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`1www.nature.com/naturechemica1lbiology
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`Nature chemical biology.
`v. 3, no. 7 (2007 July)
`0D415.A 1 N385
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`i'latural products, and terpenes in
`µarticular, have long fascinated
`scientists with their remarkable
`structural diversity and their often
`urikflown biological functions. In
`this issue, we feature a collection of
`articles meant to shed light on the
`synthesis, sources and significance
`of terpenoid natural products.
`Terpene struct,ires courtesy of Seiichi
`Matsuda. Cover art by
`Erin Boyle, based on a photo by
`Rodolto Clix.
`
`, VOLUME 3 NUMBER 7 JULY 2007
`
`nature
`chemical biology
`
`1i,i§itJnidNATURAL PRODUCTS
`
`EDITORIAL
`351 All natural
`
`COMMENTARIES
`
`353 One pathway, many products
`Michael A Fischbach & Jon Clardy
`
`356 Plant endophytes as a platform for discovery-based undergraduate
`science education
`Scott A S\robel & Gary A Strobel
`
`360 Revisiting the ancient concept of botanical therapeutics
`Barbara M Schmidt, David M Ribnicky, Peter E Lipsky & llya Raskin
`
`ELEMENTS
`367 Natural products at the Hans Knoll Institute
`
`PERSPECTIVES
`
`379 Mining and engineering natural-product biosynthetic pathways
`Barrie Wilkinson & Jason Micklefield
`
`387 Production and engineering of terpenoids in plant cell culture
`Susan C Roberts
`
`REVIEWS
`
`396 Modern synthetic efforts toward biologically active terpenes
`Thomas J Maimone & Phil S Baran
`
`408 The function of terpene natural products in the natural world
`Jonathan Gershenzon & Natalia Dudareva
`
`Nc1lwc Cnem>r.fllniology(ISSN 1552-4450)is pul)lishOO n1011U1ly by Nature Publi-shir1~Group. c lradinenameol Nolu1e Ameri, a Inc located at /~Va,i<:k
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`Copy1ighl o0200/ Na lure flublishjngGruup rrintr.d in US/\
`
`llaturc publishing group
`
`

`

`VOLUME 3 NUMBER 7 JULY 2007
`
`CORRESPONDENCE
`352 Rethinking relationships between natural products
`
`NEWS AND VIEWS
`
`368 From eye of newt to chemical structure
`Piali Sengupta & J;imes H Thomas
`(cid:141) see also p 420
`369 Calcium channels light up
`Eric Green & Ricardo E Dolmetsch
`(cid:141) see also p 423
`371 Methuselah antagonist extends life span
`Deirdre McGarrigle & Xin-Yun Huang
`(cid:141) see also p 415
`372 A LOVely view of blue tight photosensing
`Wen-Huang Ko, Abigail I Nash & Kevin H Gardner
`
`374 Cofactor-independent oxygenases go it alone
`Susanne Fetzner
`
`377 RESEARCH HIGHLIGHTS
`
`LETTERS
`
`415 Extension of Drosophila melanogaster life span with a GPCR peptide inhibitor
`William W .Ja, Anthony P West Jr, Silvia L Delker, Pamela J Bjorkm,rn,
`Seymour Benzer & Richard W Rob8rls (cid:141) see also p 371
`
`mRNA display library
`
`In vitro
`selection
`
`Immobilized t::irgt:t
`
`Methuselah
`
`Selected
`peptide
`
`420 Small-molecule pheromones that control dauer development in
`Caenorhabditis elegans
`Rebecca A Butcher, Masaki FuJila, Frank C Schroeder & Jon Clardy
`(cid:141) see also µ 368
`
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`ii
`
`NATURE CH[MICAI lli OLOGY
`
`

`

`, VOLUME 3 NUMBER 7 JULY 2007
`
`ARTICLE
`
`423 Calcium Green FIAsH as a genetically targeted small-molecule calcium indicator
`Oded Tour, Stephen R /\dams, Rex A Kerr, Rf.nr. M Ml)ijcr, Trmence J Sejnowski,
`Richard W Tsien & Roger Y Tsien (cid:141) see also p 369
`
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`
`432 CORRIGENDA
`
`NATURE CHEMICAL BIOLOGY CLASSIFIED
`
`See back pages.
`
`lliA.l 1 1RE CHEMICAL BIOLOGY
`
`iii
`
`

`

`REVIEW~ -~ - - - - -
`
`nature
`chemical biofogy
`
`Modern synthetic efforts toward biologically
`active terpenes
`
`Thomas J Maimone & Phil S Baran
`
`Terpenes represent one of the largest and most diverse classes of secondary metabolites, with over 55,000 members isolated to
`date. The terpene cyclase enzymes used in nature convert simple, linear hydrocarbon phosphates into an exotic array of chiral,
`carbocyclic skeletons. Further oxidation and rearrangement results in an almost endless number of conceivable structures. The
`enormous structural diversity presented by this class of natural products ensures a broad range of biological properties-ranging
`from anti-cancer and anti-malarial activities to tumor promotion and ion-channel binding. The marked structural differences of
`terpenes also largely thwart the development of any truly general strategies for their synthetic construction. This review focuses on
`synthetic strategies directed toward some of the most complex, biologically relevant terpenes prepared by total synthesis within the
`past decade. Of crucial importance are both the obstacles that modern synthetic chemists must confront when trying to construct
`such natural products and the key chemical transformations and strategies that have been developed to meet these challenges.
`
`With their usage dating as far back as ancient Egypt, terpenes hold a
`special place in both chemical and world history. Scientists and non(cid:173)
`scientists alike can appreciate these truly functional molecules, whose
`applications range from flavor and fragrance to hormones, medicine
`and even rubber 1• Synthetic chemists were drawn to terpenes before
`their polymeric origins were even clearly delineated (via the "biogenetic
`isoprene rule") by Ruzicka in 1953 (refs. 2,3 and references therein). The
`arrival of spectroscopic and chromatographic techniques brought about
`an explosion in the chemical aspects of terpene research that continues
`to this day. As a consequence, many highly complex terpenes have been
`prepared by total synthesis (Fig. 1 )4- 6. Although terpenes formally are
`made from only one biosynthetic unit, in contrast to the 20 proteogenic
`amino acids that make up proteins, the fact that they can be rearranged
`and highly oxidized means that the synthetic challenge of construct(cid:173)
`ing them rivals that of many other secondary metabolites in terms of
`difficulty. In addition, their ubiquity in nature often results in natural
`products of'mixed' biosynthetic origins, such as terpene alkaloids and
`terpene polyketides 7•
`
`Introduction to the synthesis of terpenes
`Because the cai:bon skeleton of a terpene is often its defining structural
`feature, it is there that synthetic chemists usually begin their planning.
`Indeed, a plethora of approaches for accessing terpene ring systems are
`often published before an actual total synthesis. Unfortunately, signifi(cid:173)
`cant difficulties are often encountered in attempting to translate the
`results of a model system to one laden with more functionality; in some
`cases an entirely new strategy must be devised to access the natural
`product8• This highlights the fact that subtle steric and electronic factors,
`
`Department of Chemistry, The Scripps Research Institute, 10550 N. Torrey Pines
`Road, La Jolla, California 92037, USA. Correspondence should be addressed to
`P,S.B . {pbaran@scripps.edu).
`
`Published online 18 June 2007; doi:10.1038/nchembio2007 . l
`
`as well as functional-group incompatibilities, are often difficult-or
`impossible-to predict at the beginning of a total synthesis endeavor9•
`So where does one start when trying to access a complex terpene skel(cid:173)
`eton? Although there are many useful guidelines that can be followed
`during the planning stage, there are simply no general rules to apply
`when synthesizing a terpene. Indeed, successful syntheses of complex
`terpenes often rely on a mixture of imaginative planning and extensive
`empirical testing. Part of the charm and appeal of such molecules to syn(cid:173)
`thetic organic chemists is the unpredictable nature that results from their
`highly rearranged and unprecedented carbon skeletons. Three diffri ent
`approaches can often aid chemists in their synthetic studies, all 1 cly(cid:173)
`ing on the principles of retrosynthetic analysis 1°. In the first appro,1ch,
`the standard logic of synthetic planning can be applied, whereby one
`looks for strategic bond disconnections within the target molecule. This
`approach largely rests on the available toolbox of known transforn1a(cid:173)
`tions, resulting, after multiple iterations, in the identification of a suit(cid:173)
`able starting material. A second approach identifies a specific strucl u ml
`motif contained within the terpene skeleton that could be made via a
`certain synthetic methodology that is either known or newly invented.
`As a third option, one can try to find a structural match between the
`target and a smaller, commercially available terpene. The large number
`of commercially available terpenes ( often in either enantiomer) cou f1led
`with the abundance of modern asymmetric transformations make the
`2
`last two methods particularly attractive for asymmetric synthesis 11
`• 1
`,
`As we will see, modern terpene syntheses are an amalgam of classical
`organic transformations, modern catalytic asymmetric reactions ;1nd
`efficient use of the pool of available chiral terpenes.
`The importance of natural products as sources of new drugs has been
`recently reviewed 13•14. Although many terpenes do not resemble 'typi(cid:173)
`cal' therapeutics (heteroatom-laden aromatics), their structures have
`presumably been selected to interact with biological targets. In addi(cid:173)
`tion, the presence of multiple stereocenters, molecular rings and di,'L'rs_e
`10
`oxygenation patterns also bodes well for sampling chemical spacc
`•
`
`396
`
`This material may be protected by Copyright law (Title 17 U.S. Code)
`
`VOLUME 3 NUMBER 7 JULY 2007 NATURE CHEMICAL BIO LOG Y
`
`

`

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`Figure 1 Highly complex terpenes that have been prnpared by total synthesis. (a) Classic terpene
`targets of the twentieth century. (b) Selected complex, biologically active te,penoids synthesized in the
`past decade (1997-2007). Ac, acetyl; Bz, benzoyl.
`
`REVIEW
`
`the most potenl tumor promoters ever isolated.
`Accordingly, these mokrnks liave received
`considerable a!lenLion from the biological and
`medical communities. More recently ingenol
`has also been shown Lu possess anti-tumor,
`anti-leukernic and anti-HIV properties (ref.
`1 9 ,rnd references tl1erein). Its structural fea(cid:173)
`tures have also fascinated synthetic chemists
`for the past 25 years, owing in large µart to a
`rare form of isomerism displayed in its Band C
`rings (Scheme la}. 'In-out' isomerism, wherein
`a bridgehead hydrogen is formally 'inside' the
`bicycle, provides ingenol with a thermody(cid:173)
`rn1mically disfavored configuration20,21 . Many
`early synthetic investigations failed to address
`this feature, although some provided evi(cid:173)
`dence lhat this isomeric fonn is required for
`biological activity22_ The first synthetic strat(cid:173)
`egr lo address this challenging ~spect of the
`molecule was described in 1987 by Winkler
`and collcagues23 and later by several other
`grouµs21 ,2•1,23; however-as a true testament to
`the difficulty ingcnol poses-it was not until
`2002 that Winklcr's group could claim a total
`synthesis of 1 (Scheme 11>) 26. After Winkler's
`synthesi,, total syntheses were reported by the
`Kuwajima group in 2003 (Scheme le) and by
`the WoCld group in 2004 (Scheme Jd)2"28.
`In ,1ddition, one formal syntl1esis and many
`apprnaches have been published 19-2~.JO_
`
`Use of the De Mayo reaction en route to the
`first total synthesis of (±)-1 (Winkler). The
`\·\'inkier group sought to assemble the in-out
`system by an i ntramolecular variant of the ve11-
`crnble De J\fayo reactio11 wherein a viuylygous
`
`ester engages an olefin in a 2+2 cycloaddition26·:;' .. ''·. The intermedi(cid:173)
`ate cydohutanc then undergoes bnse-mediated retro-aldol fragment,1-
`tion (Scheme lh). To give the desired strained bicrcle, Lhey began by
`elaborating enone 9 into key compound lU hy an t l-stcp procedure,
`Irradiation of 10 in acetonitrilc provided the desired cyclobutane 11.
`It is worth noting that the hydrogen atom in the cyclobutane ring will
`become Lhe 'in' hydrogen in the in-out bicycle, and thu.1 its position in
`the cydoaddition is critical to its position in the (>B-ring junction.
`Treatment of JI with µotassiLm1 carhonatc in methanol led to 13 ,1fter
`loss of acetone and retro-aldol fragmentation. The conversion of l 3 into
`ingenol required 33 steps owing to both the unfunctionalized nature
`or 13 and the synthetic difficulty associated with the three contiguous
`asymmetric hydroxyl groups. Cap~ble of being performed in a com(cid:173)
`plex molecular setting, the De Mnyo reaction-as demonstrated by
`Winkler-is an cxtrcmdy powerful tool for the synthesis of complex
`ring systems. Another elegant application of this strategy, in the synlbt'sis
`of.1audi11, is discussed i:Jelow.
`
`\Vhile most of the tcrpcnc.s discussed in this review may never arrive in
`your neighborhood pharmacy (although some have), the motils pres(cid:173)
`ent in these natmal products could very well find their way into future
`pharmaceuticals. Indeed, terµenes oflcn provide the impetus for the
`discovery and development of new ring-forming reactions in synthesis.
`l n addition, the synthesis of lcrpcnes can lead to a greater understand(cid:173)
`i11g of fundamental chemical reactivity, as well as proving or disproving
`i\ structural assignrncnt 16. Diversification of strategy is "Isa important
`in modern day chemists' pursuit of efficiency, selectivity and flexibility .
`. 'vlolecules discussed in this review 1vere chosen on the basis of following
`crik-ria: (i) their primary carbon skeletons are solely of terpene orig,n (or
`believed to be), (ii) they possessed interesting biological profiles at the
`time of their isolation, (iii) they possess interesting, um1sual or unprece(cid:173)
`dented strnctures and (iv) solutions to their total chemical synthesis
`have been reported only within the past decade (1997-2007). Because
`or space limitations. onl)' the key chemical transformations leading to
`successful total syntheses can be illustrated. In many ca.1e.s, the interested
`reader can find a more comprehensive survey on the approaches to these
`naturnl products elsewhere.
`
`lngenol (1)
`In 1968 Hecker and co-workers isolated the highly oxygenated diterpene
`ingenol (I) from the roots of b'11plwrbia ingem17•18. Though the tcrpenes
`are not c;u-cinogcnic themselves, esters of several ditcrpcnes derived
`from this genus-including ingenol and phorbol (Fig. 1 )-arc some of
`
`A total synthesis of (±)-L featuring Nicholas aml pinacol-typc chem(cid:173)
`istry (Kuwajima). The Kuwajirna group took a markedly different
`approach to constructing the ingt'nanc skeleton, in which they envi(cid:173)
`sioned that that C ring could be formed via a Nicholas-type reaction
`(16-, 18) (Scheme Jc) 1~·27•33. In this reaction, the presence of the
`cobalt-carbonyl complex m:,kes the neighboring acetate highly prone
`to ionii:atiou and displacement due to the bridging ability of cobalt.
`
`NATURE CHEMICAi. BIOLOGY VOLUME , NUMBER 7 JULY W07
`
`397
`
`

`

`REVIEW
`
`The A and n rings would originate fmm a pinacol-typc rearrangement
`converting the 6-5 fused ring system into the desired 7-5 system. The
`synthesis of 16 required 15 steps, and upon treatment with Lewis acid 17,
`Kuwaj ima and colleagues were ahlc to produce tricyclic compound 18. In
`a short (flve-step) sequence, 18 could he converted into 19. "li:eatmenl of
`l9 with trimethylaluminum induced the desired bond reorganization to
`give 20, which contains the complete ingcnane skeleton. lngenol could
`then be prepared in 18 steps from compound 20. This synthesis served
`to demonstrate how a complex ring system can be prepared by a careful
`orchestrntion of favorable known reactions.
`
`A ring-opening and ring-closing metathesis strategy to construct
`ingenol (Wood). Wood ,rnd co-workers began their journey to the syn(cid:173)
`thesis of ingenol with a functionafo:cd Cring possessing the requisite
`asymmetric methyl and dimethylcyclopmpyl groups (Scheme ld)2~.
`This key compound (enone 21) could be constructed from a commcr"
`cially available lerpene in ten steps, closely following a route described
`by hmk21 . Enone 21 was then coaxed into participating in a Lewis
`acid-catalyzed Diels-Alder cycloaddition with cydopentadiene to pro(cid:173)
`duce spirocycle 22, thus delivering all of lhe carbons needed for the
`fivc"mcmbcrcd A ring. ·n-eatmenl of ketone 22 with Grubb's cat,liyst
`in refluxing toluene openetl the bicyclo (2.2.l] ring system (ring-open(cid:173)
`ing metathesis) to spiro-ketonc 23, which in turn could be elaborated
`into 24 via a four-step procedure. Using Grubbs-Hoveyda catalyst 25,
`the Wood group was abk to carry mil lhe transformation 24 (cid:157)
`26
`
`(ring-dosing metathesis), thus fanning the coveted in-out systcin.
`Compound 26 could be transfol"med into ingenol in an additional ll
`s1eps. The olefin met,1 thesis reaction (whose pioneer, were awarckd the
`2005 Nobel Prize in chemistry) has proven to he one of the 111011 idi(cid:173)
`able and po,,.,erful reactions in modern chemistry for the construction
`of carbocydic rings34.
`
`Resiniferatoxin (2)
`Isofaled from E11phorbin ,·esinifem, resiniferatoxin is a powerful an,1Jge(cid:173)
`sic that has been used to treat pain for almost 2,000 years6. It belongs
`to the daphnane family of diterpenes, and its molecular ,kelctorr is
`biosynthetically related lo both the tigliane (phorbol) and ingt'nane
`(ingenol) classes (Scheme 2a). Although it lacks the in-out ring system
`of its chemical cousin, ii is still an extremely challenging symhctic larg-et
`owing to its dense, highly oxygenated skeleton. Indeed, Wender',, 1997
`total synthesis remains the only synthetic route to 2 (ref. 35), although
`various approaches towarcl obtaining the A-B-C ring system have Gem
`reported (refs. 36,37 and references therein).
`
`Total synthesis of (+)-2 featuring an ox.idopyrylium 1,3-dipolar
`cycloaddition (Wender). As an efficient synthetic entry into both the
`tigliane and daphnane terpene classes, the Wender group devclt,1.>cd
`an intramolecular variant of the oxidopyrylium I ,3-dipolar crdo(cid:173)
`,,ddition (Schemes 2b,c) (ref. 38 and references therein). This pownful
`re,1ction allows for the rapid, stereoselective construction of bridged
`
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`Scheme 1 The total synthesis of ingenol. (a) 'In-out' isomerism of tl1e C-B rings as a key synthetic challenge posed by ingenol. (bl Winkler"s approach
`featuring an intramolecular variant of the De Mayo reaction. kl Kllwajima and Tanino's approacn using a Nicholas-type cyclization and pinacol rearraneff1cnt
`to form the i11-out system. (d) Wood's approach using a ring-opening and ring-closing metathesis strategy. Cy, cyclohexyl; Mes, 2,4,6-tr1melhylphenyl; n!Ll.
`p-methoxybenzyl; TBS, t-butyldimethylsilyl; TES, triethylsilyl; TIPS, triisopropylsilyl.
`
`VOi UM, 1 NIJM~ER 7 JIJLY 2007 NATURE CHEMICAL BIOi ,JGY
`
`

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`
`t)4n•
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`r.yr.lo.'la"dol1r.-r
`
`18SO
`A'= 01¼, A"= A)= H (phortlol): A 1 = H. A~= OAc. FLJ = oen (res1niff!r~l<;-~in)
`
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`(cid:141)
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`
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`
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`cytli!.:llior1
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`
`Scheme 2 Syntlietic methods used in the construction of resiniferatoxin. (a) Resiniferatoxin's daphnane skeleton and its close chemical relatives, also from
`the plant family Euphoriaceae. (b) General method for the generation of a reactive oxidopyrylium {27) and its subsequent participation in an exo-selective
`.1,3-dipolar cycloaddition. (c) U~P. of an intramolecular oxidopyrylium cyclo;iddition as an efficient synthetic eotry into the tigliane and daµhnaoe :;keleto11s
`(Wender and colleagues). (d) Key transformations in Wonder's pioneering total synthesis of rnsiniferatoxin. Ac, acetyl: Bn, benzyl; Cp, cyclo1>entadienyl; TBS,
`t-l:>utyldimetl1ylsilyl; THF, tetrahydrofuran; TMS, trimethylsilyl.
`
`polycyclic architectures such as 28. Using thi., methodology, tricycle 28
`rnuld be fashioned and tran.sformed into 29 hy an eight-step sequence
`(Scheme 2d). ·n·eatment of29 with hL1tyl lithium and Cp2ZrC:l2 cleanly
`rormed the desired A ring, via an cnyne cyclization. Seven steps were
`required to convert 30 into 31, which was heated with zinc in etha(cid:173)
`nol to induce elimination of the extraneous oxygen bridge. It is wor(cid:173)
`lhy of note, however, that having the oxygen bridge present until then
`served both to rigidify the li-7 ring system (thus aiding intermediate
`suhstratc-controllcd reactions) as well as to protect a tertiary hydroxyl
`group. Compound 32 can he converted into rcsinifrratoxin in 16 steps.
`Although the Diels-Alder reaction has typically been the premier cyclo(cid:173)
`addition reaction in synthesis (leading to six-membered rings)19, one
`cannot ignore the power of the 1,3-dipolar cycloaddition to form botb
`live- and seven-membered ring architectures.
`
`Guanacastepenes (3)
`ln the search for biologically active natural products, fungi have tra(cid:173)
`ditionally provided fertile hMvesting ground. In 2000, Clardy and co(cid:173)
`workers isolated guanacastepeneA (3) [J"om an unidentified endophylic
`fo 11gus present on the bark of LJapil ,10psis amerimnn in Cos la Rica4u. A
`year later, 14 more guanacaslepenes were disrnveretJ'l 1. lliosynthetically,
`it has been proposed that lhe guanacaslcpenc skeleton may be related
`lll that of the well-precedented dolabcllancs (Scheme 3a)'10. lntercst
`in 3 related initially to its activity against antibiotic-resistant bacteria.
`1:urther studies, however, have shown 3 to possess hemolytic activ(cid:173)
`ity against human red blood cells, most likely acting hy nonspecific
`membrane lysis42 , In synthetic circles, the guanacastepcnes remain a
`vibrant proving grnund for the development of new synthetic mcth(cid:173)
`o,k To date, five total syntheses, two formal synthe.,cs and a myriad
`of approaches have been l'Cported (refs, 42- 50; ref. 51 and references
`I herein).
`
`A condensation and ~-elimination cascade en route to (±J-gua(cid:173)
`nacastepene A (Dani.~hefsky). The Danisl1efsky g,·oup assembled
`guanacastcpenc A (3) from the left to the right side, with the A ring
`originating from 2-mcthylcyclopentcnonc (Scheme 3b)42.43 A vicinal
`difunctionalization of this simple starti11g materi,1\ led to vinyl iodide
`33, Lithium-halogen exchange a11d intramolccular quenchingo11to the
`internal ketone led to 34after an additional oxidative allylic transposi(cid:173)
`tion step (Dauben oxidation), \i\lith the A and R rings quickly formed,
`the Danishefsky team elabornted enone 34 into keto-ester 35 in a ten(cid:173)
`step procedure. Their key step involved the base-mediated conversion
`of35 to 36. This cascade sequence probably proceeds via a Knoevenagel
`condensation with concon1itant l:l-elin1ination of the epoxide 1JJoiety.
`Conversion of 36 to (±)-3 required 12 steps. In addition to this work,
`an asymmetric synthesis was published in 2005 (ref. 44). Timi the
`Danishefsky group could arrive at a complex molecular target such as
`3 using only simple starting materials and reagents is a testament to
`their brilliant synthetic design.
`
`Diastereoselective synthesis of (±)-guanacastcpene C (43) using
`cydopentenone 'masking' (Mehta). Mehta's approach toward gua(cid:173)
`nacaslepene C (43) [ollowc<l a choreography of ring rnnslruclion
`l:l (cid:157) CJ similar to that of the JJanishdsky group (Scheme 3c)'13.
`(A (cid:157)
`Key building hlock 39 could he prepared hy a selective conjugate addi(cid:173)
`tion and alkylation of a norhornenc 'rna.skcd' cyclopcntcnonc (37),
`followed hy mask removal (that is, a retro Dicls-Aldcr reaction; sec
`38 (cid:157)
`39). Thi.1 general strategy has been hroadly popularized hy
`Wintcrfcldt52, The stercochcrnistry of the substitucnts on 39 arc ,t
`re.1ult of t he steric influence of tl1c norbo rncne, which dictates the face
`that nucleophiles and clectrophiles appro.ich from . Ketone 39 cm1ld
`be elaborated to 40 in two steps by nucleophilic addition and D,mhcn
`oxidation, Ring-closing metathesis usi11g Grubbs catalyst smoothly
`
`\i,\TURE CHEMICAL BIOLOGY VOLUME l NlJMBEK 7 JUIY ) ()(17
`
`399
`
`

`

`REVIEW
`
`a
`
`d
`
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`AelroDiel!i•
`Alder reacl ion
`
`0
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`Li. :oon'.t-aIion
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`
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`
`56
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`Elec1rochemicel
`oxidslion end
`cy,:;hza1icn
`
`Scheme 3 Sy11t11etic strategies for the construction of the guanacastepenes. (a) The biosynthesis of the guanacastepene skeleton may arise from the
`familiar dolabella11es. (b) Key steps in Danisl1efsky's total synthesis of guanacastepene A. {cl Use of a norbornene mask to control the stereocenters of the,/\
`rings en route to guanauistepenc C (Mehta and colleagues). (d) Convergent assembly of guanauistepene Evia a Jt-allyl coupling and selective cyclobutane
`fragmentation (Sorensen and colleagues)). (e) Overman's synthesis of guanacastepone N featuring a unique 7-endo Heck cyclization. (I) Trauner's conver['.eflt
`synthesis of gt1anacastepe01e E featuring an anodic oxidation and cyclization strategy. Ac, acetyl; Bn, benzyl; Cy, cyelohoxyl; dbo, dibenzylidcneocetone;
`DMA, N,N·dimethylacelamide; DMSD, dimethyl st1lfoxide; HMPA, hexamelhyl-phosphoramide; dppb, 1,4-bis(diphenylphosphino)butane; PCC, pyridinium
`chlorochromate; Ph, phenyl; RVC, reticulated vitreous carbon; TB DPS, t-butyldiphenylsilyl; Tl, trifluoromethane sulfo11ate; TH F, tetrahydrofuran.
`
`produced the Bring (40 ~ 41 ), ond several straightforward manipu•
`lations converted 41 into (±)-guanacastepene C. Though not a new
`idea, the use of a11 auxiliary to control diastereoselective reactions i.s
`still a cornerstone of modern organic synthesis.
`
`required six steps. Through a masterful choice of classic reactions,
`Sorensen's construction of guanacastepene f'. was a !l1odcl for tbe be11·
`efits of an extremely convergent synthesis.
`
`A cycloaddition and ring-fragmentation strategy en route to
`( + )-guanacastepene E (49) (Sorensen). The Sorensen grouµ develoµed
`a highly convergent strategy lo assemble the guanacasleµene skeleton 46 .
`Their plan involved the union or highly Cunctionalized A and C rings,
`with the central n ring being forme<l lasl. The premier step in thefr
`sequence was a daring 12+2] cycloaddition and ring fragmentation
`strategy to form the Bring (Scheme 3d). A palladium-mediated Stille
`coupling bdween 44 and 45 led smoothly to 46, which rnntains all of
`the carbon atoms needed for guanacastcpcne F. ( 49) 53. Irradiation of
`46 in the presence of base led to the desired cyclobutanc 47, Addition of
`the one-electron reducing agent Sml2 induced the desired cyclobutane
`fragmentation, prc.rnrnably through the intcrmediacy of a kct,11 radical,
`and farther reduction formed an enolate, which could be trapped by
`phenylsclcnium bromide forming 48. Conversion of 48 into (+ )-49
`
`Total synthesis of ( + )-guanacastepene N (55) using a 7-endo Heck
`cyclization (Overman). Much like Sorensen, Overman nnd cO·Wc)t k(cid:173)
`ers developed a highly convergent synthesis of the guanau1stq,cn,·
`skeldon47. The Overman group, which has extensive expcrien,c'. in
`the use of pallaclium-mcdiatcd reactions in complex molecule syn the·
`sis5·'l, chose to form the Bring via a fascinating 7-endo Heck cydiz.i t ion
`(Scheme 3c). The tendency of the Heck reaction to proceed via all ,,.,o,
`and not an rndo, pathway makes this choice of bond constrnctio11 1Alwr
`intriguing. In practice, heating triflatc 52 (prepared in ten ste()S fro,n
`50 and 51) with the correct palladium source a nd additives produ,:cd
`the desired dienone (53), which could be trnnsforrned into g,rnnac.iitc·
`pcne N (55) in six steps. Palladium-mediated reactions are currcnily
`one of the p remier synthet ic tools for C- C bond construction5J , and
`Ovcrman's guanacastepenc N synthesis is a beautifuJ example of tlic·ir
`utility in complex total synthesis.
`
`400
`
`VOLLJM[ .1 NUMBER 7 JLJLY 2007 NATURE CHEMICAl BIOLC H ; Y
`
`

`

`REVIEW
`
`Total synthesis of (-)-guanacastepene E (49) featuring an electro(cid:173)
`chemical strategy (Trauncr). The Trauner group also developed a
`u11ique and impressive toLtle to ,tcccss the guanacastcpe11e architecture
`(Scheme 3f)48• The key step involved an electrochemical oxidative cycli(cid:173)
`,,.tion. Tt was envisioned that ekctrochemical oxidation of silyl enol(cid:173)
`ethcr 59 would produce a radical cation (60) that could be trapped by
`tl1c pendent electron-rid! furan, thus forming the Bring. Compound
`59 in turn could originate from two pieces of roughly equal size, namely
`57 and 58. To prepare furan 57, the group turned lo the intramulecu(cid:173)
`hu· Heck cydization (56 ~ 57). The union of furnn 57 and enone 58
`proceeded smoothly and provided tctracycle 61 as a single isomer
`after anodic oxidation of a mcthanolic solution of 59. Eight steps were
`,·equired to convert 61 into guanacastcpene E. Electrochemical methods
`remain underused in organic synthesis, but as Trauncr'.s synthesis dem(cid:173)
`onstrated, these reactions should not be overlooked when approaching
`challenging bond constructions.
`
`Phomactin A (4)
`Isolated from marine fungal sources