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Marine natural products: synthetic aspects

Jonathan C. Morris*a and Andrew J. Phillipsb
Received 3rd March 2010, Accepted 7th June 2010 DOI: 10.1039/b919366a

Covering: January to December 2008. Previous review: Nat. Prod. Rep., 2009, 26, 245 An overview of marine natural products synthesis during 2008 is provided. As with earlier installments in this series, the emphasis is on total syntheses of molecules of contemporary interest, new total syntheses, and syntheses that have resulted in structure conrmation or stereochemical assignments.
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1 2 3 4 5 6 7 8 9

Introduction Review articles Pinnatoxin Theopederin D Polyketides: callystatin, aburatubolactam, 15G256 (and related compounds) and bryostatin 16 Terpenoids: vannusal B and cortistatin A Largazole and the trichodermamides Acknowledgements References

products,11 The biology and chemistry of the zoanthamine alkaloids,12 A potential source of anticancer agents: natural products and their analogs. Extraction, characterization, biological activity and synthesis,13 Synthetic efforts toward, and biological activity of, thyrsiferol and structrurally-related analogues,14 Review of cytotoxic cephalostatins and ritterazines: isolation and synthesis,15 The chemistry of marine furanocembranoids, pseudopteranes, gersolanes, and related natural products,16 and The structure activity relationship of discodermolide analogues.17 Other reviews of relevance are cited in the text.

1 Introduction
This review is designed to provide an overview of key features of the 2008 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. Tabulated data for other syntheses are also provided. While every effort has been made to be comprehensive within these boundary conditions, we apologize in advance for any oversights.2

Pinnatoxin

2 Review articles
A number of reviews that cover various aspects of marine natural products synthesis have appeared: Synthesis of marine alkaloids from the oroidin family,3 Analogues of marine pyrroloiminoquinone alkaloids: synthesis and antitumor properties,4 Synthetic studies of heterocyclic natural products,5 Amphidinolides and its related macrolides from marine dinoagellates,6 The synthetic challenge of diazonamide A, a macrocyclic indole bis-oxazole marine natural product,7 Synthesis of marine natural products with antimalarial activity,8 The continuing saga of the marine polyether biotoxins,9 Convergent strategies for the total synthesis of polycyclic ether marine metabolites,10 Natural marine antiviral
a School of Chemistry, University of New South Wales, Sydney, Australia 2052. E-mail: jonathan.morris@unsw.edu.au; Fax: +61 2 93856141; Tel: +61 2 93854733 b Department of Chemistry, Yale University, New Haven, Connecticut, 06520, USA. Footnote: This paper is part of an NPR themed issue on Synthesis, guest-edited by Andreas Kirschning and Andy Phillips.

Zakarians synthesis of pinnatoxin A 118,19 was based around the dissection of the target into two key domains, 2 and 3, and highlighted the power of the IrelandClaisen rearrangement for the establishment of quaternary stereocenters (Scheme 1).20 In this context, when ester 7 (readily prepared by EDCI-mediated coupling of 4 and 5) was subjected to deprotonation with chiral amide base 6, the desired (Z)-enolate was formed. Trapping as the silylketene acetal, followed by warming to room temperature, resulted in the desired [3,3]-rearrangment to give 9 in an excellent 94% yield. A sequence of 14 steps installed the cyclohexene ring, and advanced material to 3. Addition of the organolithium derived from 2 (with t-BuLi) to aldehyde 3 occurred in 75% yield, and three further steps (desilylation with TBAF, DessMartin oxidation, and vinylmagnesium bromide addition) gave 10. Ring-closing metathesis with the HoveydaGrubbs 2nd-generation catalyst (25 mol% loading) followed by oxidation gave 11 in 57% yield for the two steps. Diastereoselective conjugate addition of MeCu(CN)Li installed the nal remaining methyl group (11 / 12, 81%) and spiroketalization with LiBF4 in wet iPrOH led to 13 in 60% yield. This material was advanced to 14 by a sequence of 7 steps, and after Staudinger reduction of the azide with Me3P, the imine was installed using Kishis conditions (triethylammonium 2,4,6-triisopropylbenzoate in xylenes at 85  C) to yield 15 (70% over two steps). The synthesis was completed by ester hydrolysis to give (+)-pinnatoxin A. Nakamura and Hashimoto have also reported a synthesis of pinnatoxin A (Scheme 2).21 Taking a page from Trosts recent successes in complex molecule synthesis [see also the bryostatin 16 synthesis later in this review], the key step was
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Scheme 1 Zakarians synthesis of pinnatoxin A. Reagents and conditions: (1) EDCI, DMAP, DMF, 94%; (2) (a) 6, THF, then TMSCl, 78  C; (b) 25  C, 6 h, 94%; (3) 2, tBuLi, Et2O, 78  C, 75%; (4) TBAF, THF; (5) DessMartin periodinane, CH2Cl2; (6) H2C]CHMgBr, THF, 75% (over 3 steps); (7) (a) 25 mol% HoveydaGrubbs II, CH2Cl2, 40  C; (b) DessMartin periodinane, pyr, CH2Cl2, 57% (over 2 steps); (8) MeCu(CN)Li, BF3$OEt2, THF, 78  C, 81%; (9) LiBF4, 4% aq. iPrOH, 90  C, 6h, 60%; (10) Me3P, aq. THF; (11) triethylammonium 2,4,6-triisopropylbenzoate, xylenes, 85  C, 70% (over 2 steps); (12) LiOH, THFH2O, 80%.

a macrocyclization by Ru-catalyzed enyne isomerization.22 Advanced intermediate 16 was subjected to a ve-step sequence that reorganized protecting groups, and freed the primary alcohol, which was oxidized with DessMartin periodinane to

give the aldehyde 17. HornerWadsworthEmmons reaction with phosphonate 18 gave the expected enone 19 in 86% yield (two steps). Wittig methylenation (Ph3P]CH2, 92%) provided a diene, 20, that was exposed to lactone 21 (10 equivalents) in

Jonathan C. Morris obtained his B.Sc. (Hons) degree from the University of Western Australia and his Ph.D. degree from The Australian National University in Canberra, Australia. After a postdoctoral appointment with Phil Magnus at the University of Texas at Austin, he joined the faculty at the University of Canterbury, New Zealand. In 2004, he moved to the University of Jonathan C: Morris Adelaide. In late 2009, he was appointed at the University of New South Wales. His research interests focus around the synthesis of biologically active natural products.
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Andrew J: Phillips

Andrew J. 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. In mid2010 he joined the faculty at Yale University. His research interests are broadly dened by the chemistry and biology of small molecules, including natural products.

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Scheme 2 The synthesis of pinnatoxin A by Nakamura & Hashimoto. Reagents and conditions: (1) TBAF, THF, reux, 72 h; (2) TBSCl, imid., DMF, 95% (2 steps); (3) TESOTf, 2,6-lut., CH2Cl2, 94%; (4) TBAF, THF, 0  C, 91%; (5) DessMartin periodinane, pyr, CH2Cl2, (6) 18, LiCl, DIPEA, MeCN,  86% (2 steps); (7) MePPh3Br, nBuLi, THF, 92%; (8) 21 (10 equiv), 4 A MS, p-xylene, 160  C, 12 h, 35% of desired (+ 46% of other cycloadducts); (9) [CpRu(MeCN)3]PF6 (10 mol%), acetone, 50  C, 15 min, 79%.

p-xylenes at 160  C. Under these conditions the desired endo product was obtained in 35% yield [3 other diastereomers were formed, with a total yield in the cycloaddition of 83%]. A sevenstep sequence advanced material to enyne 23, and when treated with 10 mol% of [CpRu(MeCN)3]PF6, macrocyclization to the desired product 24 occurred in an impressive 79% yield. This result underlines the value of this catalyst in complex molecule synthesis. The synthesis was completed by a further nine steps that paralleled the general strategy used by Kishi and Zakarian.2325

ability to generate N-acyliminium ions under such mild conditions is especially noteworthy given the delicate substrate, and this example should underscore the value of this approach for complex molecule synthesis. The synthesis was completed by a four-step sequence that involved oxidation of the lactol-derived acetal to the lactone with Jones reagent, removal of the Cbz group, acylation of the aminal with acid chloride 26 and, nally, removal of the benzoyl group. The overall synthesis provided theopederin D 25 in 16 steps (longest linear sequence).

4 Theopederin D
Floreancigs plan for the synthesis of theopederin D 2526 was based around connection of known acid chloride 26 with aminal 27 (Scheme 3).27,28 One of the key bond formations en route to 27 was an electron-transfer-initiated cyclization29,30 whereby an N-acyliminium ion was generated and intercepted by a proximal acetal. The synthesis of 27 commenced with known homoallylic alcohol 28, which was converted in six steps and 33% overall yield to dihydropyran 29. DMDO epoxidation of 29, followed by addition of trivinylalane to the intermediate alkoxy epoxide and protection of the alcohol as the 4-(benzyloxy)butyl ether, produced an intermediate (77% for the three steps) that was readily ozonized and converted to sulnylimine 30 by reaction with (R)-tert-butylsulfonamide in 50% yield. Addition of benzylmagnesium chloride, followed by (i) sulfonamide hydrolysis, (ii) hydrogenolysis of the benzyl ether and (iii) Cbz group installation gave alcohol 31. When subjected to iodobenzene diacetate and I2 under irradiation, Surez oxidative ethera ication31 occurred to give 32 in 80% yield, and set the stage for the key electron-transfer initiated cyclization. Irradiation of 32 (medium-pressure Hg lamp with Pyrex ltration) in the presence of 6 mol% of N-methylquinolinium hexauorophosphate (NMQPF6) and O2 provided 33 in 76% yield as a 2 : 1 mixture of diastereomers at C10. The reaction presumably proceeds via N-acyliminium ion 34, followed by oxononium ion 35. The
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5 Polyketides: callystatin, aburatubolactam, 15G256 (and related compounds) and bryostatin 16

The Micalizio group has reported a synthesis of callystatin A 36 that features a novel direct reductive coupling of two alkynes with Ti(II) reagents (Scheme 4).32 The subunit coupling commenced with a palladium-catalyzed coupling between the vinylzinc reagent derived from vinyl iodide 37, and (E)-vinyl iodide 38 and was followed by removal of the terminal TMS group to give 39. The direct titanium-mediated cross-coupling between alkyne 40 and diene 39 was accomplished with ClTi(OiPr)3 and cyclopentylmagnesium chloride in 75% yield (>5 : 1 regioselectivity) to give 41 (presumably via 42), which contains the complete callystatin A carbon backbone. TMS deprotection followed by oxidation and TBS removal concluded a total synthesis that proceeds in a remarkable 11-step longest linear sequence. In a follow-up to their earlier synthesis of the macrolactam tetramic acid cylindramide A,33 the Phillips group has described a total synthesis of aburatubolactam A 43 (Scheme 5).34 In the same vein as cylindramide A, the bicyclo[3.3.0]octane domain was formed by tandem metathesis of a readily accessible Diels Alder adduct. In the case at hand, treatment of 44 with 2.5 mol% of the Grubbs 1st-generation catalyst under an atmosphere of ethylene led to fused bicyclic compound 45 in 90% yield. A 15-step sequence advanced this compound to stannyldioxenone 46 in 9% overall and set the stage for an endgame that
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Scheme 4 Micalizios Ti-based route to callystatin A. Reagents and conditions: (1) 37, ZnCl2, tBuLi, Et2O then 38, cat. Pd(PPh3)4; (2) TBAF, THF 60% (2 steps); (3) nBuLi, ClTi(OiPr)3, c-C5H9MgCl, PhMe, 78  C then NH4Cl, 30  C, 75%; (4) PPTS, H2O, acetone; (5) PCC, AcOH; (6) HF$pyr, pyr, THF, 24% (3 steps).

Scheme 3 Floreancigs synthesis of theopederin D. Reagents and conditions: (1) DMDO, acetone, then (H2C]CH)3Al, CH2Cl2, 100%; (2) BBMCl, DIPEA, CH2Cl2, 77%; (3) O3, CH2Cl2, 78  C; then (R)-tBuS(O)NH2, Ti(OiPr)4, CH2Cl2, 50%; (4) BnMgCl, THF, 65%; (5) HCl, MeOH, 80%; (6) H2, Pd/C, MeOH; then CbzCl, Et3N, CH2Cl2, 70%; (7) PhI(OAc)2, hn, cyclohexane, 80%; (8) hn, NMQPF6, O2, NaOAc, Na2S2O3, PhMe, DCE, 76%. BBMCl 4-(benzyloxy)chlorobutane, NMQPF6 N-methylquinolinium hexauorophosphate.

commenced with thermolysis of 46 in the presence of amine 47 to give b-ketoamide 48. Stille coupling with tert-butyl-b-iodoacrylate produced the dienoate, and LaceyDieckmann cyclization gave 49 in 50% yield (over three steps). Despite the potential for subversion of the macrolactamization by stereochemical questions with respect to the exocyclic olen of the tetramic acid, treatment of 49 with TFA to remove the Boc carbamate and tertbutyl ester, followed by DEPC, smoothly produced the desired macrocycle. Removal of the TBS group with HF completed the total synthesis (46% yield over 3 steps). Barrett and coworkers have developed total syntheses of the marine antifungal agents 15G256p (50), 15G256i (51), and 15G256b (52), using a biomimetic late-stage aromatization strategy (Scheme 6).35 This strategy involves the thermolysis of
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Scheme 5 Phillips synthesis of aburatubolactam A 43. Reagents and conditions: (1) 2.5% Grubbs I, CH2]CH2 (1 atm), CH2Cl2, 90%; (2) PhMe, 110  C; (3) tert-butyl-b-iodoacrylate, 10 mol% Pd2(dba)3, Ph3As, NMP; (4) NaOMe, MeOH, 50% (3 steps); (5) TFA, CH2Cl2; (6) DEPC, Et3N, DMF, rt; (7) HF, MeCN, 46% (3 steps). DEPC diethylphosphoryl cyanide.

dioxinones such as 55 and trapping of the resulting triketoketenes with an alcohol to afford 54. Treatment of 54 with base generates the aromatic system 55. To prepare these natural products, an efcient synthesis to the 15G26 monomer unit 60 is required. Using acid chlorides 64 and 65, the readily available dioxinone 56 could be sequentially C-acylated to provide access to dioxinone 57 in 66% overall yield
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Scheme 6 Resorcylate lactones and a late-stage aromatization strategy.

Scheme 8 Completion of Barretts synthesis of 15G256p (50), 15G256i (51), and 15G256b (52). Reagents and conditions: (1) 63, 2,4,6-trichlorobenzoyl chloride, iPr2NEt, then 62, DMAP, PhMe, 86%. (2) Pd(PPh3)4, morpholine, THF, 87%; (3) H2, Pd/C, EtOAc; (4) HF, THF, pyr, 86% (2 steps); (5) HF, THF, pyr; (6) 2,4,6-trichlorobenzoyl chloride, DIPEA, DMAP, PhMe, 76% (2 steps); (7) H2, Pd/C, EtOAc, 75%; (8) 68, 2,4,6-trichlorobenzoyl chloride, iPr2NEt, then 66, DMAP, PhMe, 71%; (9) Pd(PPh3)4, morpholine, THF; (10) HF, THF, pyr; (11) 2,4,6-trichlorobenzoyl chloride, DIPEA, DMAP, PhMe, 65% (3 steps); (12) H2, Pd/C, EtOAc, 85%.

Scheme 7 Barretts synthesis of key monomers 62 and 63. Reagents and conditions: (1) 64, Bi(OTf)3, 15 / 20  C, 80%; (2) 65, MgCl2, pyr, CH2Cl2, 0 to 20  C, 83%; (3) Pd(PPh3)4 4 mol%, morpholine, CH2Cl2, 0 to 20  C, 89%; (4) 66, PhMe, 110  C; (5) K2CO3, iPrOH, CH2Cl2, HCl, MeOH, 70% (2 steps); (6) Cs2CO3, BnBr, DMF, 0 / 20  C, 92%; (7) HF, THF, pyr, 85%; (8) Pd(PPh3)4, morpholine, THF, 93%.

Conversion of 68 to the symmetrical natural product 15G256i (51) required a three-step procedure, with the silyl group being removed rst, then a Yamaguchi lactonization, followed by debenzylation. A 57% yield for the three steps was achieved. The more complex macrolactone 15G256b (52) was accessed by rstly converting 68 to macrolactone 69, using a four-step procedure. Debenzylation of 14 provided the natural product 52 in 85% yield. The bryostatins are an exciting class of macrolactone natural products that exhibit exceptional biological activity.36,37 In particular, it has been found that they have great potential as anticancer agents when used in combination with other therapeutic agents. Due to the scarcity of the natural material and the need for analogues, there has been much interest in the development of efcient syntheses.38 Trost and Dong have reported a highly convergent total synthesis of bryostatin 16 70 which is a key parent structure that

(Scheme 7). The tri-keto ester 58 was obtained in 89% yield after application of a palladium-catalyzed deallylationdecarboxylation procedure (4 mol% Pd(PPh3)4, morpholine). Thermolysis of the dioxinone in the presence of the chiral alcohol 66, followed by sequential reaction with potassium carbonate and methanolic hydrogen chloride gave the 15G256 monomer unit 60 in 70% yield for the two steps. Benzylation (BnBr, Cs2CO3, DMF, 92%) gave 61, which could then be converted into either alcohol 62 or acid 63 by the use of selective deprotection protocols. A Yamaguchi esterication of 62 and 63 gave the tetraester 67 in 86% yield (Scheme 8). Selective deallylation (4 mol% Pd(PPh3)4, morpholine, 87%) gave the acid 68, which is the key material for preparing the natural products. 15G256p (50) was prepared in 86% yield by removal of the benzyl ethers (H2, Pd/C), then desilylation (HF$pyr).
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Scheme 9 An overview of Trosts synthesis plan for bryostatin 16.

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could allow access to many other bryostatins.39 Starting from the readily available aldehyde 75, the synthesis requires 39 steps in total, with the longest linear sequence being 26 steps. As detailed in Scheme 9, it was envisaged that the macrocycle could be formed from 71 using a palladium-catalyzed alkynealkyne coupling, followed by a metal-catalyzed 6-endo-dig cyclization. The key substrate 3 would be assembled from the fragments 72, 73, and 74. Lactone 73 was prepared in 11 steps from the readily available aldehyde 75 (see Scheme 2) (Scheme 10). The same aldehyde was also used to produce the alkyne coupling partner 72 by rstly forming the enal, followed by an indium-mediated propargylation. To obtain the enantio-enriched material, the racemic 72 was rstly oxidized (DessMartin periodinane) to the ketone, then a CoreyBakshiShibata reduction gave (R)-72 in 90% ee and 90% overall yield. A chemoselective ruthenium-catalyzed tandem alkenealkyne coupling Michael addition (13 mol% CpRu(MeCN)3PF6, DCM) was used to form the cis-tetrahydropyran 76 in 34% yield (80% based on recovered starting material). Bromination of the vinyl silane (NBS, DMF), followed by an acid-catalyzed process (10 mol% CSA, MeOH) afforded the alcohol 77 in 94% overall yield for the two steps. With the A-ring and B-ring substructures in place, 77 was transformed into the desired acid 79 in six steps. Esterication of 79 with the

readily available 74 was achieved using Yamaguchis conditions (2,4,6-Cl3C6H2COCl, DMAP, NEt3, PhMe), affording 80 in 92% yield. Removal of the PMB protecting groups, using oxidative conditions (DDQ, pH 7 buffer, 2 cycles), gave the macrocycle precursor 81. The macrocycle 82 was generated in 56% yield by reaction of 81 with 12 mol% of palladium acetate and 15 mol% tris(2,6dimethoxyphenyl)phosphine in PhMe at room temperature (Scheme 11). It was found that the reaction had to be run at low concentration (0.002 M) and that the choice of solvent and the ligand/palladium ratio were critical to the success of the reaction. Treatment of the resulting alcohol 82 with a cationic gold catalyst (Au(PPh3)SbF6, NaHCO3) initiated a 6-endo-dig cyclization and afforded the desired ring system 83 in 73% yield. After pivalation of the secondary alcohol (Piv2O, DMAP, 62%), efforts focused on the global deprotection to afford bryostatin 16. After some experimentation, it was found that treatment of 84 with 5 equivalents of tetrabutylammonium uoride gave bryostatin 16 70 in 52% yield, after purication using reverse-phase HPLC. Keck and his group40 have developed a convergent strategy to highly potent bryostatin analogues, while Wender and coworkers have reported41 on the development of new highly potent analogues of the bryostatins, using a Prins-driven macrocylization strategy to allow efcient access to the target molecules. The isolation of (+)-neopeltolide 85a was reported42 in early 2007, and has attracted a great deal of attention due to the reported potent biological activity and structural complexity of the natural product. Indeed, there have been seven total

Scheme 10 Trost & Dongs synthesis of acid 79. Reagents and conditions: (1) (Z)-1-bromo-2-ethoxyethene, tBuLi, Me2Zn, then 75, Et2O, 78  C, 97%; (2) (3-bromo-1-propynyl)trimethylsilane, In powder, InF3 (10 mol%), THF, 65  C, 68%; (3) (i) DessMartin periodinane, NaHCO3, CH2Cl2; (ii) (S)-2-methyl-CBS-oxazaborolidine (5 mol%), catecholborane, CH2Cl2, 78  C, 90%, 90% e.e. (2 steps); (4) 1.2 equiv 73, CpRu(MeCN)3PF6 (13 mol%), CH2Cl2, 34% (80% b.r.s.m.); (5) NBS, DMF, 98%; (6) CSA (10 mol%), MeOH, 0  C, 9396%; (7) PdCl2(MeCN)2 (10 mol%), dppf, CO, MeOH, NEt3, DMF, 80  C, 83% (90% b.r.s.m.); (8) DessMartin periodinane, NaHCO3, CH2Cl2, 88%; (9) OhiraBestmann reagent, K2CO3, MeOH, 97%; (10) TBAF, HOAc, THF, 90% (96% b.r.s.m.); (11) Me3SnOH, 1,2-DCE, 80  C, 84%; (12) TESOTf, 2,6-lutidine, CH2Cl2, 10  C / 0  C, 7679%.

Scheme 11 Completion of Trost & Dongs synthesis of bryostatin 16 (70). Reagents and conditions: (1) 79, 2,4,6-trichlorobenzoyl chloride, NEt3, PhMe, then 74, DMAP, 92%; (2) DDQ, pH 7.0 buffer, DCM, 2 cycles, 75%; (3) Pd(OAc)2 (12 mol%), TDMPP (15 mol%), PhMe, 56%; (4) AuCl(PPh3) (20 mol%), AgSbF6 (20 mol%), NaHCO3, DCMMeCN, 0  C to rt, 73%; (5) Piv2O, DMAP, DCM, 50  C, 62%; (6) TBAF, THF, 52%.

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Scheme 12 The original and revised structures of neopeltolide.

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syntheses and one formal synthesis of the compound since its isolation. Importantly, the rst total syntheses of the proposed structure 85a, by the groups of Panek43 and Scheidt44 respectively, lead to the realization that the original stereochemical assignment was incorrect. Both groups independently assigned the conguration to structure 85b, and conrmed this by synthesis (Scheme 12). Their syntheses of the revised structure are discussed below. The synthetic plan pursued by the Panek group revolved around a Yamaguchi macrocyclization and StillGennari olenation (Scheme 13). Key building blocks were allyl silane 86 and aldehyde 87. Synthesis of the C7C16 fragment 87 of neopeltolide was achieved in 10 steps, starting from commercially available (R)-(+)-3-methylglutarate (88) (Scheme 14). The dihydropyran 91 was prepared in 75% yield (10 : 1 diasteromeric ratio) by reacting 87 with the readily available allylsilane 86, using a triic acid promoted [4 + 2] annulation. A four-step sequence was then utilized to prepare the seco acid 92 required for the macrocyclization. After macrocyclization (2,4,6-Cl3C6H2COCl, DMAP, PhMe, 44%), the axial C5 alcohol 93 was obtained by carrying out a selective oxymercuration (Hg(O2CCF3)2; NaBH4, 63%, >20 : 1 ratio) of the pyran alkene 92. To attach the side-chain, Panek and coworkers employed a StillGennari olenation. Acylation of alcohol 93 with bis(2,2,2-triuoroethyl)phosphonoacetic acid (EDCI$HCl, HOBt$H2O, 99%) afforded phosphonate 94. Deprotonation (KHMDS, 18-crown-6, 78  C) of the phosphonate 94, followed by addition of the readily available aldehyde 95 at 85  C provide a 7 : 1 mixture of neopeltolide (85b) and the corresponding (E)-olen. The longest linear sequence was 19 steps, with an overall yield of 1.3%.

Scheme 14 Paneks synthesis of (+)-neopeltolide (85b). Reagents and conditions: (1) BH3$SMe2, THF, 0  C to rt; (2) TBDPSCl, imid., DMF, 0  C to rt, 80% (over 2 steps); (3) DIBAL-H, diethyl ether, 78  C; (4) 1,3-propanedithiol, I2, CHCl3, rt, 85% (over 2 steps); (5) t-BuLi, HMPA, THF, 90, 78  C, 68%; (6) CaCO3, MeI, MeCNH2O, rt, 73%; (7)  Zr(OtBu)4, iPrCHO, PhMe, 78  C; (8) Me3OBF4, Proton Sponge, 4 A molecular sieves, CH2Cl2, rt, 90% (over 2 steps); (9) 49% HF in H2O, MeCN, rt, 91%; (10) (COCl)2, DMSO, CH2Cl2, Et3N, 78  C to rt, 89%. (11) 86, TfOH, CH2Cl2benzene (3 : 1), 78  C, 75% (d.r. 10 : 1); (12) NaCN, DMF, 60  C, 84%; (13) DIBAL-H, Et2O, 78  C, 96%; (14) DIBAL-H, CH2Cl2, 78  C, 60%; (15) NaClO2, 2-methyl-2-butene, NaH2PO4$H2O, tBuOH, H2O, 85%; (16) 2,4,6-trichlorobenzoyl chloride, PhMe, DMAP, Et3N, 44%; (17) Hg(O2CCF3)2 then NaBH4, THFH2O (1 : 1), 63% (d.r. >20 : 1); (18) (CF3CH2O)2P(O)CH2CO2H, EDCI$HCl, HOBt$H2O, CH2Cl2, 99%; (19) 94, 18-crown-6, KHMDS, 78  C, then 95, 85  C, 62%.

The Scheidt synthesis also focuses on the preparation of the macrolactone moiety, but the endgame differs in that it was proposed to attach the side-chain 96 via a Mitsunobu inversion (Scheme 15). To prepare the macrolactone 97, they planned to

Scheme 13 Paneks retrosynthetic analysis of (+)-neopeltolide (85b).

Scheme 15 Scheidts retrosynthesis of (+)-neopeltolide (85b)

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construct the tetrahydropyran and macrolactone simultaneously, using methodology they had developed previously. The macrocyclization precursor 98 should be readily available from acid 99 and alcohol 100. Scheidt prepared the C7C16 fragment 100 of neopeltolide in seven steps and 19% overall yield, starting from the ester 101 (Scheme 16). Dienoxy silane 103 was converted to the required dioxinone acid 104 in four steps (46% yield, 88% ee). Conversion to the macrocyclization precursor 98 was achieved by Yamaguchi coupling of 100 and 104, silyl deprotection (HF$pyr) and selective oxidation of the primary alcohol (TEMPO, PhI(OAc)2). This three-step procedure proceeded in 76% overall yield. Treatment of 98 with scandium(III) triate initiated the Prins-type macrocyclization, and after heating of the resulting dioxinone 105 in DMSO the macrolactone 106 was afforded in 21% yield. To complete the synthesis, the carbonyl group of 106 was reduced (NaBH4) and the resulting alcohol underwent a Misunobu reaction with acid 96 to yield (+)-neopeltolide, 85b in 76% yield. The longest linear sequence was 14 steps, with an overall yield of 1.0%.
Scheme 16 Scheidts synthesis of (+)-neopeltolide (85b). Reagents and conditions: (1) H2N(Me)OMe$Cl, iPrMgBr, THF; (2) PMBOC(NH)CCl3, PPTS, cyclohexaneCH2Cl2 68% (2 steps); (3) 102, t-BuLi, pentaneEt2O, 78  C; (4); MeOTf, DTBMP, CH2Cl2, 30% (2 steps); (5) DDQ, pH 7 buffer, CH2Cl2, 83%; (6) 4-NO2C6H4CO2H, DEAD, PPh3, C6H6, 0  C, 73%; (7) K2CO3, MeOH, 70%; (8) Ti(iPrO)4,  (R)-BINOL, 4 A sieves, CH2Cl2, 63%; (9) TBSOTf, 2,6-lutidine, CH2Cl2; (10) PPTS, EtOH; (11) PDC, DMF, 73% (3 steps); (12) 2,4,6-trichlorobenzoyl chloride, DMAP, THF; (13) HF$pyr, THF; (14) TEMPO, PhI(OAc)2, CH2Cl2, 76% (3 steps); (15) Sc(OTf)3, CaSO4, MeCN; (16) DMSO, H2O, 130  C, 21% (2 steps); (17) NaBH4, MeOH, 0  C; (18) DIAD, Ph3P, 96, benzene, 76% (2 steps).

Scheme 17 Summary of all of the other total and formal syntheses of (+)-neopeltolide (85b).

Scheme 18 Nicolaus synthesis of the proposed structure of vannusal (107). Reagents and conditions: (1) 109 (1.3 equiv), tBuLi (2.6 equiv), THF, 78 / 40  C, then 108 (1 equiv). 40 / 0  C, 80%; (2) TBAF, THF, 98%; (3) TESCl, imid., CH2Cl2, 25  C, 99%; (4) KHMDS, ClCO2Me, NEt3, THF; (5) HF$pyr/pyr (1 : 4), 0 / 25  C, 88% (2 steps); (6) TEMPO, PhI(OAc)2, CH2Cl2, 25  C, 98%; (7) SmI2, HMPA (15 equiv), THF, 10 / 25  C, 80% (113a: 28%, 113b: 52%); (8) POCl3, pyr, 60  C, 81%; (9) (i) CS2, NaH, THF, 0 / 25  C, then MeI, then 185  C (microwave), 1,2-DCE, 92%; (10) ThexBH2, THF, 10 / 25  C, then BH3$THF, 0 / 25  C, then 30% H2O23 N NaOH, 65%; (11) o-NO2C6H4SeCN, nBu3P, pyr, THF, then 30% H2O2, 67%; (12) KHMDS, TESCl, NEt3, THF, 78 / 25  C, 84%; (14) LiDBB (excess), THF, 78 / 50  C, 84%; (15) Ac2O, NEt3, DMAP, CH2Cl2, 25  C, 100%; (16) HF$pyrTHF (1 : 4), 25  C, then 3 N aq. HClTHF (1 : 3), 25  C, 80%.

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The syntheses and subsequent structural revisions of Panek and Scheidt have triggered a great deal of work, with a further six new syntheses (Kozmin,45 Maier,46 Lee,47 Fuwa-Sasaki,48 Paterson,49 and Taylor50) reported in 2008. Due to space constraints, these syntheses are not discussed, but a summary of the number of steps and the overall yield for the sequence is provided in Scheme 17. It should be noted that all but one (Taylor) have utilized the Scheidt endgame, whereby they attach the oxazole sidechain using a Mitsunobu inversion. Kozmin and coworkers have carried out an investigation of the mode of action of neopeltolide, 85b and have identied the cytochrome bc1 complex of the mitochondrial respiratory chain as the primary cellular target.45
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6 Terpenoids: vannusal B and cortistatin A

Vannusal B 107 represents a signicant synthetic challenge, with seven rings and 13 stereogenic centers.51 However, Nicolaou and

coworkers have synthesised the proposed structure of vannusal B using a convergent strategy, starting from aldehyde 108 and iodide 109 (Scheme 18).52 Unfortunately, the spectroscopic data for the synthesized material does not match the reported data of the natural product. A six-step sequence, starting from 108 and 109, generates the aldehyde carbonate 112. Formation of the carbon skeleton 113 (as a 1.9 : 1 mixture of alcohols) was achieved in 80% yield by treatment of 112 with samarium iodide. Each of the diastereomers of 113 could be independently deoxygenated to afford diene 114. This material was transformed to the proposed structure 107 using a seven-step sequence. At the time of writing, the Nicolaou group has revised the structure on the basis of further synthetic studies.53,54 The cortistatin family of steroidal alkaloids have generated signicant interest from the synthesis community55 since their discovery in 20062007.5658 Aside from their interesting 9-(10,19)-abeo-androstane type skeleton, attention has no doubt

Scheme 19 Highlights of the rst three total syntheses of cortistatin A by Baran, Nicolaou & Chen, and Shair. (A) Barans synthesis. Reagents and conditions: (1) Co(acac)2 (0.2 equiv), PhSiH3 O2, THF, HC(OMe)3, 23  C, 12 h; then TsOH$H2O, rt, 2 h; then K2CO3 MeOH, 6 h, 65%; (2) PhI(OAc)2 (5 equiv), Br2 (5 equiv), CH2Cl2, 30  C, 10 h; then TMSCl, imid., 57%; (3) DBU, LiCl, THF, 85%; (4) SmI2, DMPUTHF, 23  C; then TBCHD (1.1 equiv), 23  C, 5 h; (5) LiBr, Li2CO3, DMF, 80  C, (65% over 2 steps); (6) AlH3, THF, 23  C, 1 h; then K2CO3, MeOH, 23  C, 12 h; then Ac2O, Et3N, DMAP, CH2Cl2, 89%; (7) MgBr2$Et2O, 2,6-tBu2Py, PhH; then PPTS, butanone: H2O, 90  C; then K2CO3, MeOH, 82%; (8) (a) N2H4, Et3N, EtOH, 50  C, 6 h, then I2 (2 equiv), Et3N (3 equiv), THF, 23  C, 5 min; (b) 7-(trimethylstannyl)isoquinoline (4 equiv), Pd(PPh3)4 (0.5 equiv), CuCl, LiCl, DMSO, 23  C, 10 min, 53% (over 2 steps); (9) RANEY Ni, iPrOH, H2O, 50  C, 1 h, 50% (at $50% conversion). (B) Nicolaou & Chens synthesis. Reagents and conditions: (1) 3-oxocyclohex-1-enyl triuoromethanesulfonate, 10% Pd(PPh3)4, CuI, Et3N, DMF, 85%; (2) IBX, DMSO, 81%; (3) Pd/BaSO4 (5% wt/wt, 0.24 equiv), H2, MeOHTHF, 64%; (4) K2CO3, dioxane, 52%; (5) tBuOOH, DBU, CH2Cl2, 70%; (6) NaBH4, CeCl3, MeOH, 80% (dr $ 1 : 1); (7) Me2NH, THF, Ti(OiPr)4, 80  C, 5 h, 45%. (C) Shairs synthesis. Reagents and conditions: (1) PPTS, Me2COH2O; (2) NaOMe, MeOH, 70  C, 1 h (49%, 2 steps); (3) SOCl2, pyr, CH2Cl2; (4) NaHMDS, THF, then PhNTf2; (5) Me(OiPr)2SiCH2MgCl, 5 mol% Pd(PPh3)4, THF, rt, 62% (3 steps); (6) CHBr3, KOtBu, hexane, 0  C; (7) TASF (1.2 equiv), DMF, 80  C, 30 min, 66% (2 steps); (8) Me2NH (3 equiv), ZnBr2 (1.5 equiv), CH3CN, 50  C, 40 min, 65% (3 steps).

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been honed by their impressive biological activities, most notably cortistatin A (115), which has highly selective and potent activity against HUVEC cells (IC50 1.8 nM). The Baran synthesis of cortistatin A 115 commenced with readily availabile prednisone (116), which was converted in ve steps and 26% overall yield to 117 (Scheme 19).59 Mukaiyama hydration of the olen with Co(acac)2 and PhSiH3, followed by orthoamide formation and acetate cleavage (65% for the three operations) gave an intermediate that was subjected to a newly developed procedure that used in situ-formed acetylhypobromite for the functionalization of hydrocarbons. Under direction of the proximal alcohol, the C19 methyl group was dibrominated to give 118 in 57% yield (with the alcohol being protected as the TMS ether to prevent intramolecular etherication). Treatment of 118 with DBU at elevated temperature resulted in enolization and intramolecular alkylation with the germinal dibromide to provide bromocyclopropane 119 as a single diastereomer. Ring expansion mediated by SmI2, followed by treatment with 2,4,4,6tetrabromo-2,5-cyclohexadienone (TBCHD), gave 120. Elimination with LiBr/Li2CO3, removal of the orthoester, and nally acetylation produced diene 121. Lewis acid-mediated SN20 reaction installed the oxabicylo[3.2.1]octane motif, and removal of the protecting groups led to 122. Barton iodination of the ketone 122 produced an intermediate iodide that was readily coupled with 7-(trimethylstannyl)isoquinoline, leading to 123 in 53% yield (over the two steps). The synthesis was completed by hydrogenation of the styryl olen using RANEY nickel to give cortistatin A, 115 in 50% yield (at $50% conversion). The Nicolaou synthesis, which was executed in conjunction with David Chen at A-Star in Singapore, began with hydrindane 124, a derivative of the HajosParrish ketone (Scheme 19).60 Nine steps converted 124 to alkyne 125, and set the stage for a key four-step sequence that assembled the polycyclic

framework of cortistatin. After Sonagashira coupling of the alkyne with 3-(triyloxy)cyclohexenone (125 / 126), the dithiane was removed under oxidative conditions with IBX, and reduction of the alkyne with H2 and Pd/BaSO4 gave 127. An elegant sequence of tandem heteroconjugate addition and aldol condensation gave 128. After conversion of 128 to 129 (9 steps, 6% overall), functionalization of the cyclohexenone ring commenced with conjugate epoxidation from the b-face to give epoxyketone 130. Subsequent reduction with NaBH4/CeCl3 gave the desired alcohol as a 1 : 1 mixture of separable diastereomers (the minor could be recycled by quantitative oxidation with DessMartin periodinane), and the synthesis was completed by Ti(OiPr)4-mediated epoxide opening with Me2NH to yield cortistatin A, 115 in 45% yield (unoptimized). The departure point for the Shair synthesis was the Hajos Parrish ketone 131, which was advanced to 132 by a ve-step sequence of standard transformations (Scheme 19).61 Removal of

Scheme 20 (a) The synthesis of the pentacyclic cortistatin core by Yamashita & Hirama. Reagents and conditions: (1) cyclohexane-1,3dione, piperidine, EtOAc, 87%, d.r. 5 : 1; (2) HF$pyr, THF, rt; (3) I2, Ph3P, imid., THF, 87% (2 steps); (4) Et3B, (Me3Si)3SiH, THF, 78  C. (b) The key step of the Danishefsky synthesis of the cortistatin core. Reagents and conditions: (1) TBAF, THF, 88%.

Scheme 21 (a) Sarpongs synthesis of the pentacyclic cortistatin core. Reagents and conditions: (1) 1020 mol% PtCl2, PhH, rt / 40  C; (2) TsNHNH2, Et3N, 1,2-DCE, 65  C, 95% (after one recycle); (3) MgBr2$OEt2, Me2S (20 equiv), CH2Cl2, 78  C / rt; (4) TESCl, imid., DMF; (5) MCPBA, NaHCO3, CH2Cl2, 0  C, 46% (3 steps); (6) nBuLi, THF, 0  C, 1 h; (7) PhI(OAc)2, CH2Cl2iPrOHTFE (5 : 3 : 2), 0  C, 30 min, 60% (2 steps). (b) Coreys benzylic cyanation and Demjanov rearrangement approach to the cortistatin core. Reagents and conditions: (1) DDQ, TMSCN, LiClO4, CH2Cl2, 10  C, 95%; (2) LiAlH4, THF, 98%; (3) NaNO2, AcOH, H2OTHF, 61%.

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Scheme 22 An overview of macrocyclization strategies for largazole, and the syntheses by Luesch and Williams. (a) Solution structure of largazole [as determined by Phillips and co-workers]. (b) Sites of macrocyclization. (c) Luesch & Hongs synthesis. Reagents and conditions: (1) Et3N, EtOH, 51%; (2) TFA, CH2Cl2; (3) 158, DMAP, 94% (2 steps); (4) Boc-L-valine, 2,4,6-trichlorobenzoyl chloride, Et3N, DMAP, CH2Cl2, 99%; (5) LiOH, THFH2O; (6) TFA, CH2Cl2; (7) HATU, HOAt, DIPEA, CH2Cl2, 64% (3 steps); (8) Grubbs II (30 mol%), PhMe, 41%. (d) Williams synthesis. Reagents and conditions: (1) Fmoc-L-valine, EDCI, DMAP, CH2Cl2; (2) Et2NH, CH3CN; (3) PyBOP, DIPEA, CH2Cl2, 78% (3 steps); (4) TFA, CH2Cl2; (5) HATU, HOBt, DIPEA, CH2Cl2, 77% (2 steps); (6) iPr3SiH, TFA, CH2Cl2; (7) H3C(CH2)6COCl, Et3N, CH2Cl2, 89% (2 steps).

the cyclic ketal with PPTS, followed by intramolecular aldol reaction, produced 133 in 49% yield. A three-step process of SOCl2-mediated elimination to the a,b-unsaturated ketone, vinyl triate formation and Pd(0)-catalyzed coupling with Me(OiPr)2SiCH2MgCl provided 134 in 62% overall for the three steps. Cyclopropanation with dibromocarbene (generated from CHBr3 with tBuOK as base) gave 135. Warming this compound in the presence of TASF at 80  C in DMF produced the desired ring-expanded compound 136 in 66% yield (over 2 steps). Five further steps were employed to convert 136 to the precursor 137, which is required for the key tandem Mannich-etherication process. In this sequence, treatment of the aldehyde 137 with Me2NH and ZnBr2 in CH3CN at 50  C resulted in iminium ion formation, cyclization of the olen onto the iminium ion, and trapping of the carbenium ion with the MEM ether. Termination of this cascade occurred by scission of the MEM ether to give 138 in an excellent 65% yield (over the proceeding three steps). A further six steps converted 138 into cortistatin A, 115. Cortistatin also stimulated a number of studies that resulted in novel and/or concise approaches to the framework of the cortistatins. Yamashita and Hirama employed a Knoevenagel reaction of 139 with cyclohexane-1,3-dione in the presence of piperidine at room temperature (Scheme 20).62 The intermediate product, 140, underwent electrocyclization to produce tetracycle 141 in 87% yield and with 5 : 1 diastereoselectivity. Removal of the TBS ether and conversion of the alcohol to the iodide (141 / 142, 87%) was followed by radical cyclization with Et3B and (Me3Si)3SiH to give 143 in 78% yield. A similar strategy
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Scheme 23 (a) The syntheses of largazole by Phillips and Cramer. Reagents and conditions: (1) Fmoc-L-valine, EDCI, DMAP (Phillips) or Fmoc-L-valine, DIC, DMAP (Cramer); (2) Et2NH, 62% (2 steps, Phillips) or piperidine, 93% (2 steps, Cramer); (3) DCC, PFP, 52% (Phillips) or DCC, DMAP, 97%, (Cramer); (4) TFA, CH2Cl2 (Phillips) or TFA, Et3SiH, CH2Cl2; (5) PyAOP, MeCN, DMAP, 50% (2 steps, Phillips) or HATU, DIPEA, THF, 6878% (2 steps, Cramer); (6) 157, 20% Grubbs II, 34% (Phillips) or 157, 20% Grela catalyst, 54%. (b) The Ghosh macrolactamization leading directly to largazole. Reagents and conditions: (1) TFA, CH2Cl2; (2) HATU, HOAt, DIPEA, CH2Cl2, 40% (2 steps).

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involving formation of the pentacyclic core by an alkylative dearomatization was published by Danishefsky. In this case, the key step was the reaction of 144 with TBAF, which proceeded to give 145 in an excellent 88% yield.63 Danishefsky has also published a synthesis of the cortistatin core that employs a novel a,b-unsaturated nitronearyne [3 + 2] cycloaddition followed by NO bond reduction, elimination and electrocyclization.64 Sarpong and co-workers decribed a concise synthesis of the pentacyclic cortistatin core that employed enyne cyclization chemistry developed in their group (Scheme 21).65 When the key substrate 148 (obtained from 146 and 147 in a four-step sequence) was subjected to PtCl2, the desired product 149 was obtained in 95% yield. A three-step sequence of (i) selective reduction of the least hindered double bond with diiimide, (ii) exchange of the PMB group for a TES group, and (iii)

epoxidation led to 150. Eliminative opening of the epoxide 150 gave the allylic alcohol, which upon exposure to PhI(OAc)2 was oxidized to the dienone and resulted in the formation of the oxabicylo[3.2.1]octene ring, yielding 151 in 60% yield (over two steps). Corey has also described preliminary ring-expansion studies directed toward the cortistatins (Scheme 21).66 Readily available estrone derivative 152 was treated with DDQ and TMSCN (at levels great enough to ensure that [TMSCN] > 3.0 M) to yield the benzylic cyanide 153. Reduction to the primary amine (LAH, 98%, 153 / 154) was followed by a Demjanov ring expansion using NaNO2 and AcOH to give 155 in 61% yield. Other reports on the cortistatins include a CD-ring synthesis by intramolecular Michael-aldol reaction and an intramolecular [4 + 3] cycloaddition approach to a tetracyclic model system.67,68

Scheme 24 The syntheses of trichodermamide by Zakarian and Joulli. (a) Zakarian: Reagents and conditions: (1) vinylidene carbonate, 165  C, 64%; e (2) LiOH, aq. THF, 90%; (3) TBSCl, imid., DMAP, DMF, 90  C, 96%; (4) SmI2, MeOH, THF, 99%; (5) (i) MePPh3Br, KHMDS, THF, 99%, then (ii) 9-BBN, THF then NaOH, H2O2, 92%; (6) Swern oxidation, 99%; (7) (i) NaClO2, NaH2PO4, 2-methyl-2-butene, tBuOH, H2O, then TMSCHN2, CH2Cl2MeOH, 94%; (8) LDA, Me3SiCl, THF; (9) iC5H11ONO, TiCl4, DBMP, CH2Cl2, 82% (2 steps); (10) EDCI, DMAP, CH2Cl2, 62%; (11) Zn(OTf)2, EtSH, NaHCO3, CH2Cl2, 88%; (12) MsCl, pyr, CH2Cl2, 90%; (13) LiCl, DMF, 74%; (14) aq. HF, THF, 90%. (b) Joulli: Reagents and e conditions: (1) TFAA, 90% H2O2, Na2HPO4, CH2Cl2, 95%; (2) TsOH, 2,2-DMP, acetone, 99%; (3) NaBH4, CeCl3, EtOH, 15  C, 80%; (4) NaBH4, EtOH, 95%; (5) DessMartin reagent, CH2Cl2, 95%; (6) NH2OH$HCl, NaOAc, EtOHH2O then NaOH, 65%; (7) TBDPSCl, imid., CH2Cl2, quant.; (8) FeCl3$H2O, CH2Cl2, 85%; (9) 1,10 -thiocarbonyldiimidazole, PhMe, reux, 95%; then P(OMe)3, MW, 150  C, 84%; (10) EDCI, 30% pyr, CH2Cl2, 83%; (11) K2CO3, MeOH, 72%; (12) TBAF, THF, 85%; (13) MsCl, NEt3, LiCl, CH2Cl2, 60%.

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Table 1 First total syntheses of marine natural products reported in 2008 Compound Reference Gung and Omollo81 Notes  5 steps from known compound  Resolution  Absolute conguration determined

Giddens et al.82

 Pseudopyrinone A: 3 steps from known compound  Pseudopyrinone B: 5 steps from known compound  Biological activity: good potency and selectivity against parasitic protozoa

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Greshock et al.83

 18 steps from commercially available 6hydroxyindole  Biomimetic synthesis  Racemic synthesis

Kumar and Shaw84

 16 steps from commercially available materials  Non-racemic synthesis  Biological activity: potent cytotoxicity

Ghosh, Kumar and Shashidhar85

 21 steps from known compound  Non-racemic synthesis  Determined absolute conguration  Biological activity: cytotoxic against 3YI rat normal broblast cells

Skepper et al.86

 5 steps from pentadecyne  Non-racemic synthesis  Biological activity: signicant antifungal

Cordes et al.87

 7 steps from 2,6-dimethoxybenzaldehyde

Crimmins and Ellis88

 8 steps from known intermediate used to prepare 11-acetoxy-4-deoxtasbestinin D  Non-racemic synthesis

Soyev, Navarro and Trauner89

 13 steps from known compounds  Biomimetic synthesis  No protecting groups used

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Table 1 (Contd. ) Compound Reference Seden et al.

90

Notes  16 steps (longest liner sequence) from 3-benzoyloxypropanal  Non-racemic synthesis

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Hamel et al.91

 24 steps (longest liner sequence) from known compound  Non-racemic synthesis  Biological activity: potent in vitro antiproliferative activity

Niethe, Fischer and Blechert92

 19 steps (longest linear sequence) from alanine  Non-racemic synthesis  Established absolute conguration of natural product  Biological activity: activity against malaria causing plasmodia and some trypanosomes

Hupp and Tepe93

 14 steps from known compound  Racemic synthesis  Biological activity: cytotoxicity

Xie et al.94

 19 steps (longest linear sequence) from alanine  Non-racemic synthesis  Established absolute conguration of natural product  Biological activity: activity against malaria causing plasmodia and some trypanosomes

Jiang et al.95

 16 steps (longest linear sequence) from commercially available (+)-dehydroepiandrosterone  Non-racemic synthesis  Biological activity: cytotoxic against human solid tumour cell lines

Ard et al.96 a

 16 steps (longest linear sequence) from L-glutamic acid  Non-racemic synthesis

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Table 1 (Contd. ) Compound Reference Liu, Cui and Nan

97

Notes  15 steps (longest linear sequence) from known compound  Non-racemic synthesis  revision of structure

Lewis, Daniels and Lindsley98

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 3 steps from known compounds  Non-racemic synthesis  Revision of stereochemistry  Biological activity: antileishmanial

Eade et al.99

 6 steps from known compound  Racemic synthesis  Biomimetic synthesis

Paterson, Razzak and Anderson100

 17 steps from known compound  Non-racemic synthesis  Biological activity: ornithine decarboxylase induction inhibitors

Li et al.101

 11 steps from known compound  Non-racemic synthesis  Biological activity: antifungal

Smith et al.102

 Data for the synthetic material doesnt match that reported for each natural product  25 steps from known compound  Non-racemic  Potent cytotoxicity

7 Largazole and the trichodermamides

Along with cortistatin A, largazole 156 proved to be one of the hottest targets of the year. In both cases the high level of interest was underpinned by some very impressive biological activity in
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the case of largazole it was nanomolar GI50 values against a number of cancer cell lines, with $15-fold differential activity for transformed vs. non-transformed cells. The structure elucidation by Luesch69 was quickly followed by several total syntheses, including those of Luesch,70,71 Williams,72 Phillips,73
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Table 2 New total syntheses of marine natural products previously prepared that were reported in 2008 Compound Aaptamine Aigialomycin D ()-Amathaspiramide F Attenols A and B Chondramide C Dictyopterene A Eicosanoid ()-Flustramines A and C, ()ustramide A, and ()- and (+)-debromoustramines A (+)-Isolaurepan Malyngamide U and its 20 -epimer (+)-Monocerin (+)-Phorboxazole A (+)-Psymberin (irciniastatin A) Solandelactones A, B, E and F (+)-Tedanolide and (+)-13deoxytedanolide Reference Larghi et al.103 Chrovian et al.105 Sakaguchi et al.107 Fuwa et al.109 Eggert et al.111 Hohn et al.113 Kumaraswamy and Padmaja115 Kawasaki et al.117 Tripathi and Kumar119 Feng et al.121 Kwon et al.123 Smith III et al.125 Smith III et al.127 White et al.129 Dunetz et al.131 Compound ()-Agelastatin A Amaminol B Amphidinolide J (-)-Brevenal ()-Cylindricine C ()-Dysibetaine Et-743 ()-Hirsutene and ()-1desoxyhypnophilin Lamellarins O, P, Q and R Manzacidins A and C Pachastrissamine (jaspine B) Preclathridines A and C, and isonaamines A and C Siphonarienal and siphonarienone (+)-Spongistatin 1 ()-Tridachiahydropyrone Reference Yoshimitsu et al.104 Jacobs et al.106 Barbazanges et al.108 Ebine et al.110 Flick et al.112 Isaacson et al.114 Fishlock and Williams116 Jiao et al.118 Fukuda et al.120 Oe et al.122 Passiniemi and Koskinen124 Alifanov et al.126 Lum et al.128 Smith III et al.130 Sharma et al.132

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and Cramer.74 Further syntheses continued at a steady rate through 2008, and by the end of year a further three had been recorded (by Ghosh,75 Ye,76 and Doi77). Perhaps not surprisingly given the relative simplicity of the target, key strategic questions revolved around the timing of the thioester incorporation and the position of macrocyclization. Most groups arrived at overlapping solutions, and the position of macrocyclization is shown in Scheme 22, along with the almanac of key building blocks employed in the various approaches (157 / 160). The Luesch synthesis involved the coupling of thiazolyl nitrile 162 and a-methylcysteine 163 to give thiazolylthiazoline 159 in 51% yield. Removal of the Boc carbamate and acylation of the amine with acid 158 under standard EDCI conditions produced 164 in 94% yield (over 2 steps) and was followed by coupling with Boc-valine under Yamaguchi mixed anhydride conditions to yield the precursor to the macrocyclization, 165. Removal of the methyl ester (LiOH, aq. THF) and the Boc group (TFA) was followed by HATU-mediated cyclization to give the desired macrocycle 166 in 64% yield (over 3 steps). The synthesis was then completed by appending the thioester side chain by crossmetathesis between 164 and 157 in the presence of 30 mol% Grubbs 2nd-generation catalyst, to give largazole in 41% yield. The Williams synthesis involved acylation of alcohol 167 with Fmoc-valine to produce 168 (Scheme 22). Removal of the Fmoc carbamate was followed by coupling to acid 169 in the presence of PyBOP, to give 170 in 78% yield (over 3 steps). Treatment with TFA in CH2Cl2 removed the Boc and TMSE protecting groups, and was followed by macrolactamization with HATU to give 171 in 77% yield (over 2 steps). Liberation of the thiol with TFA iPr3SiH, followed by acylation with capryloyl chloride, gave largazole in 89% yield for these two steps. The Phillips group and the Cramer group arrived at remarkably similar syntheses in an independent fashion (Scheme 23). Readily accessible allylic alcohol 158 was acylated with Fmoc valine and after removal of the Fmoc group, thiazolylthiazoline acid 169 could be coupled to the amine to give 174. Acidic conditions cleaved the acid-sensitive Boc carbamate and tertbutyl ester, and macrocyclization was readily achieved with
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either PyAOP (Phillips, 50% over 2 steps) or HATU (Cramer, 6878% over 2 steps). The syntheses were then completed by cross-metathesis with olen 157 in the presence of either Grubbs 2nd-generation catalyst 175 (Phillips, 41%) or the Grela catalyst 176 (Cramer, 54%). An alternative macrocyclization substrate was reported by Ghosh as a part of their total synthesis of largazole (see also Scheme 23). Treatment of 177 with TFA removed the tert-butyl ester and Boc carbamate, and the intermediate amino acid salt could by cyclised with HATU/HOAt to give largazole directly in 40% yield. Both the Zakarian and Joulli groups have completed total e syntheses of the 4H-5,6-dihydro-1,2-oxazine-containing natural product trichodermamide B, and the Joulli group has also e completed trichodermamide A (Scheme 24).78,79 The Zakarian synthesis is predicated on the formation of the oxazine by application of an enolate nitrosation followed by a Lewis acid mediated hetero-Cope rearrangement as the key reaction, and the synthesis commenced with a DielsAlder reaction between 179 and vinylidene carbonate to give 180 in 64% yield. Hydrolysis of the carbonate was accompanied by a surprising inversion of the stereochemistry at the b-hydroxy position to give 181, and after removal of the methoxy groups and protection of the alcohols as TBS ethers, 181 was obtained. Wittig olenation, hydroborationoxidation and conversion to the methyl ester gave 184 (via 183) and set the stage for the key transformation. Deprotonation of the ester and conversion to the silylketene acetal 185 was followed by treatment with isoamyl nitrite in the presence of TiCl4 to give 186 in an excellent 82% yield over the two steps. A sequence of seven steps advanced material to 187, which was readily reacted with aminocoumarin 188 to yield 189. Removal of the benzylidene acetal with Zn(OTf)2 and EtSH, followed by mesylation of the less hindered alcohol, gave 190. SN2 displacement of the mesylate was readily achieved with LiCl in DMF, and the synthesis was completed by removal of the TBDPS protecting group with aqueous HF. The Joulli synthesis employed ()-quinic acid 192 as a starte ing material, and a 13-step sequence led to 193. Epoxidation with in situ-formed CF3CO3H and acetonide formation gave 194.
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Reduction of the lactone in two steps was accompanied by migration of the TBDPS group to the primary alcohol, which facilitated the protecting group and redox reorganizations required to arrive at ketone 195. Upon reaction with hydroxylamine, an intermediate oxime was presumably formed that underwent intramolecular O-alkylation with the epoxide to provide oxazine 196 as a single diastereomer in 65% yield. A three-step sequence of TBDPS protection, acetonide cleavage and CoreyWinter olenation gave 197. Oxidation-state manipulations over ve steps gave 198, and at this juncture the synthesis could be completed by a sequence that was analogous to that described by Zakarian. A large number of other total syntheses of marine natural products were reported in the review period, and papers describing rst total syntheses are presented in Table 1. New total syntheses of compounds previously prepared are summarized in Table 2.

8 Acknowledgements
We would like to thank Professor John Blunt and Professor Murray Munro (University of Canterbury, Christchurch, New Zealand) for a copy of the 2008 version of the MarinLit database80 which facilitated data collection for this review. Members of the Morris group are thanked for their assistance in drawing structures.

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