Marine natural products: synthetic aspects

Contents

• 1 Introduction

• 2 Review articles

• 3 Azaspiracid-1

• 4 Polyethers

• 5 Batzelladines

• 6 Amphidinolides

• 7 Dictyostatin-1 and discodermolide

• 8 Total syntheses of other compounds

• Acknowledgements

• References

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Abstract

Covering: January to December 2004. Previous review: Nat. Prod. Rep., 2005, 22, 144

An overview of marine natural products synthesis during 2004 is provided. As with the previous installment of this series, the emphasis is on total syntheses of molecules of contemporary interest, new total syntheses, and syntheses that have resulted in structure confirmation or stereochemical assignments.

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Gillian M. Nicholas

Gillian Nicholas received her B.Sc., M.Sc., and Ph.D. degrees from the University of Canterbury, where she worked on the isolation and structure elucidation of biologically active compounds from fungal sources with John Blunt and Murray Munro. Postdoctoral research with Ted Molinski at UC Davis and Carole Bewley at the National Institutes of Health was followed by a 2 year stay at Hauser Inc. in Denver, CO. She is currently a Principal Analytical Research Chemist at Roche Colorado Corporation in Boulder, CO.

Andrew J. Phillips

Andy Phillips obtained his B.Sc. (Hons) and Ph.D. degrees from the University of Canterbury in Christchurch, New Zealand. After a postdoctoral appointment with Peter Wipf at the University of Pittsburgh, he joined the faculty at the University of Colorado. His research interests focus around the development of new methods and strategies for the synthesis of complex natural products.

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1 Introduction

This review is designed to provide an overview of key features of the 2004 literature covering the synthesis of marine natural products and should act as a companion to the Marine Natural Products review published in this journal.¹ The emphasis is on total syntheses of molecules of contemporary interest, as well as syntheses that have resulted in structure reassignments. Tabulated data for other syntheses are also provided.

2 Review articles

A number of reviews that cover various aspects of marine natural products synthesis have appeared: “Chemistry and biology of curacin A”,² “Progress in studies of novel marine bis(indole) alkaloids”,³ “Total synthesis of polycyclic ether natural products based on Suzuki–Miyaura cross-coupling”,⁴ “The chemistry of vicinal tricarbonyls and related systems”,⁵ “Synthesis of polyheterocyclic nitrogen-containing marine natural products”,⁶ “Bioorganic studies on marine natural products with bioactivity, such as antitumor activity and feeding attractance”,⁷ “Recent advances in the synthesis of trans-fused polycyclic ethers by hydroxy-epoxide-cyclization and ether-ring-expansion reactions”,⁸ “Elisabethin A: A marine diterpenoid yet to surrender to total synthesis”,⁹ “(+)-Discodermolide: a marine natural product against cancer”,¹⁰ “Lamellarins, from A to Z: A family of anticancer marine pyrrole alkaloids”,¹¹ “Amphidinolides, bioactive macrolides from symbiotic marine dinoflagellates”,¹² “Marine natural products”,¹³ “Recent advances in the total syntheses of oxazole-containing natural products”,¹⁴ and “Evolution of dithiane-based strategies for the construction of architecturally complex natural products”.¹⁵ Other reviews of relevance are cited in the text.

3 Azaspiracid-1

In one of the significant achievements in the review period, the Nicolaou group has employed a combination of degradative studies and synthesis to revise the structure of azaspiracid-1.¹⁶ In work described in 2003, Nicolaou and co-workers established by synthesis^17,18 that the initially proposed structure¹⁹ for azaspiracid-1 was incorrect (1, Scheme 1). Upon realizing that there were structural questions remaining to be resolved, the first path was to degrade natural azaspiracid-1 to smaller fragments and then locate the positions of error by synthesis. This approach was also expected to allow the determination of the relative stereochemistry between the ABCDE and FGHI domains. To this end, an authentic sample of azaspiracid was reacted with TMSCHN₂ and the methyl ester obtained was treated with NaIO₄, which resulted in cleavage of the C20–C21 bond. This provided lactone 3 and aldehyde 2, which were subjected to short sequences of common transformations to yield alcohol 6 and acid 7 (the stereochemistry shown for these compounds corresponds to that originally proposed).

Scheme 1 Chemical degradation and derivatization of azaspiracid-1 (originally proposed structure) to C1–C20 alcohol 6 and C26–C40 carboxylic acid 7. Reagents and conditions: (1) TMSCHN₂, MeOH, 25 °C; (2) NaIO₄, MeOH–H₂O (4 : 1), 25 °C, ∼100% over 2 steps; (3) NaBH₄, MeOH, 25 °C, ∼90%; (4) 5% Pd/C, H₂, MeOH, 25 °C, ∼90%; (5) O₃, Me₂S, MeOH, −78 °C; (6) NaOH (0.1 N), MeOH–H₂O (4 : 1), 25 °C, 2 h; (7) TMSCHN₂, MeOH, 25 °C, ∼90% over 3 steps; (8) NaIO₄, MeOH–H₂O (4 : 1), 25 °C, ∼90%.

Key steps of the synthesis of the EFGHI ring containing system 8 are shown in Scheme 2. The primary alcohol of dithiane 9 was acetylated, and subsequent dithiane deprotection with PhI(TFA)₂ followed by oxidation of the lactol to the lactone with N-iodosuccinimide produced 10 in 51% over the three steps. Stille coupling with stannane 11 in the presence of Pd(0) resulted in the formation of dihydropyran 12. Removal of the TES ether with HF·pyridine, followed by treatment with N-iodosuccinimide to induce iodoetherification, produced iodoether 13 in 38% yield (for the three steps). Two further steps (removal of the iodide and cleavage of the Teoc carbamate) gave the structure corresponding to degradation product 3 and showed the structure of the compound obtained by degradation is in fact epimeric, in terms of the stereochemistry around the E ring, to that which was originally proposed. A synthesis of the compound in which the FGHI rings were enantiomeric was also completed by this route, but it did not match the data for 3. These, and related studies that involved the synthesis of acid 7, also established the absolute stereochemistry for this domain.

Scheme 2 Synthesis of the EFGHI ring containing lactone. Reagents and conditions: (1) Ac₂O, 2,4,6-collidine, CH₂Cl₂, 85%; (2) PhI(TFA)₂, MeCN–pH 7 buffer, 81%; (3) NIS, TBAI, CH₂Cl₂, 74%; (4) 3.0 equiv. lactone 10, 90 mol% [Pd₂dba₃], LiCl, AsPh₃, DIPEA, syringe pump additon of stannane; (5) HF·py, THF–py; (6) NIS, NaHCO₃, THF, 38% (3 steps).

At this juncture, attention turned to questions regarding the connectivity and stereochemistry of the ABCD ring containing domain. Desilylation of previously synthesized compound 14 to give 15 provided material that could be compared with degradation product 4 (Schemes 1 and 3). The spectroscopic data for these two samples differed substantially, particularly in the A ring. Progress towards a corrected structure was assisted by comparison of NMR data with a related compound, lissoketal (16).²⁰ Based on this comparison, a new structure in which the A ring double bond has been relocated was proposed; however, final resolution of the problem did not come until the synthesis of several closely related structures had been completed. Based on this work the stereochemistry and connectivity shown in compound 17 was secured as corresponding to degradation compound 4.

Scheme 3 Comparison of synthetic and proposed ABCD ring containing alcohols. Reagents and conditions: (1) TBAF, THF, 88%.

Armed with the information gleaned from these studies, and the earlier synthesis, plans could be laid to complete the total synthesis by employing the key couplings shown in Scheme 4.

Scheme 4 Key carbon–carbon bond-forming reactions in the Nicolaou azaspiracid-1 synthesis.

Key steps of the route to the ABCDE domain are shown in Scheme 5. Malic acid derived tetrahydrofuran 18 was treated with TMSOTf in CH₂Cl₂ at low temperature to induce the desired deprotection–spirocyclization sequence to give 19 in 89% as a single stereoisomer. A sequence of 6 steps led to allylic carbonate 20, and deoxygenation of this compound to give 21 was achieved by employing a modification of an earlier-described Pd-catalyzed method²¹ which produced the desired compound in 82% yield (with 7 : 1 selectivity for the Δ^7,8 olefin). After advancement to pentafluorophenyl ester 22, introduction of the C21–C27 domain involved acylation of the dithiane anion derived from 23 to give 24 in 50% yield. Six further steps provided compound 25 (see Scheme 6) which served as the key precursor to the A→E domain for the final steps of the synthesis.

Scheme 5 Synthesis of the ABCDE domain. Reagents and conditions: (1) TMSOTf (4.0 equiv.), CH₂Cl₂, −90 °C, 30 min, 89%; (2) [Pd₂dba₃]·CHCl₃ (0.125 equiv.), ⁿBu₃P (0.48 equiv.), LiBH₄ (10.0 equiv.), DME, 0 °C, 1 h, 82%, Δ^7,8/Δ^8,9 = 7 : 1; (3) 23 (7.0 equiv.), ⁿBuLi–ⁿBu₂Mg (4.7 equiv.), THF, 0 → 25 °C, 1.5 h, then −90 °C, then 22, 30 min, 50%. PFP = pentafluorophenyl.

Scheme 6 The closing stages of the Nicolaou synthesis of azaspiracid-1. Reagents and conditions: (1) 25, [Pd₂dba₃] (0.3 equiv.), AsPh₃ (0.3 equiv.), LiCl (6.0 equiv.), DIPEA, then 26 (3.0 equiv. in THF by syringe pump addition), NMP, 40 °C, 1 h, 55%; (2) TBAF (1.2 equiv.), THF, 0 °C, 80%; (3) NIS (2.0 equiv.), NaHCO₃, THF, 0 °C, 12 h, 62%; (4) Et₃B (0.2 equiv.), ⁿBu₃SnH–PhMe (1 : 2), 0 °C, 5 min, 86%.

The closing stages of the synthesis are illustrated in Scheme 6. The crucial coupling of the ABCD and FHI subunits occurred by Pd-mediated Stille-type reaction between allylic acetate 25 and dihydropyranyl stannane 26 to give 27 in 55% yield. Removal of the C34 TES ether (TBAF, 80%) and iodoetherification with N-iodosuccinimide produced 28 in an impressive 62% yield given the complexity of the substrate. Subsequent deiodination with Bu₃SnH and Et₃B give the fully elaborated A→I ring system (29) of the natural product, and the synthesis was completed by a short sequence of 5 steps that consisted of redox chemistry and protecting group manipulations.

In other studies on azaspiracid-1, Forsyth has descibed a concise approach to the trioxadispiroketal ABCD ring system 31 (the stereochemistry at C6 is epimeric to the final stereochemistry determined by Nicolaou). The key step consists of treatment of the ynone 30 with p-TsOH in toluene at room temperature for 1–2 days. Under these conditions the C6 and C17 TES ethers are removed and the ensuing sequence of hemiacetal formations and conjugate additions leads to 31 in 55% over two steps.²²

Carter and Zhou have described a concise 23-step synthesis of the ABCDE ring system 32 from N-propionyl-(S)-benzyloxazolidinone.²³ Ishikaway and Nishiyama have described a synthesis of compound 33, which contains the ABCD ring system, as well as related studies.^24,25

4 Polyethers

Structurally complex polyethers continue to draw significant attention from the synthesis community, and a total synthesis of brevetoxin B²⁶ has been reported by Nakata and co-workers (Scheme 7). Key features of this synthesis include the coupling of two large fragments by a Wittig reaction and then formation of the H ring by reductive etherification of an O,S-acetal. Advanced intermediate 36 (prepared in 17 steps from tri-O-acetyl-D-glucal) was advanced by a nice two-directional strategy that involves reductive cyclizations and selective Wittig reactions (Scheme 7). The intial reaction with ethyl propiolate gave β-alkoxyacrylate 37 in 95% yield. SmI₂-induced reductive cyclization, followed by treatment with acidic ethanol, gave 38 in 79% yield over the two steps. Silylation of the tertiary alcohol and double reduction to the lactol-aldehyde 39 with DIBAL-H set the stage for the Wittig reaction sequence. Reaction, first with Ph₃P=C(Me)CO₂Et at 0 °C to rt, followed by reaction with Ph₃P=CHC(O)Me at 100 °C, gave 41 in 67%. Silylation of the tertiary alcohol followed by a sequence of 28 steps then yielded advanced intermediate 40 that contains the A→G rings. Subunit coupling with aldehyde 35, followed by TMS ether hydrolysis and formation of the O,S-acetal gave 42. Reduction of the O,S-acetal was achieved with Ph₃SnH under radical conditions to yield 43. A short sequence of three steps that mirrored the Nicolaou synthesis provided brevetoxin B.

Scheme 7 Key steps of Nakata's total synthesis of brevetoxin B. Reagents and conditions: (1) ethyl propiolate, N-methylmorpholine, CH₂Cl₂, rt, 95%; (2) SmI₂, MeOH, THF, rt; (3) p-TsOH, EtOH, 80 °C, 79% (2 steps); (4) TMSOTf, 2,6-lutidine, CH₂Cl₂, −78 °C, 100%; (5) DIBAL-H, PhMe, −78 °C; (6) Ph₃P=C(Me)CO₂Et, PhMe, 0 °C → rt, then Ph₃P=CHCOMe, 100 °C, 67% (2 steps); (7) TMSOTf, py, CH₂Cl₂, −78 °C, 98%; (8) (a) 41, ⁿBuLi, HMPA, THF, −78 °C, then 35, −78 °C → rt; (b) PPTS, CH₂Cl₂,–MeOH, rt, 68% (2 steps); (c) AgClO₄, NaHCO₃, SiO₂, 4 Å MS, MeNO₂, rt; (9) Ph₃SnH, AIBN, PhMe, 110 °C; (10) TBAF, THF, rt, 71% (3 steps); (11) PCC, benzene, 80 °C, 51%; (12) HF·py, CH₂Cl₂, 0 °C, 72%.

Fujiwara and co-workers have reported a formal total synthesis²⁷ of hemibrevetoxin B²⁸ by a route that reaches 53, and bisects the Yamamoto synthesis (Scheme 8). The synthesis commences with the synthesis of 50 from butyrolactone by an 18-step sequence that employs a ring-closing metathesis for the synthesis of the 7-membered ring (46 → 48). Aldehyde 50 is coupled with the anion derived from 49 (synthesized from tri-O-acetyl-D-glucal 47 by a 14-step sequence) to give 51 in 86% yield. Acidic hydrolysis of the (methylthio)(methylsulfinyl)acetal and removal of the TBS ether gave hydroxyl ketone 52, from which compound 53 was prepared by a 7-step sequence.

Scheme 8 Fujiwara's formal synthesis of hemibrevetoxin B. Reagents and conditions: (1) TBSOTf, 2,6-lutidine, CH₂Cl₂, 99%; (2) DDQ, CH₂Cl₂–H₂O (10 : 1), 93%; (3) acryloyl chloride, DIPEA, CH₂Cl₂, 94%; (4) Grubbs’ 2^nd-generation catalyst, CH₂Cl₂, reflux, 89%; (5) 49, LDA then 50 (0.37 equiv.), −78 °C, 86%; (6) TFA–THF–H₂O (1 : 5 : 5), 0 °C → rt, 71%.

Inoue and Hirama have described the end-game of a 2^nd-generation total synthesis of ciguatoxin CTX3C²⁹ that involves milder conditions for the preparation of O,S-acetals (Scheme 9).³⁰ Aldehyde 55 was converted to the α-chlorosulfide 58 by a sequence of three straightforward reactions (reduction, sulfide formation and chlorination). The authors note that ‘the reproducibility of the chlorination reaction … required the addition of 1 equiv. of NCS in CH₂Cl₂ to a solution of 57 in CCl₄ at room temperature. The obtained solution of 58 in CH₂Cl₂/CCl₄ (1:6) was directly used in the subsequent reaction because of the instability of 58 to any standard workup.’ Coupling of this α-chlorosulfide with alcohol 54 was effected by treating a CH₂Cl₂ solution of the alcohol, DTBMP, and AgOTf (2.0 equiv.) with the α-chlorosulfide. Removal of the C21 TIPS ether (TBAF, 85%) and conversion to the β-alkoxyacrylate (ethyl propiolate, NMM, 100%) set the stage for the radical cyclization to form the G ring. To this end, treatment of 60 with Bu₃SnH and AIBN in PhMe led to 61 in 54% yield (along with 27% of the compound obtained from cyclization onto the C21 olefin). Two further steps (DIBAL-H reduction of the ester and olefination with Ph₃P=CH₂, 92% over two steps) provided the substrate for a RCM analogous to that of the 1^st-generation synthesis. Subjecting 62 to Grubbs’ I catalyst in CH₂Cl₂ at reflux produced 90% of protected CTX3C, and subsequent removal of the naphthylmethyl (NAP) ethers with DDQ gave 63% of CTX3C. This sequence is 4 steps shorter than the 1^st-generation synthesis. Inoue and Hirama have also provided a detailed account of their 1^st-generation synthesis³¹ and also a review of their recently developed methods for the synthesis of CTX3C,³² and Inoue has reviewed the use of acetal-linked intermediates for the synthesis of complex polyethers.³³

Scheme 9 Key steps from the Inoue–Hirama 2^nd-generation synthesis of ciguatoxin CTX3C. Reagents and conditions: (1) NaBH₄, MeOH–CH₂Cl₂, 81%; (2) PhSSPh, Bu₃P, py, 93%; (3) NCS, CH₂Cl₂–CCl₄ (1 : 6); (4) 54 (1.2 equiv.), AgOTf (2.0 equiv.), DTBMP, 4 Å MS, CH₂Cl₂–CCl₄, 70% from 58; (5) (a) TBAF, THF, 85%; (b) methyl propiolate, NMM, CH₂Cl₂, 100%; (6) ⁿBu₃SnH, AIBN, PhMe, 54%; (7) (a) DIBAL-H, CH₂Cl₂; (b) Ph₃PCH₃ Br, ^tBuOK, THF, 90% (2 steps); (8) (Cy₃P)₂Cl₂Ru=CHPh (30 mol%), CH₂Cl₂, 40 °C, 90%; (b) DDQ (6.0 equiv.), CH₂Cl₂–H₂O (20 : 1), 63%.

In other studies on polyethers, Clark and co-workers³⁴ have described a 12-step synthesis of the A ring fragment of the gambieric acids.³⁵ The key step is a [2,3]-sigmatropic rearrangement of an allylic oxonium ylide generated from the intramolecular reaction of a crotyl ether with a copper carbenoid. Related studies have shown that sequential ring-closing enyne and cross metathesis³⁶ of carbohydrate systems is a useful method for the synthesis of polyether building blocks. Isobe and co-workers have developed an approach to the HIJ ring system of ciguatoxin that features an intromolecular Nicholas reaction for the synthesis of the 8-membered I ring (Scheme 10).³⁷ Full details of the Sasaki total synthesis of gambierol have been reported, along with initial SAR studies that delineate some of the features required for potent toxicity.³⁸

Scheme 10 Isobe's intramolecular Nicholas approach to the I ring of ciguatoxin. Reagents and conditions: (1) Co₂(CO)₈, CH₂Cl₂, 87%; (2) BF₃·OEt₂, CH₂Cl₂, 60%.

An improved synthesis of key intermediate 66 in the Hirama ciguatoxin CTX3C has been reported. The sequence to this compound is now 38 steps, and displays improved stereochemical control over the earlier route.³⁹

The synthesis of models of the CDE–FG ring systems of the prymnesins has suggested that a reassignment of relative stereochemistry should be considered in this region.⁴⁰ A series of gambierol analogs have been synthesized from advanced intermediates in the Sasaki total synthesis and evaluated for toxicity against mice. These SAR studies indicate that the C28–C29 double bond (in the H ring) and the unsaturated side chain are crucial and that the C1 and C6 hydroxy groups, the C30 Me group, and the C37–C38 olefin have minimal influence on toxicity.⁴¹ Trost has described the Ru-catalyzed cycloisomerization and oxidative cyclization of bis-homopropargylic alcohols as a rapid iterative approach to the pyranopyran rings found in ladder toxins such as prymnesin and yessotoxin.⁴²

5 Batzelladines

Several syntheses of members of the batzelladine family of the guanidinium alkaloids have been described in 2004. Overman's continuing work in this area has produced a synthesis of (−)-dehydrobatzelladine C⁴³ that is based around the use of Biginelli condensations to produce the tricyclic core (Scheme 11). β-Ketoester 67 was transesterified with N-Boc-protected 4-aminobutanol under catalysis by DMAP to give 68 in 78% yield. Biginelli condensation of 68 with guanidinium aminal 69 (synthesized in 10 steps from commercial materials) in trifluoroethanol at elevated temperature produced 70 with >10 : 1 diastereoselectivity. Oxidation of the crude product with CAN and reverse-phase preparative HPLC gave compounds 71 and 72 in 45% combined yield for the two steps (this material consisted of 33% of the N-Boc compound, and 12% of the amine hydrochloride). Removal of the Boc group with TFA quantitatively led to 72, and the guanidinium group was then introduced by reaction with N,N′-di(tert-butoxycarbonyl)thiourea in the presence of HgCl₂ and Et₃N. Removal of the Boc groups then yielded (−)-dehydrobatzelladine C in 90% yield over the final two steps. Overman has also reviewed the applications of the tethered Biginelli reaction in natural products synthesis.⁴⁴

Scheme 11 Overman's synthesis of (−)-dehydrobatzelladine C. Reagents and conditions: (1) HO(CH₂)₄NHBoc, DMAP, PhMe, 100 °C, 78%; (2) morpholinium acetate, Na₂SO₄, CF₃CH₂OH, 65 → 70 °C; (3) CAN, MeCN, rt (45%, 2 steps); (4) 1 : 1 TFA–CH₂Cl₂, rt, ∼100%; (5) S=C(NHBoc)₂, HgCl₂, Et₃N, CH₂Cl₂, rt; (6) 1 : 1 TFA–CH₂Cl₂, rt, 90%.

Nagasawa has described a synthesis of batzelladine A⁴⁵ that is based around the use of diastereoselective 1,3-dipolar cycloadditions of nitrones with olefins to provide precursors to the bicyclic and tricyclic guanidinium units (Scheme 12).

Scheme 12 An overview of the retrosynthetic analysis of batzelladine A by Nagasawa and co-workers.

The bicyclic guanidinium domain synthesis commenced with the 1,3-dipolar cycloaddition reaction between nitrone 74 and ester 80 to give isoxazolidine 81 as a single diastereomer (Scheme 13).⁴⁶ Reduction of the ester with LiAlH₄ and removal of the TIPS group with CsF gave 82 in 59% overall yield from 81. After selective protection of the primary alcohol with TBSCl and pyridine, removal of the secondary alcohol at C9 was achieved by a Barton–McCombie reaction to produce 83 (44% over 3 steps). A sequence of 9 steps then led to alcohol 84.

Scheme 13 Nagasawa's synthesis of batzelladine A. Reagents and conditions: (1) 1-undecene, PhMe, 90 °C, 75%; (2) methyl crotonate, PhMe, 100 °C, >60%; (3) (a) TBAF, THF, 97%; (b) Jones’ reagent, acetone; (4) PhMe, 90 °C; (5) LiAlH₄, Et₂O, 0 °C, then CsF, EtOH, 90 °C (59%, 3 steps); (6) (a) TBSCl, py, 81%; (b) ClC(S)OPh, py, DMAP, 58%; (c) ⁿBu₃SnH, AIBN, 94%; (7) EDCI, DMAP, CH₂Cl₂ (60%, 2 steps from acid); (8) HF·py, THF, 80%; (9) (a) Pd/C, H₂; (b) PPh₃, DEAD, PhMe; (c) TFA–CH₂Cl₂ (24%, 3 steps).

The synthesis of acid 79, which ultimately serves as a progenitor of the tricyclic guanidine, commences with the diastereoselective 1,3-dipolar cycloaddition of 1-undecene and nitrone 74 to give 75 in 75% yield (see also Scheme 13). After a 4-step sequence of deprotection, acylation with ClC(S)OPh, Barton–McCombie deoxygenation, and oxidation with MCPBA, nitrone 76 was then subjected to cycloaddition with methyl crotonate to give 77. This material was advanced to compound 78, which was deprotected (TBAF, 97%) and oxidized with Jones' reagent to give acid 79. Subunit coupling of this acid with bicyclic guanidine 84 was achieved by esterification with EDCI in the presence of DMAP under carefully controlled conditions (epimerization at C24 occurred at room temperature, but could be supressed at 0 °C) to furnish 85 in 60% yield. Deprotection of the secondary alcohol with HF·pyridine yielded 86 in 80% yield. After removal of the Cbz protecting groups under standard hydrogenolysis conditions the resulting bicyclic guanidine was converted to the tricyclic guanidine by an intramolecular Mitsunobu reaction. The remaining four Boc groups were cleaved with TFA, and after purification by reverse-phase HPLC, batzelladine A was obtained as the trifluoroacetate salt in 24% yield for the 3 steps from 86.

In other studies on the batzelladines, Elliott has described the application of diastereoselective three-component coupling of an alkenylpyrrolidine, an aldehyde and Si(NCS)₄ as a method to prepare the bicyclic core of the batzelladine alkaloids.⁴⁷ In a collaboration between the Bewley and Overman groups, a synthetic library of 28 batzelladine analogs was tested for the ability to inhibit HIV-1 envelope-mediated cell–cell fusion.⁴⁸ SAR relationships indicated that the best inhibitors of fusion were most similar in structure to natural batzelladine F, with IC₅₀ values ranging from 0.8 to 3.0 µM.

6 Amphidinolides

The amphidinolides continue to provide a fertile environment for the development of new methods and strategies, and the review period has seen new syntheses of several members of this class. As noted in the previous review in this series, synthesis also continues to play an important role in structural studies for this class of compounds. The story of (+)-amphidinolide A1⁴⁹ provides a notable example of the value of synthesis to the structure elucidation of complex marine natural products. Kobayashi's initially proposed structure was synthesized in 2002 in independent efforts by the groups of Trost,⁵⁰ Pattenden⁵¹ and Maleczka.⁵² However, none of these efforts produced material that matched the reported data, which suggested that there were questions regarding the stereochemistry of the molecule remaining to be answered. This puzzle was solved in 2004 by Trost and Harrington, when they described the structure elucidation of (+)-amphidinolide A1 by a combination of total synthesis and NMR analysis.⁵³

The synthesis highlights Trost's new methodology for the construction of 1,4-dienes by the Ru-catalyzed coupling of alkenes and alkynes (Scheme 14).⁵⁴ The first subunit coupling was achieved by reaction of 89 with 90 in the presence of Cp*Ru(MeCN)₃PF₆ as catalyst (Scheme 14). This catalyst provided the branched product 91 in 23% yield (39% yield based on recovered starting material). A straightforward sequence of 3 steps provided acid 92 which was coupled to the potentially sensitive epoxy alcohol 93 under Kita's conditions⁵⁵ to give ester 94 in 51% yield. After removal of the triethylsilyl ethers with TBAF–AcOH, [Cp*Ru(MeCN)₃]PF₆-catalyzed macrocyclization of 95 provided amphidinolide A1, 96. Although the yield may seem modest (33% or 38% based on recovered starting material) this an impressive example of the remarkable selectivity of the Ru-catalyzed alkene–alkyne addition. The spectral data for synthetic material matched very well to the natural product, with only two protons deviating by more than 0.01 ppm from the reported values (the two deviations were by 0.03 ppm and by 0.02 ppm). The ¹³C NMR spectrum deviated by 0.1 ppm or less in CDCl₃, J values in three solvents were also in agreement, and the optical rotation was also consistent with reported data (synthetic [α]²⁴_D +56 (c 0.05, CHCl₃) cf. reported [α]²⁴_D +46 (c 1.0, CHCl₃)). Even with these excellent comparisons, in the absence of authentic material for comparison, Trost and Harrington conclude their paper with guarded comments: “In conclusion, we have employed a combination of synthesis and NMR spectroscopy as tools to determine the correct structure of amphidinolide A1. Although the lack of a sample of the natural product prevents a definitive comparison, the excellent correlation [of our synthetic compound] strongly suggests it is (+)-amphidinolide A1.”

Scheme 14 Trost's synthesis of amphidinolide A1. Reagents and conditions: (1) 89 (5 equiv.), [Cp*Ru(MeCN)₃]PF₆, 23% (39% brsm); (2) (i) [RuCl₂(p-cymene)]₂, ethoxyacetylene; (ii) 93, CSA, 51%; (3) TBAF, AcOH, 79%; (4) [Cp*Ru(MeCN)₃]PF₆, 33% (38% brsm).

Trost has also completed a synthesis of amphidinolide P⁵⁶ that employs the Ru-catalyzed alkene–alkyne coupling for subunit assembly (Scheme 15). Coupling of β-lactone 98 (3.5 equivalents) and enyne 97 in the presence of 10 mol% [CpRu(CH₃CN)₃]PF₆ in acetone at room temperature gave 99 in 75% yield, and with no trace of linear product detectable. Four further steps led to amphidinolide P.

Scheme 15 The key Ru-catalyzed alkene–alkyne coupling en route to amphidinolide P. Reagents and conditions: (1) 10 mol% [CpRu(CH₃CN)₃]PF₆, acetone, 75%.

Ghosh has synthesized amphidinolide W⁵⁷ and corrected the stereochemistry at C6.⁵⁸ The synthesis of the originally proposed structure employs a Ru-catalyzed cross-metathesis for subunit coupling (Scheme 16). Among various protecting groups and catalysts surveyed, an acetate protecting group on the secondary allylic alcohol of 102 and second generation Grubbs’ catalyst gave the best result, affording the desired compound 103 along with the Z-isomer (E/Z ratio 11 : 1) in 85% yield. A short sequence of protecting group and oxidation state manipulations provided seco-acid 104. Macrolactonization under Yamaguchi conditions provided the desired macrolactone 105 along with an epimer as a 1 : 1 mixture in 50% combined yield. Removal of dioxolane and MOM protecting groups produced the target compound, which was not identical to the natural material. After determining the stereochemistry at C6 to be the likely culprit, this sequence was repeated (details not discussed in the paper) to provide synthetic amphidinolide W whose spectral data (¹H and ¹³C NMR) were identical to those of natural amphidinolide W.²

Scheme 16 Ghosh's synthesis of the proposed structure for (+)-amphidinolide W. Reagents and conditions: (1) (H₂IMes)(PCy₃)Cl₂Ru=CHPh (5 mol%), CH₂Cl₂, 45 °C, 85%; (2) ⁱPr₂NEt, 2,4,6-trichlorobenzoyl chloride, then DMAP, PhH, 80 °C, 50%.

Jamison has described a concise, modular synthesis of amphidinolide T1⁵⁹ that employs a Ni-catalyzed reductive macrocyclization of an alkyne with an aldehyde (Scheme 17).⁶⁰ Esterification of alcohol 106 and carboxylic acid 107 under standard DCC-based conditions in the presence of 4-pyrrolidinopyridine gave ester 108. Removal of the TBS ether and oxidation with Dess–Martin periodinane gave the precursor to the macrocyclization, 109, in 59% yield for the three steps. Exposure of 109 as a 0.05 M solution to catalytic Ni(cod)₂, Bu₃P, and Et₃B in toluene at 60 °C produced the desired allylic alcohol 110 with excellent stereocontrol (>10 : 1 dr) and in 44% yield. Protection of the secondary alcohol as the TBS ether, ozonolysis, selective methylenation using a modification of Takai's method,⁶¹ and finally desilylation with HF·pyridine led to amphidinolide T1, 111.

Scheme 17 Key steps of Jamison's synthesis of amphidinolide T1. Reagents and conditions: (1) DCC, 4-pyrrolidinopyridine; (2) TBAF, THF; (3) Dess–Martin periodinane, 59% (3 steps); (4) 20 mol% Ni(cod)₂, 40 mol% Bu₃P, Et₃B, PhMe, 60 °C, 44% (>10 : 1 dr); (5) (a) TBSOTf, 2,6-lutidine; (b) O₃, then Me₂S; (c) CH₂I₂, Zn, ZrCl₄, PbCl₂; (d) HF·py, 25% (4 steps).

Amphidinolide X⁶² has been synthesized by Fürstner.⁶³ The synthesis features subunit coupling by esterification and B-alkyl Suzuki reactions (Scheme 18). Acid 112 and alcohol 113 were coupled using Yamaguchi's conditions to give ester 114 in 96% yield. Reaction of this compound with boronate 119 (which was derived from the corresponding iodide that was in turn synthesized by a 12-step sequence involving the application of a newly developed iron-catalyzed ring-opening reaction of a propargyl epoxide with a Grignard reagent as a method for the synthesis of an allenol en route to a dihydrofuran) in the presence of Pd(0) produced 115 in an excellent 74% yield. Removal of the methyl ester with LiI followed by unmasking of the ketone with aqueous AcOH led to 116 in 53% yield over the two steps, and subsequent removal of the PMB group with DDQ in the presence of pH 7 buffer produced seco-acid 117 in 84% yield. The synthesis was then completed by Yamaguchi macrolactonization to yield amphidinolide X, 118, in 62% yield.⁶⁴

Scheme 18 Subunit couplings and the closing stages of Furstner's synthesis of amphidinolide X. Regents and conditions: (1) 112, 2,4,6-trichlorobenzoyl chloride, Et₃N, PhMe, then 113, DMAP, 96%; (2) (dppf)PdCl₂, Ph₃As, K₃PO₄, aq. DMF, 74%; (3) LiI, py, 125 °C; (4) aq. AcOH, 53% (over 2 steps); (5) DDQ, CH₂Cl₂, pH 7 buffer, 84%; (6) 2,4,6-trichlorobenzoyl chloride, Et₃N, THF, then DMAP, PhMe, 62%.

In other studies on the amphidinolides, a synthesis of the C11–C29 fragment of amphidinolide F⁶⁵ has been accomplished using a diastereoselective [3 + 2]-annulation reaction of an allylsilane and ethylglyxolate to produce the key tetrahydrofuran.⁶⁶ A synthesis of the C19–C26 subunit of amphidinolides B1 and B2 has been completed using a boron-mediated aldol reaction, and a synthesis of the C19–C26 subunit of amphidinolide B3 has also been completed.⁶⁷ Ghosh has also provided a detailed account of their synthesis of amphidinolide T1.⁶⁸

7 Dictyostatin-1 and discodermolide

Dictyostatin-1, a macrolide that is closely related to discodermolide and also displays impressive growth inhibition of the P388 murine leukemia cell line (ED₅₀ 0.38 ng mL⁻¹), along with differential cytotoxicity in the NCI 60-cell line screen, has received substantial attention in 2004. Dictyostatin's planar structure was first described by Pettit and co-workers who isolated the natural product from a Spongia sp. marine sponge collected in the Republic of Maldives.⁶⁹ Re-isolation of the compound by Wright and co-workers at the Harbor Branch Oceanographic Institute from a Corallistidae sp. lithistid sponge provided material that was used to assign the relative stereochemistry.⁷⁰ Shortly after the stereochemistry was available, simultaneous publications from the Curran⁷¹ and Paterson⁷² groups described the first syntheses of (−)-dictyostatin. Both syntheses employ similar strategies for the coupling of subunits, and conclude with Yamaguchi macrolactonization (Scheme 19).

Scheme 19 A comparison of key reactions in the Paterson and Curran dictyostatin-1 syntheses.

The Paterson synthesis ultimately commences with methyl (3S)-hydroxy-2-methylpropionate (the ‘Roche ester’, 119, Scheme 20). A sequence of 14 relatively routine steps from the Roche ester led to β-ketophosphonate 120, and an 11-step synthesis produced aldehyde 121. These two fragments were coupled by a Horner–Wadsworth–Emmons reaction employing Ba(OH)₂ in wet THF⁷³ to give enone 122 in 92% yield. Conjugate reduction of the enone with the Stryker's reagent,⁷⁴ followed by removal of both PMB groups with DDQ provided an intermediate β-hydroxyketone, which underwent reductione in a 1,3-syn-selective fashion when exposed to Zn(BH₄)₂ in Et₂O to produce triol 123 (>20 : 1 dr).

Scheme 20 Paterson's intial fragment coupling en route to dictyostatin. Reagents and conditions: (1) 120, Ba(OH)₂·8H₂O, THF, 1 h, then 121, 40 : 1 THF–H₂O, 92%; (2) [Ph₃P·CuH]₆, PhH, H₂O, rt; (3) DDQ, pH 7 buffer, CH₂Cl₂, 0 °C; (4) Zn(BH₄)₂, Et₂O, −30 °C, 66% (3 steps, >20 : 1 dr).

Key fragments 124 and 125 were coupled by a Still–Gennari-modified Horner–Wasdworth–Emmons olefination to give α,β-unsaturated ketone 126 with good levels of selectivity (Z/E = 5 : 1, 77%, Scheme 21). Stille coupling of the vinyl iodide with stannane 127 under Liebeskind conditions⁷⁵ followed by cleavage of the TIPS ester with KF in THF–MeOH gave the seco-acid 128 in 83% overall yield for these two steps. Yamaguchi macrolactonization furnished the macrocycle in 77% yield, and reduction of the C9 ketone under Luche conditions provided the final stereocenter under macrocyclic stereocontrol (70%). Global deprotection of the TBS groups with HCl in methanol gave dictyostatin-1 in 87% yield.

Scheme 21 Final steps of the Paterson synthesis of dictyostatin-1. Reagents and conditions: (1) K₂CO₃, [18]-crown-6, PhMe, rt, Z/E = 5 : 1, 77% (from the primary alcohol preceding 124); (2) CuTC, NMP, rt, then KF, THF–MeOH, rt, 83% (2 steps); (3) 2,4,6-trichlorobenzoyl chloride, Et₃N, DMAP, PhMe, 60 °C, 77%; (4) NaBH₄, CeCl₃·7H₂O, EtOH, −30 °C, 70%; (5) 3 N HCl, MeOH, rt, 87%.

Curran's synthesis of dictyostatin is also predicated on the observation that the Roche ester can serve as the starting material for the β-ketophosphonate 129 and alkyne 130 (Scheme 22). The intial subunit coupling was achieved by the reaction of the lithiated acetylide derived from 130 with Weinreb amide 131 to give ynone 132 in 93% yield. The C9 stereocenter was set by reduction with Noyori's Ru(II)-(S,S)-N-p-toluenesulfonyl-1,2-diphenylethylenediamine catalyst with ⁱPrOH as hydrogen donor, and subsequent Lindlar reduction of the alkyne and silylation with TBSOTf gave 133 (91% and 99% for the last two steps).

Scheme 22 Fragment coupling of the C10–C18 and C3–C9 domains. Reagents and conditions: (1) 130, ⁿBuLi, THF, then 131, 93%; (2) S,S Noyori catalyst (20 mol%), ⁱPrOH, 79%; (3) Lindlar catalyst, H₂, PhMe, 91%; (4) TBSOTf, 2,6-lutidine, CH₂Cl₂, 99%.

Introduction of the final fragment was achieved by a Horner–Wadsworth–Emmons reaction between aldehyde 134 (obtained from 133 by desilylation with HF·pyridine in 67% yield and Dess–Martin oxidation) employing the Ba(OH)₂ system (Scheme 23). Reduction of the enone was achieved by treatment with NiCl₂–NaBH₄, and the ketone was reduced with NaBH₄ to give the desired alcohol 136 in 70% yield (along with 29% of the α-diastereoisomer). This compound was advanced to dictyostatin by a 12-step sequence similar to the approach employed by Paterson that featured Yamaguchi macrolactonization after the installation of the diene.

Scheme 23 The second key fragment coupling of the Curran synthesis of dictyostatin-1. Reagents and conditions: (1) Ba(OH)₂, 129 (see Scheme 21), then 134, THF–H₂O, 80% (2 steps from the alcohol); (2) NiCl₂, NaBH₄, MeOH–THF, 76%; (3) NaBH₄, MeOH–THF, 70% (β), 29% (α).

In other work on dictyostatin, an approach to mixed polyacetate-polypropionates based on the cyclization of (silyloxy)enynes has been reported in the context of a synthesis of the C9–C19 subunit.

Discodermolide also continues to draw attention, and one of the highlights of 2004 in this area is the description of work at Novartis that resulted in the preparation of 60 g of discodermolide. The route is a hybrid of the Smith and Paterson synthetic route and involves 39 steps in totala (26 steps in the longest linear sequence).⁷⁶ This work has also been reviewed by Mickel.^77,78 Paterson has reported a 3^rd-generation synthesis that takes advantage of a Still–Gennari-modified HWE reaction that is similar to the one employed en route to dictyostatin-1.⁷⁹ Several subunit syntheses have been described including: (i) an approach to the C15–C24 subunit employing desymmetrization of a meso dialdehyde with the Haffner–Duthaler crotyltitanium reagent,⁸⁰ (ii) syntheses of the C1–C8 and C15–C21 subunits by diastereoselective dihydroxylation of dihydropyranones and subsequent α-deoxygenation,⁸¹ (iii) a highly diastereoselective and practical route to a lactone that serves as a key building block for the Novartis synthesis⁸² and (iv) an approach that exploits the pseudosymmetry of the C1–C13 region.⁸³ A series of 7-deoxydiscodermolide analogs in which the lactone was replaced by aromatics were designed, synthesized, and evaluated for cytotoxicity.⁸⁴ The majority of the compounds in this study displayed low micromolar IC₅₀ values against a variety of cancer cell lines. In other studies a series of analogs (which are minor side products generated during the final stages in the synthesis of (+)-discodermolide) were evaluated for in vitro cytotoxicity against 6 cell lines.⁸⁵ These compounds showed significant variation of cytotoxicity, and suggest the relevance of the C11 hydroxyl group, the C13 double bond, and the 16S stereochemistry are important for potent cytotoxocity.

8 Total syntheses of other compounds

The polycyclic alkaloid dragmacidin F⁸⁶ has been synthesized by Stoltz (Scheme 24).⁸⁷ Weinreb amide 138, which was prepared from the corresponding acid (synthesized in 6 steps from quinic acid), was reacted with lithiated pyrrole 139 to give ketone 140 in 66% yield from the acid. Exposure of this compound to Pd(OAc)₂ produced bicylic pyrrole 141 in 74% yield, which was advanced to tosyl oxime 142 by a 9-step sequence. Sequential treatment of this compound with KOH in EtOH–H₂O, followed by 6 N HCl, and finally K₂CO₃ produced amino ketone 143 (isolated as the trifluoroacetate) in an excellent 86% yield for the Neber rearrangement (as well as removal of the SEM and Ts protecting groups). Treatment with trimethylsilyl iodide to remove the methyl ethers, followed by reaction with cyanamide, gave dragmacidin F in 82% yield for these two operations.

Scheme 24 Key steps of the Stoltz synthesis of dragmacidin F. Reagents and conditions: (1) lithiopyrrole 139, THF, 66% from the acid; (2) Pd(OAc)₂, DMSO, ^tBuOH–AcOH, 74%; (3) KOH, H₂O, EtOH, then 6 N HCl, then K₂CO₃, THF–H₂O, 96% (3 steps); (4) (a) TMSI, CH₃CN; (b) H₂NCN, NaOH, H₂O, 82% (2 steps).

Birman et al.⁸⁸ and Baran et al.⁸⁹ have independently described sequences that lead to members of the sceptrin class. The Baran synthesis of sceptrin proceeds in an excellent 24% overall yield from dimethylacetylene dicarbocylate and employs the acid-catalyzed rearrangement of 3-oxaquadricyclane 144 to cyclobutane 145 as the key step (Scheme 25).

Scheme 25 The key step from the Baran synthesis of sceptrin. Reagents and conditions: (1) H₂SO₄, MeOH, 24 h, 50%.

Based on their synthetic studies, Baran has synthesized ageliferin⁹⁰ in a single step from sceptrin by heating sceptrin in H₂O in a microwave (Scheme 26).⁹¹ Based on this result, Baran and co-workers have proposed an alternative hypothesis to the long-held [4 + 2]-cycloaddition biogenesis of these compounds and related structures such as axinellamine and palau'amine (Scheme 27).

Scheme 26 Conversion of sceptrin to ageliferin. Reagents and conditions: (1) H₂O, 195 °C, microwave, 1 min, 40% (plus 52% recovered sceptrin)

Scheme 27 Baran's proposed sequence for the conversion of dibromosceptrin to axinellamine A in nature. A similar sequence can be drawn for palau'amine.

Spongidepsin⁹² has been synthesized by both the Forsyth and Ghosh groups, and the relative and stereochemistry has been established to be as shown.^93,94

A synthesis of bistramide A⁹⁵ that confirms Wipf's stereochemical assignment for bistramide C has been completed by Kozmin.⁹⁶ The synthesis involves 15 steps in the longest linear sequence and features a nice application of the ring-opening cross-metathesis of a cyclopropene acetal (Scheme 28) as a novel method for the rapid assembly of precursors to spiroacetals. Readily accesible alkene 150 was subjected to 10 mol% Grubbs’ 2^nd-generation catalyst in the presence of 1.5 equivalents of cyclopropenone acetal 152, and then aqueous acid to give dienone 151 in 63% over the two steps. Cross-metathesis with alkene 153 then provided 156 in 68% yield. Hydrogenolysis of the benzyl groups and the dienone resulted in acetalization, and subsequent Dess–Martin oxidation gave aldehyde 157 in 53% yield over the two steps. A sequence of three steps led to amino alcohol 158, and completed a very concise approach to this fragment. The synthesis was then completed by PyBOP-mediated acylation of the amine with 154 to produce 159. Removal of the Fmoc protecting group and acylation with activated ester 155 produced bistramide A in 65% over these final two steps.

Scheme 28 The Kozmin synthesis of bistramide A. Reagents and conditions: (1) 10 mol% Grubbs’ 2^nd-generation catalyst, 1.5 equiv. 152, PhH, 60 °C then 1 M H₂SO₄, MeCN, 63%; (2) 153, 10 mol% Grubbs’ 2^nd-generation catalyst, 68%; (3) H₂ (80 psi), Pd(OH)₂/C; (4) Dess–Martin periodinane, 53% (2 steps); (5) 154, PyBOP, DMF, 85%; (6) Et₂NH, DMF; (7) 155, DMF, 20 °C, 65%.

A large number of other total synthesis of marine natural products were reported in the review period, and papers describing first total syntheses are presented in Table 1. New total syntheses of compounds previously prepared are summarized in Table 2.

Table 1 First total syntheses of marine natural products reported in 2004

Compound	Reference	Notes
(+)-Xyloketal D	Krohn et al.^98	• 5 Steps
		• Non-racemic
		• Bioactivity: potent acetylcholine esterase inhibition
Cyercene A	Baldwin et al.^99	• 4 Steps from known compound
		• Bioactivity: may act as mediators in tissue regeneration and chemical defence in the mollusc
Plakortone G	Nishiyama et al.^100	• 19 Steps
		• Non-racemic
		• Bioactivity: cytotoxic
Austrodoric acid	Gavagnin et al.^101	• 7 Steps from known compound
		• Non-racemic
		• Bioactivity: unknown
(+)-Agelasine D	Gundersen et al.^102	• 4 Steps from (+)-manool
		• Non-racemic
		• Bioactivity: related compounds are cytotoxic and antimicrobial
Hachijodine B	Lee et al.^103	• 10 Steps
		• Non-racemic
		• Bioactivity: cytotoxic against the P388 cell line
(18S)-Variabilin	Takabe et al.^104	• 11 Steps
		• Non-racemic
		• Bioactivity: compounds of this class have shown antiviral and cytotoxic activity
(−)-Presphaerene	Lee et al.^105	• 18 Steps
		• Non-racemic
		• Bioactivity: none described
Dolastatin 18	Pettit et al.^106	• 5 steps from N-(benzyloxycarbonyl)-N-methylphenylalanine (Z-N-Me PheOH)
		• Non-racemic
		• Bioactivity: human cancer cell-growth inhibitor
Barettin	Bergman et al.^107	• 3 Steps from known compound
		• Non-racemic
		• Bioactivity: not stated
No name	Kende et al.^108	• 5 Steps from known compound (Kende)
	Bewley and Fetterolf^109	• 7 Steps from 3,5-dibromotyrosine (Bewley and Fetterolf)
		• Bioactivity: inhibits the mycobacterial enzyme mycothiol S-conjugate amidase
(+)-Phomopsidin	Nakada et al.^110	• 37 Steps
		• Non-racemic
		• Bioactivity: inhibitor of microtubule assembly
Phakellistatins 3 and 13	Van Vranken et al.^111	• 3 Steps from linear precursor synthesized on solid phase
		• Non-racemic
		• Bioactivity: cytotoxic against the P388 cell line
(−)-Aurilide	Suenaga and Kigoshi et al.^112	• 16 Steps
		• Non-racemic
		• Bioactivity: cytotoxic
Eurypamide A	Nishiyama et al.^113	• 19 Steps from known compound
		• Non-racemic
		• Bioactivity: none described, although related compounds are known to exhibit antimicrobial, cytotoxic and enzyme inhibition activity
(±)-Maculalactones A and B	Brown and Wong^114	• 6 Steps each
		• Racemic
		• Bioactivity: inhibitor of marine herbivore foraging and barnacle settling
(+)-Milnamide A	Molinski et al.^115	• 8 Steps from indole
		• Non-racemic
		• Bioactivity: disrupts microtubule assembly during cell division and inhibits growth of cultured tumor cells
Subarine	Delfourne et al.^116	• 5 Steps from phenanthroline
		• Bioactivity: no significant antitumor activity
(+)-SCH 351448	Lee et al.^117	• 27 Steps
		• Non-racemic
		• Bioactivity: activator of low-density lipoprotein receptor promoter with IC50 25 µM
Xestodecalactone A	Bringmann et al.^118	• 5 Steps
		• Non-racemic
		• Bioactivity: antifungal activity against Candida albicans
Lepadins B, D, E and H	Pu and Ma^119	• 21 Steps to lepadins B, E, and H
		• 20 Steps to lepadin D
		• Non-racemic
		• Bioactivity: significant in vitro cytotoxicity against several human cancer cell lines
(+)-Tricycloclavulone	Iguchi et al.^120	• 21 Steps
		• Non-racemic
		• Bioactivity: related compounds have antiproliferative activity against human cancer cell lines
Cribostatin 6	Nakahara and Kubo^121	• 10 Steps from known compound
		• Bioactivity: growth inhibitor of cancer cell lines and antibacterial activity
Oscillarin	Hanessian et al.^122	• 13 Steps from dimethyl-N-BocGlyOH
		• Non-racemic
		• Bioactivity: potent inhibition of thrombin
(+)-Eupenoxide and (+)-Phomoxide	Mehta and Roy^123	• 9 Steps from known compound to eupenoxide
		• 8 Steps from known compound to phomoxide
		• Non-racemic
		• Bioactivity: antibiotic
Basiliskamides A and B	Panek et al.^124	• 11 Steps to each compound
		• Non-racemic
		• Bioactivity: potent in vivo activity against Candida albicans and Aspergillus fumigatus
Myriaporones 1, 3, and 4	Taylor and Fleming^125 and Echavarren^126	• 20 Steps from known compound (Taylor)
		• 14 Steps from known compound (Echavarren)
		• Non-racemic
		• Bioactivity: inhibits growth of a range of cancer cell lines
Norrisolide	Theodorakis et al.^127	• 24 Steps from known compound
		• Non-racemic
		• Bioactivity: not described
6-Hydroxy-7-methoxyisoquinolinemethanol	Saito et al.^128	• 5 Steps from known compound
		• Bioactivity: not described
Plakortone E	Hayes and Kitching^129	• 10 Steps
		• Racemic
		• Bioactivity: no significant antitumor activity
Caulibugulones A–E	Wipf et al.^130 (A–E) and Tamagnan et al.^131 (A–D)	• 2–3 Steps each from 5-hydroxyisoquinoline (Wipf)
		• 4–5 Steps (Tamangan)
		• Bioactivity: cytotoxic; potent inhibitors of dual specificity phosphatase Cdc25B
Cyclomarin C	Wen and Yao^132	• 21 Steps from known compound
		• Non-racemic
		• Bioactivity: not described
Aigialomycin D	Geng and Danishefsky^133	• 18 Steps from 2-deoxyribose
		• Non-racemic
		• Bioactivity: potent antimalarial and antitumor activity
Kalihinol C	Wood et al.^134	• 24 Steps
		• Non-racemic
		• Bioactivity: related compounds show potent antimalarial activity
(6R,7S)-7-Amino-7,8-dihydro-α-bisabolene	Kochi and Ellman^135	• 9 Steps
		• Non-racemic
		• Bioactivity: antimicrobial

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Table 2 New total syntheses of marine natural products previously prepared that were reported in 2004

Compound	Reference	Compound	Reference
Helianane	Venkateswaran and Sabui^136	(±)-Pseudopterosins A–F and K–L aglycones	Harrowven and Tyte^137
(−)-Salicylihalamides A and B	Yadav and Srihari^138	(R)-Strongylodiols A and B	Lee and Baldwin et al.^139
Cryptophycin-24	Tripathy and Georg^140	(+)-Cylindricine C	Kibayashi et al.^141
(−)-Agelastatin A	Hale et al.^142	Siphonarienolone	Negishi et al.^143
(+)-Anatoxin-a	Brenneman and Martin^144	Haliclorensin and isohaliclorensin	Huang et al.^145
Lamellarin G trimethyl ether	Handy et al.^146	(−)-Callystatin A	Langille and Panek^147
Bacillariolide III	Suh et al.^148	Macrosphelides A, B, and E	Nemoto et al.^149
Caulersin	Bergman et al.^150	(−)-Myclamaide A	Trost et al.^151
Octalactins A and B	Burton and Holmes et al.^152	(+)-Tanikolide	Borhan and Schomaker^153
(+)-Pinnatoxin A	Inoue and Hirama et al.^154	Lamellarins K and L	Ruchirawat et al.^155
(+)-Tanikolide	Masaki et al.^156	6-Chlorohyellazole	Knölker et al.^157
Lyngbic Acid	Braddock and Matsuno^158	Hapalosin	Mandai et al.^159 and Palomo et al.^160
Pulchellalactam	Takabe et al.^161	(−)-Dysibetaine	Wardrop and Burge^162
Bistratamide G	Shin et al.^163	Pulchellalactam	Mangaleswaran and Argade^164
(−)-Pateamine A	Pattenden et al.^165	(+)-Kalkitoxin	White et al.^166
(±)-Pinnaic acid and (±)-tauropinnaic acid	Christie and Heathcock^167	(−)-Doliculide	Hanessian et al.^168
(−)-Flustramine B	MacMillan et al.^169	Peridinin	Katsumura et al.^170
Petrobactin	Phanstiel et al.^171	(−)-Cycloepoxydon	Mehta and Islam^172
(−)-α-Kainic Acid	Hoppe and Martinez^173	(−)-Apicularen A	Rizzacasa et al.^174
(±)-Halichlorine and (±)-pinnaic Acid	Kibayashi et al.^175	(+)-Brasilenyne	Denmark and Yang^176
Callipeltoside A	Panek and Huang^177	(+)-Acanthodoral	Zhang and Koreeda^178
(±)-Dibromophakellstatin	Austin et al.^179	Hamigerans A, B and E	Nicolaou et al.^180
7-Epicyclindrospermopsin	Looper and Williams^181

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9 Acknowledgements

We would like to thank Professor John Blunt and Professor Murray Munro (University of Canterbury, Christchurch, New Zealand) for a copy of the 2005 version MarinLit database⁹⁷ which facilitated data collection for this review. We thank Jim Henderson for assistance in drawing structures.

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