials, and converting them into 353 and 354, respectively.¹⁹⁴ The key reactions in the synthesis are Suzuki coupling between aryl halide 353 and boronate 354 and an SmI₂-induced heteropinacol coupling of 355 to produce the 12-membered heterocyclic core. This macrocycle was converted, via356, into (−)-diazonamide A (352) by the following sequence of reactions: oxazole construction, macrolactamisation, aminal formation, chlorination, and peptide coupling.

Scheme 57 Reagents and conditions: i, Pd(dppf)Cl₂·CH₂Cl₂, K₂CO₃, DME, 85 °C; ii, TBAF, THF, 45 °C; iii, Et₃N, pyridine·SO₃, DMSO, CH₂Cl₂, 0 °C; iv, MeONH₂·HCl, DMSO; v, SmI₂, DMA, THF, then sat. aq. NH₄Cl, solvent removal, then Fmoc–Val–OH, EDC, HOBt, DMF; vi, TPAP, NMO, 4 Å MS, CH₂Cl₂; vii, POCl₃, pyridine, 70 °C; viii, aq. HF, MeCN, 0 °C; ix, IBX, DMSO; x, NaClO₂, NaH₂PO₄, resorcinol, DMSO, H₂O; xi, Et₂NH, THF; xii, HATU, collidine, DMF, CH₂Cl₂; xiii, H₂, Pd(OH)₂/C, EtOH; xiv, CbzCl, NaHCO₃, dioxane; xv, NCS, CCl₄, THF, 60 °C; xvi, BCl₃, CH₂Cl₂, −78 °C, then aq. NaOH, THF, −78 to 25 °C; xvii, DIBAL-H, THF, −78 to 25 °C; xviii, 357, EDC, HOBt, NaHCO₃, DMF.

Another total synthesis of (−)-diazonamide A (352) has been accomplished starting from 7-bromotryptophan methyl ester (Scheme 58).¹⁹⁵ The key reactions in the synthesis are oxidative cycloaddition of 358 to produce the aminal 359 and photoinduced macrocyclisation of 360 to generate 361. Compound 361 was converted into (−)-diazonamide A (352) by the following sequence of reactions: reductive removal of phenol, acylation, chlorination, deprotection, and condensation with (S)-α-hydroxy isovaleric acid (357).

Scheme 58 Reagents and conditions: i, PhI(OAc)₂, LiOAc, 2,2,2-trifluoroethanol, inverse addition, −20 °C; ii, PhSH, Na₂CO₃, DMF, rt; iii, TeocCl, CH₂Cl₂, aq. K₂CO₃; iv, LiOH, aq. MeOH; v, 7-hydroxytryptamine, TBTU, i-Pr₂NEt, DMF; vi, Ac₂O, pyridine, CH₂Cl₂, THF; vii, DDQ, THF, H₂O; viii, PPh₃, (CCl₃)₂, Et₃N, CH₂Cl₂, 15 min; ix, hν (300 nm), LiOH, MeCN, H₂O; x, 4-nitrophenyltriflate, K₂CO₃, DMF; xi, 20% Pd(OH)₂/C, H₂, AcOEt, MeOH, rt; xii, diallyldicarbonate, Et₃N, THF, rt, then TeocCl, Et₃N, rt, then [Pd(PPh₃)₄], morpholine, 0 °C; xiii, 2,3,4,5,6,6-hexachloro-2,4-cyclohexadien-1-one, DMF, rt; xiv, (Me₂N)₃SSiMe₃F₂, DMF, rt; xv, 357, (EtO)₂P(O)CN, N-methylmorpholine, THF, rt.

A formal total synthesis of TMC-95 A (362a) and B (362b), isolated from the fermentation broth of Apiospora montagnei Sacc. TC1093,¹⁹⁶ has been accomplished starting from N-Cbz-serine methyl ester (Scheme 59).¹⁹⁷ The key steps in the synthesis include a stereoselective modified Julia olefination reaction between sulfone 363 and 7-iodoisatin (364), a diastereoselective dihydroxylation to construct 365, and macrocyclisation leading to 366 with limited use of protecting group chemistry. Compound 366 has been converted into TMC-95 A (362a) and B (362b) by Danishefsky's group.¹⁹⁸

Scheme 59 Reagents and conditions: i, LiHMDS, DMF, DMPU, 0 °C; ii, K₂CO₃, Pd(dppf)Cl₂, aq. DME; iii, LiOH, THF, H₂O, 0 °C; iv, H₂N–Asn–OBn, 1-hydroxy-7-azabenzotriazole, EDCI, NMM, CH₂Cl₂, 0 °C; v, OsO₄, pyridine, H₂O, 0 °C, then NaHSO₃, THF, MeOH; vi, TFA–H₂O (1 : 1); vii, 3-methyl-2-oxopentanoic acid, 1-hydroxy-7-azabenzotriazole, EDCI, THF; viii, Pd black, H₂, EtOH; ix, EDCI, 1-hydroxy-7-azabenzotriazole, CH₂Cl₂–DMF (1 : 1), 1 µM; x, TESOTf, 2,6-lutidine, CH₂Cl₂, DMF, 0 to rt.

An efficient, convergent total synthesis of TMC-95A (362a) has been achieved starting from 367 (Scheme 60).¹⁹⁹ The key transformations in the synthesis are a new deprotection protocol for the removal of the hindered carbamate and acetonide of 368, conversion of the aniline 369 into the oxindole 370 by lowering the pH, a Suzuki–Miyaura coupling reaction of 371 with 372, and macrolactamisation to creat the macrocyclic framework (373), and a mild decarboxylative anti-elimination to selectively produce the (Z)-1-propenylamide, part of structure 374. Compound 374 was then converted into TMC-95A (362a) by the following sequence of reactions: removal of the TES group, selective oxidation of the C-35 alcohol with Dess–Martin periodinane, protection of the C-7 alcohol with chloroacetyl anhydride, and exposure to acid and then base in one pot.

Scheme 60 Reagents and conditions: i, Mg(ClO₄)₂, MeCN, 50 °C; ii, ethyl vinyl ether, PPTS, THF, 35 °C; iii, n-BuLi, ICH₂CH₂I, THF, −60 °C to rt; iv, KOt-Bu, H₂O, Et₂O, rt; v, H₂O, TsOH, MeOH, rt; vi, ZCl, Et₃N, DMF, 0 °C to rt; vii, p-MeOC₆H₄CH(OMe)₂, TsOH, THF; viii, Pd(PPh₃)₄, Na₂CO₃, DMF, H₂O, 95 °C; ix, LiOH, THF, H₂O; x, H–Asn–OBn·TFA, EDC·HCl, HOBt, DMF, 0 °C; xi, H₂, Pd(OH)₂/C, THF–H₂O (1 : 1); xii, EDC·HCl, 1-hydroxy-7-azabenzotriazole, DMF, 0 °C; xiii, TBAF, 4 Å MS, THF; xiv, TESCl, imidazole, DMF; xv, Zn(OTf)₂, EtSH, NaHCO₃, CH₂Cl₂; xvi, pyridine·SO₃, Et₃N, CH₂Cl₂, DMSO, rt; xvii, NaClO₂, NaH₂PO₄, 2-methyl-2-butene, t-BuOH, H₂O, rt; xviii, L-allo-Thr–OBn·TFA, EDC·HCl, HOBt, DMF, 0 °C; xix, H₂, Pd(OH)₂/C, THF–H₂O (1 : 2); xx, DEAD, PPh₃, 4 Å MS, 0 °C to rt; xxi, HF·pyridine, THF; xxii, Dess–Martin periodinane, CH₂Cl₂; xxiii, (ClCH₂CO)₂O, pyridine, CH₂Cl₂, 0 °C; xxiv, aq. HCl (1 M)–THF (3 : 1), rt, then sat. aq. NaHCO₃.

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