synthetic approaches to coronafacic acid, coronamic acid

Synthesis Review / Short Review

TemplateforSYNTHESIS©ThiemeStuttgart·NewYork 2016-09-21 page1of18

Synthetic Approaches to Coronafacic Acid, Coronamic Acid, andCoronatine

Received: Accepted: Published online: DOI:

Abstract The phytotoxin coronatine (COR) is a functional mimic of the active plant hormone (+)-7-iso-jasmonoyl-L-isoleucine (JA-IIe), which regulates stress responses. Structurally, COR is composed of a core unit, coronafacic acid (CFA), which is connected to coronamic acid (CMA), via an amide linkage. COR has been found to induce a range of biological activity in plants and based on its biological profile, COR, as well as CFA, and CMA are attractive starting points for agrochemical discovery, resulting in numerous total synthesis efforts. This review will discuss the synthetic approaches towards CFA, CMA and, ultimately COR, to date.

Key words Agrochemistry, asymmetric synthesis, bicyclic compounds, carbocycles, stereochemistry, total synthesis.

Contents 1. Introduction 2. Total synthesis of coronafacic acid (CFA, 4)

2.1 Mapping synthetic strategies 2.2 Intermolecular Diels-Alder approaches 2.3 Intramolecular Diels-Alder approaches 2.4 Conjugate addition approaches 2.5 Haller-Bauer approaches 2.6 Intramolecular cyclisation approaches 2.7 Oxy-Cope approaches

3. Total synthesis of coronamic acid (CMA, 5) 3.1 Mapping synthetic strategies 3.2 Final installation of C1 3.2 Final installation of C2 3.3 Final installation of C3

4. Total synthesis of coronatine (COR, 1) 5. Conclusions Acknowledgement References Author biographies

1.Introduction

Thephytotoxincoronatine(COR)1,whichwasisolatedfromthebacteria Pseudomonas Syringae,1 has been a popular synthetictarget since its structural elucidation in 1977.2,3 1 has beenfoundtobeafunctionalmimicoftheactiveplanthormone(+)-7-iso-jasmonoyl-L-isoleucine(JA-IIe,2)4,whichregulatesstressresponses in plants (Figure 1).5 The jasmonate receptor is athree component, co-receptor complex consisting of the F-boxprotein COI1, the JAZ1 degron peptide, and inositolpentakisphosphate, where all three components are essentialfor normal activity.6 Jasmonic acid (3) is produced

enzymatically from linolenicacid7and isactivated inplantsbyconjugation with L-isoleucine.8 The active hormone elicitsubiquitination and subsequent degradation of JAZ proteins,which leads to transcriptional activation of genes involved inplant development and defence.9,4 Acting as a JA-lle agonist,1has been found to induce a range of biological responses inplants, including chlorosis,10,11 inhibition of root elongation,12increased production of protease inhibitors,10 and growth-regulator type activity,13 including enhanced ethyleneproduction,14inducedhypertrophy,12andtendrilcoiling.1

Figure 1 Coronatine (COR, 1), (+)-7-iso-jasmonoyl-L-isoleucine (JA-IIe, 2),

and jasmonic acid (3).

Structurally,1 is composed of a bicyclic core unit, coronafacicacid (CFA,4) that is connected to coronamic acid (CMA,5), aderivativeofisoleucine,viaanamidelinkage(Figure2).

Figure 2 Coronatine (1), coronafacic acid (4), and coronamic acid (5).

Basedon itsbiologicalactivity,1 andanalogueshavepotentialas starting points for agrochemical design, as demonstrated inseveral communicationsdescribing thebiological evaluationofanaloguesof1.15Derivativesofboth1and3havebeenusedtogenerate structure-activity relationships (SAR) for herbicidal

O

Me

O NH

Me

Me

HO

O

O

Me

O OH

(3R,7S)-JA-L-IIe 2 Jasmonic acid 3

O H

H

Me

HN O

OH

O

Me

Coronatine (COR) 1

O H

H

Me

HN O

OH

O

Me1 Coronafacic acid

(CFA) 4Coronamic acid

(CMA) 5

NH2

O

OHMe

12

33a

456

7

7a1

2

3

O H

H

Me

HO O

Mairi M. Litt lesona Claire J . Russel lb El izabeth C. Fryeb Kenneth B. L ingb Craig Jamiesona Al lan J . B. Watson*a

a Department of Pure and Applied Chemistry, WestCHEM, University of Strathclyde, Thomas Graham Building, 295 Cathedral Street, Glasgow, G1 1XL, UK.

b Syngenta, International Research Centre, Jealott's Hill, Bracknell, West Berkshire RG42 6EY.

* [email protected].

O H

H

Me

HN O

OH

O

MeCoronatine

NH2

O

OHMe

O H

H

Me

HO O

Coronafacic acid Coronamic acid

Total synthesisMethodology development

Agrochemical discovery



activity.15 Inaddition, therehasbeensignificant interest in thestructurally simpler 1 mimic coronalon (6),16 and the oximederivative of 1 (7), which has been reported to possessantagonist activity in the jasmonic acid signalling pathway(Figure 3).5 Lastly, 1 has been functionalized to allow itsincorporation into biological probes,17,18 and, furthermore,antibodies have been developed for the quantification of 1 incompetitiveenzyme-linkedimmunosorbentassays(ELISAs).19

Figure 3 Coronalon (6) and COR oxime (7).

Through the efforts of various research groups, there is anemerging SAR associated with 1. The cis-ring junction of 4 isalsoobservedin2,andisimportantforbiologicalactivity,20asisthepositionofthecarboxylmoietyrelativetothecyclopropanering.21 Variation of the amino acid portion of 1 (i.e., 5) istolerated21whiletheethylunitof4 isnotcrucial forbiologicalactivity.21However,despitesignificantinterestin1asastartingpoint for agrochemical development, current synthetic routesdonotallowflexibleaccessto1 insufficientquantitiesorwithembedded useful functionality for analogue generation.20Overall, based on the above, efficient methodology givingsyntheticaccess to1 andanalogueswouldbeadvantageous toallow interrogation of SAR and the potential development ofmorepotentderivatives.20

In this review, we summarise and discuss the reportedsynthesesof4,5,andultimately1intheliteraturetodate,andprovideanassessmentoftheseroutesinsupportingfurtherSARworkaroundthispromisingtarget.

2.Totalsynthesisofcoronafacicacid(CFA,4)

2.1Mappingsyntheticstrategies

The popularity of 1 as a target can be seen from the totalsyntheses of its constituent natural products, 4 and 5.Numerous total syntheses of racemic 4 have been reported,alongwithseveralenantiopurepreparations.Table1showsthereported syntheses of 4 in chronological order and groupedaccordingtotheirassociatedkeystep;Figure4showsthesekeystepsinmoredetail.Typically,syntheticroutestowards4havebeen somewhatprotractedandultimately lowyielding.TheC6ethylunitmustbeinstalledtrans-relativetothecis-ringjunctionof the bicycle, and this relationship must be preserved. Oftenmixturesofdiastereoisomersarecarriedthroughseveralstepsofthesynthesis,resultingindifficultproductisolationaswellasissueswithcharacterization.22

Synthetic strategies towards 4 can generally be grouped intofive approaches based on the key transformation in the route:inter- and intramolecular Diels-Alder (DA) reaction, conjugateaddition,Haller-Bauer reaction, intramolecular cyclization, and

oxy-Copemethodology.Eachoftheselynchpinstrategieswillbereviewedinthefollowingsections.

Table 1 A summary of the total syntheses of CFA.

Author

(Year)

Key step

(No. steps)

Racemic/

enantiopure

Overal l

Yield (%)

Ref.

Ichihara (1977) Diels-Alder (10a) Racemic Unknown 23

Ichihara (1980) Diels-Alder (14b,c) Racemic 0.4 29

Jung (1981) Diels-Alder (8d) Racemic 7 31 Llinas-Brunet

(1984)

Diels-Alder (9a) Racemic 4 24

Yates (1990) Diels-Alder (12b) Racemic 24 34 Charette

(2007)

Diels-Alder (6a) Racemic 29 32

Ueda (2009) Diels-Alder (12a) Racemic 5 26 Ueda (2010) Diels-Alder (8a) Racemic 28 17

Ichihara (1996) Conjugate

addition (7a)

Racemic 25 35

Ichihara (1997) Conjugate

addition (9b)

Enantiopure 24 36

Shibasaki (1998)

Conjugate addition (6e)

Enantiopure 9f 37

Mehta (1993) Haller-Bauer (8a) Racemic 11 40

Mehta (1999) Haller-Bauer (12a) Enantiopure 5 43

Tori (2000) Intramolecular

cyclisation (18d)

Racemic 0.9 45

Tsuji (1981) Intramolecular cyclisation (15a)

Racemic Unknown 46

Nakayama

(1981)

Intramolecular

cyclisation (12b)

Racemic 0.9 49

Nakayama

(1983)

Intramolecular

cyclisation (12a)

Enantiopure 0.1 53

Blechert (1996) Intramolecular cyclisation (9b)

Racemic 16 47

Taber (2009) Intramolecular

cyclisation (12a)

Enantiopure 4 57

Kobayashi

(2011)

Intramolecular

cyclisation (12a,c)

Enantiopure 15 22

Kobayashi (2013)

Jung (1980)

Intramolecular cyclisation (11a,c)

oxy-Cope (14a)

Enantiopure

Racemic

1.6

1.7

56

60 a From a non-commercial starting material. b From commercial starting materials. c Based on longest linear sequence. d Starting material commercial but not readily accessible. e A required catalyst is not commercial. f Based on an assumed yield from referenced publication.

O

CO2H

Me

NOMe

OHN

Me

H

H

OH

O

Me6 7



Figure 4 Overview of the key steps towards CFA.

2.2IntermolecularDiels-Alderapproaches

The presence of the cyclohexene-derived core within 4 hasrenderedtheDiels-Alderreactionacommonkeydisconnection.In 1977, Ichihara reported the first synthesis of (±)-4 via anintermolecular Diels-Alder reaction.23 Despite requiring harshconditionsandproceeding inonlymoderateyield, thereactionprovidedaccesstobicycle10,asa1:1mixtureofdiastereomers,containingthedesiredcis-ringjunction(Scheme1).23

Scheme 1 Ichihara’s Diels-Alder strategy to (±)-4.

Despite having accessed the complete carbon framework, afurther nine transformations, for which yields were notcommunicated,wererequiredtodeliver(±)-4.

Reductionofthecyclopentanone(10)fromtheconvexfacegavealcohol11.Subsequenthydrolysisoftheenoletherafforded12asamixtureofdiastereomersatC6,forwhichtheratiowasnotcommunicated. 12a, bearing the desired relativestereochemistry,was found to be themore stable isomer, andthe undesired isomer 12b could be epimerized to 12a upontreatmentwithbase.THPprotectionwasfollowedbyformationoftheformylatedcompound14,whichwasconvertedto15byalcohol protection, ketone reduction, and subsequent acid-mediated dehydration. Deprotection to alcohol 15 and a finalJones oxidation afforded the first example of synthetic (±)-4.Given the lack of yield information, it is difficult to commentfurther on the utility of this process for rapid analoguegeneration.Ifsufficientquantitiesof(±)-4canbeobtained,thiscouldfacilitateevaluationofCMAreplacements.

Using an alternative intermolecular Diels-Alder reaction, (±)-4was synthesized by Llinas-Brunet et al, again allowing thecomplete carbon framework to be rapidly assembled (Scheme2).24

Scheme 2 Llinas-Brunet’s Diels-Alder strategy to (±)-4.

Heatingcyclopentendione16withdiene1725inPhMesmoothlyaffordedbicycle18,whichcouldbeadvancedto4ineightsteps.Chlorination using phenyldichlorophosphate gave amixture ofregioisomers19a and19b in a ratio of 2:3, respectively.Withrespect to analogue generation, these intermediates arepotentiallyusefulforSARdevelopmentaroundthecyclopentaneringof4basedonthesyntheticutilityofthechloroenone.19awas converted to bicycle 20 in one step via chemoselectivehydrogenation, as a mixture of diastereomers at C7a. Despitethis, conversion of19b to20 required amultistep procedure:treatment with AgNO3 inMeOH afforded21. LiAlH4 reductiondelivered enone 22, which was converted to 20 via Jonesoxidation, esterification, and chemoselective hydrogenation oftheenonealkene.20wastreatedwithNaOEttobringtheC5-C6doublebondintoconjugationwiththeesterandacid-mediatedhydrolysis of the ester, which afforded (±)-4with the desiredrelative stereochemistry (52% yield over two steps (notshown)).Thissyntheticroutewasusedtoprepare11mg(±)-4,whichisinsufficientforfurtherSARdevelopment;however,theroutemaybeamenabletoscaleup.

A similarDiels-Alder reaction approachwas communicatedbyUedaetal(Scheme3).26Functionalizedhydroxypyrone23was

Conjugate Addition

Diels-Alder

Intramolecular Cyclization

O H

H

Me

HO O

Haller-Bauer

Oxy-Cope

4

O

H

H O

CO2Et

Me

O

H

O

MeO OMe

OO

Me Me

Me

CO2Et

Me

O

H

OMs

OOMe

MeO2CH

H

Me

O

OHC

OCO2Me

OPh

O

OMe

OMe

O

O

Me

CO2Et

Me

OH

CO2Et

O

O

O O

OHMe

Me

OTBDMS

OH

O

Me

Me

Me

O

O

CO2Et

MeO

H

CO2Me

MeO2C

O

xylenes, 200 °C8

9 NaBH4

NaOMe

(±)-4

10

HCl

O H

H

Me

HO O

O H

H

Me

11

HO H

H

Me

12a

HO H

H

Me

12b

HO H

H

Me

38% yield1:1 dr

i) i-PrIii) LiAlH4

iii) AcOHthen H3O+

DHP

13

THPO H

H

Me

Jones ox.

yield unreported

yield/dr unreported

NaH

14

THPO H

H

Me

O

yield unreported

3:1 dr

HCO2Et

15

HO H

H

Me

yield unreported

yield unreported

OMe OMe

OOO

OH O

Me

OMe

O

OCO2Et

O

O

H

HCO2Et

Me

16 17 18

Mei) LiH, (Me2N)3P

ii) PhPO2Cl2, LiCl

LiAlH4

AgNO3MeOH, 70 °C

PhMe, reflux

67% yield

O

Cl

H

HCO2Et

Me

19a

Cl

O

H

HCO2Et

Me

19b

64% yield 19a:19b = 2:3

O H

HCO2Et

Me

20

Pd/C, H2, NaHCO3

83% yield9:1 dr

MeO

O

H

HCO2Et

Me

21

O H

H

Me

22 OH

i) Jones ox.ii) EtI, K2CO3iii) Pd/C, H2

74% yield

45% yield−20 to 0 °C60% yield

(3 steps)



accessedinfourstepsfromcommercialmaterials,27whichaddsto the synthetic complexity of the route. The Diels-Alderreaction of 1624 and 23 gave access to bridged tricycle 24 inhighyieldandwithmoderateexo-selectivity,rationalisedduetoa greater stability of the exo-transition state, resulting fromstericclashesincurredintheendo-model.26

Scheme 3 Ueda’s Diels-Alder strategy to (±)-4.

Intermediate 24 was then converted to (±)-4 in seven steps.Removal of the C3 carbonyl was achieved using a two-stepproceduresimilartotheLlinas-Brunet24approach:chlorinationusing triphosgene provided chloroenone 25, which washydrogenatedtoaffordketone26.Sodiummethoxide-mediatedeliminationofthecarboxylateandsubsequenthydrogenationofthe resulting enone alkene gave intermediate27 in 90% yieldover two steps. Methyl ester formation (28) was followed bydehydrationtogive29,whichwasthenhydrolyzedto(±)-4.Theauthors reported that the last three synthetic steps could bereplaced by a single step in which 27 was refluxed in H2SO4.Whilerequiringfewersteps,theoverallyieldfrom27usingthisapproach was found to be significantly lower (24% vs. 66%).Ueda used this synthetic sequence to prepare 65 mg (±)-4,suggestingthisroutecouldpotentiallybeusedtoaccessusefulquantitiesofCFAforanaloguedevelopment.

Followingthis initialsynthesis,Uedareportedanimprovementoftheirsyntheticsequence,17givingaccesstointermediate26inanimprovedstepcountandassociatedyield(Scheme4).26

Scheme 4 Ueda’s improved strategy to intermediate 26.

Notably, the associated key Diels-Alder reaction using themonoketal derivative of 16 (30)28 was considerably moreselective. Reduction and subsequent acid-mediatedhydrolysis/elimination delivered 32, which underwenthydrogenationtorapidlydelivertheadvancedintermediate26.Significantly,the(±)-4preparedusingthisroutewasthenusedinthesynthesisofabiologicalprobe,17illustratingthepotentialof this route todeliversufficientquantitiesof (±)-4 for furtherstudy.

2.3IntramolecularDiels-Alderapproaches

IntramolecularDiels-Alderreactionshavebeenusedfrequentlyas a strategy towards (±)-4. Themajority of these approacheshave focused on the generation of the triene intermediate 33and related derivatives (Figure 5). The Diels-Alder reaction of33 has been found to be exo-selective, resulting in thepharmacologically undesired trans ring junction. However, thestereochemistry atC7a of34a is readily epimerised to give thedesiredcisdiastereoisomer.29

Scheme 5 Intramolecular Diels-Alder reaction of key triene 33.

Ichihara reported the first intramolecular Diels-Alder reactionstrategytowards(±)-4in1980,utilizingalatestageconrotatoryring opening, followed by a retro-Diels Alder reaction to giveaccesstothedesiredtriene,and,finally,aDiels-Alderreactioninaone-potproceduretoaffordbicycle37 in92%yield(Scheme6).29

Scheme 6 Ichihara’s cascade Diels-Alder strategy to (±)-4.

Whileproviding37veryrapidlyandinhighyield,formationofintermediate 35 required twelve steps, albeit from simplestarting materials,29,30 which limits the utility of the route toaccesssufficientquantitiesof(±)-4foranaloguegeneration.Therequired reactive diene and dienophile were masked bythermally labile protecting groups throughout these steps.Acetal intermediate 37 was isolated with the expected transringjunctionandwasisomerizedtothecisisomerusingNaOMe.(±)-4 was then quickly accessed from 37 by one-pot acetaldeprotection/Jones oxidation, proceeding in 22% yield (notshown).

O

O

OH

Me

O

O

Me

HO

O

ONEt3, CH2Cl2, 0 °C

23 24

O

O

Me

HO

O

ClO

O

MeHO

O

H

0 °C - RT28% yield

Pd/C, H2

74% yield

i) NaOMe, 0 °Cii) Pd/C, H2

80% yield

POCl3, py, RT

83% yield

99% yieldHCl, reflux

H2SO4, reflux

2526

93% yieldexo:endo = 5:1

O H

HCO2Me

Me

(±)-29

O H

H CO2Me

Me

28

HO

TsOH, MeOHreflux

triphosgenei-Pr2NEt

H

90% yield (2 steps)

O H

H CO2H

Me

27HO

24% yield

O H

HCO2H

Me

(±)-4

O

O

16

O

O

OH

Me

O

O

Me

HO

O

ONEt3, 0 °C

23

O

O

Me

HO

O

O

O

MeHO

O

H

56% yield

Pd/C, H2

87% yield

26

97% yieldexo:endo > 25:1

H

OO

O

OH

1) BH3, 0 °C

2) HCl

30 3231

Me

CO2Et

O

33 34a

Me

O

CO2Et

H

H

Me

O

CO2H

H

H

Diels-Alder acid or base

7a 7a

(±)-4

OOO

Me

Me

Me

PhMe, 185 °C

92% yield

MeO

O O

O H

H

Me

O O

35 36

37



A similar conrotatory ring opening approach to unmask areactivedienefor intramolecularDiels-AlderreactionhasbeencommunicatedbyJungetal(Scheme7).31

Scheme 7 Jung’s cascade Diels-Alder reaction strategy to (±)-4.

An intramolecular (2+2) cycloaddition of ynoate39 generatedcyclobutene40andestablished thedesiredstereochemistryatC3 and C4.31 Despite optimization, this transformation waslimited to 16% yield but with significant recovered startingmaterial. This low yielding step early in the synthetic routelimitstheutilityofthesequencewithrespecttothepreparationofsignificantquantitiesof(±)-4.Aseriesofsimple,highyieldingsteps then gave access to key intermediate44: acid-mediatedester hydrolysis was followed by PCC oxidation, addition ofvinylmagnesiumbromide,andasecondoxidation.Thermolysisof 44 generated triene 33 in situ, which, on increasing thetemperature, underwent the expected Diels-Alder reaction todeliver34a/binhighyieldandinapproximately60:40ratioinfavour of the desired cis isomer 34b. This mixture wasconverted to (±)-4 in a single step by ester hydrolysis withconcomitantepimerisationoftheringjunctiontothecisisomer(notshown).Theauthorsalsodemonstratedthat(±)-4couldbeaccessed in nine steps with an overall yield of 7% whentelescopedwithoutpurificationoftheintermediates.

In2007,theutilityofspeciesrelatedtotriene33asaprecursorto(±)-4wasagaindemonstratedbyCharetteetal(Scheme8).32In this example, the triene precursor was formed viadiastereoselective boron-mediated aldol reaction of ester 45withaldehyde46todeliveraldolproducts47a/47bina87:13anti:syn ratio. This aldol reaction was significant since thesereaction conditions typically favour the cis enolate and,accordingly,thesynaldolproduct.33However,theauthorsfoundthatwhileα-branchedaldehydesgavetheexpectedsynproduct,linear aldehydes gave the anti product predominantly.Significantly, 47a and 47b were readily separated by flashchromatography and, in a convergent strategy, each could beindependently and selective dehydrated to afford the desiredtriene48.

Theauthorsdemonstratedthat48couldbeadvancedto33,viaacetate hydrolysis and oxidation, and ultimately to 34a/bthroughtheknownDiels-Alderreactionapproach(notshown).However, theydevelopedanalternativeDiels-Alderreaction inwhichbothesterswerereducedtogivethecorrespondingdiol49, and then the primary alcohol selectively protected as theTBDMSether50.Oxidationof50toenone51enabledathermalDiels-Alderreactiontogive52inlowyieldof24%,proposedtobe the result of decomposition of triene 51 occurring at thelowertemperaturethanthedesiredcyclization.Thisyieldcouldbe improved to 61% by simply heating50 in the presence ofPDC,allowingforoxidationandDiels-Alderreactioninonepot.Whilethetransbicycleproductwouldbeexpected,theauthorsfound that epimerization of C7a occurred during flashchromatography on silica gel to provide the cis product 52.Treatment of52with TBAF and a subsequent Jones oxidationcompleted a concise synthesis of (±)-4. It should be noted,however, that aldehyde 46 is not commercially available andrequiredsixstepstoprepare,ultimatelyaddingtothelengthofthe overall synthesis and limiting the prospect for analoguegenerationviathisroute.

Scheme 8 Charette’s Diels-Alder strategy to (±)-4.

AnalternativeintramolecularDiels-Alderreactionwasfavouredby Yates et al who demonstrated the utility of their tandemWessely oxidation/Diels-Alder reaction methodology towards(±)-4(Scheme9).34

CO2Et

CO2H

OH

Me

AlCl3

16% yield

38 39 40

HCl

PCC

100% yield

MgBr

77% yield

PDC

84% yield

4142

43 44

100 °C

33(±)-34a/b

H2SO4100% yield

180 °C96% yield

Me

O

CO2Et

H

92% yield

EtOH

H

Me

CO2Et

O

H

MeO

CO2Et

H

MeHO

CO2Et

H

MeO

CO2Et

H

MeHO

O

H

O

Me

Me

O

O

Me

CO2EtOHC

OAc

1) Bu2BOTf DIPEA, -78 °C

2)

85% yieldanti:syn = 87:1345

4647a 47b

DEAD, PPh3−40 °C - RT88% yield

48

HOMe

MeO

DIBAL-H, −78 °C

PDC

42% yield

78% yield

49

NaH, TBDMSCl85% yield

51

CuCl (cat.)DCC, 80 °C86% yield

Me

CO2Et

AcO

MeHO

50O H

H

Me

52OTBDMS

61% yield PDC, PhMe155 °C PhMe, 155 °C 24% yield

1) TBAF

2) Jones ox.

OH

OTBDMSOTBDMS

O H

HCO2H

Me

(±)-4

70% yield(2 steps)

CO2Et

OH

Me

AcOCO2Et

OH

Me

AcO



Scheme 9 Yates’ Diels-Alder strategy to (±)-4.

Intermediate phenol 53, which was synthesized in four highyielding steps from commercially available starting materials,underwent oxidation with Pb(OAc)4 to furnish the quinonederivative, followed by a thermal Diels-Alder reaction to giveisotwistanone54.34Hydrogenationafforded55 asamixtureofdiastereomers before acetate hydrolysis to give 56. Oxidativering opening then gave the key bicyclic structure 57, as amixture of diastereomers at C6. Pb(OAc)4/Cu(OAc)2-mediatedoxidativedecarboxylationgaveaccessto58witholefinicisomer59.However,58couldbeconvertedto59upontreatmentwithNaOEt.Afinalhydrolysisof59usingaqueousacidafforded(±)-4 (not shown),with the correct cis ring junction, in87%yieldfollowing several recrystallizations. Despite this syntheticapproach being high yielding overall (24%), the use ofmetal-mediatedtransformationsatseveralstepsthroughouttheroute,in particular the use of Pb(OAc)4, may limit its attractivenesswithregardtoscaleupprocedures.

2.4Conjugateadditionapproaches

Annulationvia conjugateadditionasa route toboth (+)-4 and(±)-4 has also been thoroughly explored. Again, the mainobjectiveinthisapproachisthesettingofthecis-ringjunction,relative to the trans-ethyl unit. Ichihara et al applied theirconjugate addition based approach towards hydrindanescaffoldstothesynthesisof(±)-4(Scheme10).35

Scheme 10 Ichihara’s conjugate addition strategy to (±)-4.

Protection of ketone 60 as the ketal gave intermediate 61,which took part in an aldol reactionwith aldehyde62 to give

the syn adduct 63. The authors carried out this syntheticsequence using four differently substituted aldehydes,demonstrating the potential of thismethodology to synthesizeanalogues of (±)-4. Mesylate formation and subsequent base-mediated elimination gave access to dienoate 64 as the soleproduct, which was deprotected to give the key cyclizationprecursor 65. Following optimization, it was found thatjudicious choice of reaction conditions allowed65 to undergoan intramolecular 1,6-addition to afford 34b as the mainproduct,albeitinmoderateoverallyield.

Theauthorsreasonedthatthedesiredproductwasformedfromkinetic protonation of the cyclopentanone enolate. Under thereaction conditions, the stereochemical integrity of 34b wasfound to erode over time to deliver increased quantities ofdiastereoisomers66and58.Finally,(±)-4wasobtainedin70%yield by acidic hydrolysis of 34b (not shown). This approachprovided efficient access to (±)-4, requiring only seven stepsfrom 60 and giving an overall yield of 25% – a significantimprovement over previous syntheses. The scalability of thisroute was not commented on in the text;35 however, theefficiency of the route to access (±)-4 certainly renders itattractive with respect to potential scale-up and subsequentanaloguegenerationforSARscanning.

Theauthorssubsequentlyreportedanasymmetricsynthesisof(+)-4 by exploiting the same synthetic route usingenantioenriched68(Scheme11).36

Scheme 11 Ichihara’s conjugate addition strategy to (+)-4.

AcatalyticasymmetricMichael additionofdiethylmalonate67to cyclopentenone9 delivered68,whichwasprotected as theketalandsubjectedtoKrapchodecarboxylationtoprovide71in70%yieldand98%eeoverthreesteps.Totalsynthesisof(+)-4followed the previously described strategy,35 with the keyintramolecular conjugate addition proceeding in an improvedyield and product ratio. Enantioenriched (+)-4 was thenpreparedbyesterhydrolysis(notshown)andinoverallyieldof24%and inonlyninesteps from9.Theauthorscomment thatthe relatively high overall yield of the synthetic routemake itpossible to gain access to practical quantities of (+)-4, andsubsequently(+)-1.

In a later communication, Shibasaki et al37 used Ichihara’sapproach35 todemonstratetheutilityof theirchiralaluminiumcatalyst in a similar asymmetric conjugate addition of

MeOH

CO2Et

OAc

O

EtO2C

Me

1) Pb(OAc)4, AcOH

2) xylenes, 140 °C

53 54

OAc

O

EtO2C

MeOH

O

EtO2C

Me

Pd/C, H2

97% yield

Ba(OH)2

93% yield

NaIO4

94% yield

Pb(OAc)4

NaOEt

91% yield

5556

57 58 59

64% yield(2 steps)

O

Me

H

HCO2Et

CO2H 88% yield

O

Me

H

HCO2Et

O

Me

H

HCO2Et

Cu(OAc)2

OO

OH

Me

EtO2CH

PTSA 1) LDA

2)

92% yield

1) MsCl, DMAP2) DBUPTSA

60 61 62

6365

53% yield(± )-34b:66:58 = 3:1:0

58(±)-34b 66

89% yield

83% yield(2 steps)

EtO2C

Me

H

O

NaOEtO

Me

CO2EtH

HO

Me

CO2EtH

H O

Me

CO2EtH

H

99% yield

HOOH

64EtO2C

Me

H

OO

Me

O

OO

CO2EtCO2Et

O

Ga-Na-(S)-BINOLPTSA

88% yield

84% yield(98% ee)

9 68

7071

76% yield(+)-34b:66 = 3:1

72

(+)-34b 66

NaOt-Bu

95% yield

CO2Et

Me

H

O

NaOEt H

H

Me

CO2Et

O H

H

Me

CO2Et

O

OO

CO2Et

CO2EtH

CO2Et

CO2EtH

OO

CO2Et

H

OO

Me

Me

OO

CO2EtEtO2C

85% yield(4 steps)

LiClDMSO, Δ

67

69

(98% ee)



triethylphosphonoacetate using an aluminium lithiumbis(binaphthoxide) complex (ALB) to access phosphonate 73(Scheme12).38

Scheme 12 Shibasaki’s conjugate addition strategy to (+)-4.

The1,4-additionproceededinhighyieldandhighee;however,desired E-isomer was the minor product formed in thesubsequent Horner-Wadsworth-Emmons reaction, which gavethe Z-isomer preferentially in 43% yield. Following Ichihara’sprocedure,35diene72wasthenconvertedto(+)-4.

2.5Haller-Bauerapproaches

TheHaller-Bauerreaction39hasalso featured inCFAsynthesis.Mehta et al applied the Haller-Bauer reaction to access cis-hydrindanescaffoldsforthesynthesisof(±)-4(Scheme13).40-42

Scheme 13 Mehta’s Haller-Bauer strategy to (±)-4.

Compound74waspreparedfollowingthethree-stepprocedureof Chapman in 43% yield.41 Reduction and deprotection of74delivered 75, which underwent a Haller-Bauer reaction usingAmberlyst resin to give bicycle76. The regioselectivity of theHaller-Bauer reaction was found to be predictable, withcleavage occurring between C1 and C10. The double bond wasfoundtomigrateintoconjugationwiththeesterfunctionalityinsitu and no C7a epimerization was observed. Followingformation of acetal 77, allylic oxidation provided suitablecarbonyl functionality at C6 (78) for a subsequent Wittigreaction to install the required ethyl unit (79). Substrate-controlled stereoselective hydrogenation from the convex facegave thedesiredstereochemistryof theethyl substituent,withchemoselectivity over the enone, to provide 80. Acidichydrolysis of the ketal and ester provided (±)-4 in 70% yield

(not shown). The authors comment that this concise approachoffersconsiderablepotentialforderivatization,highlightingthat74 can be accessed in multi-gram quantities. Mehta has alsoreportedtheenzymaticresolutionof74using lipasePS,givingaccess toenantiopure(+)-4 followingthesamesyntheticroute(notshown).43,44

2.6Intramolecularcyclizationapproaches

Intramolecular cyclization has been a popular strategy forassembly of the carbocyclic scaffold of 4. Tori et al applied aSmI2-initiatedradicalcyclizationtowardsthesynthesisof(±)-4(Scheme14).45

Scheme 14 Tori’s intramolecular cyclisation strategy to (±)-4.

Commercially available alcohol 81 was oxidised to thecorrespondingketonebeforeBaeyer-Villigeroxidationtoaffordlactone82.TreatmentwithNaOMegavealcohol83,whichwasprotected before ester reduction provided alcohol 84 in goodyield.SwernoxidationwasfollowedbyadditionofGrignard85,and TBAF deprotection to afford diol 86. Swern oxidation ofboth alcohols was followed by an intramolecular aldolcondensationtoaffordcyclopentenone87 inmoderateyield.Afinal Swern oxidation gave access to the key intramolecularcyclization precursor, aldehyde 88. Exposing 88 to SmI2initiateda6-endo-trigcyclization,whichdeliveredamixtureoffourstereoisomers,where89wasthemajorproduct.Followingketal formation, the secondary alcohol was oxidised, prior tobase-mediated epimerization of C3a to the desired cisstereochemistry. Formation of triflate 92 and subsequent Pd-catalyzedcarbonylationgaveaccessto(±)-4afteracid-mediatedhydrolysis. The low overall yield obtained from this syntheticsequence (0.9%) reduces the utility of the preparation withrespecttogeneratingpracticallyusefulquantitiesof(±)-4.

O (EtO)2P OEt

OOO

CO2Et

P(OEt)2HO

H(S)-ALB, NaOt-Bu

91% yield (94% ee)

O

CO2H

Me

H

H

O

CO2Et

Me

H

1)O

O

Me

Me

PTSA

2) NaOt-Bu, 2-ethylacrolein3) PTSA9 73

72(+)-4

27% yieldE-isomer

53% yield (2 steps)

69

OO

O

H

HO

H

H

O

1) LiAl(OMe)3H, CuBr, −78 °C2) H2SO4 Amberlyst-15

95% yield

PDC, t-BuOOH61% yield

10% Pd/C86% yield

PTSA

110

74 75

767778

79 80

90% yield(2 steps)

60% yield

H

H

O

CO2Me

HOOH

H

HCO2Me

OOH

HCO2Me

OO O

EtPPh3Brn-BuLi

57% yield

H

HCO2Me

OO

MeH

HCO2Me

OO

Me

110

1) Jones ox.

2) m-CPBA, reflux

NaOMe

1) DHP, PPTS2) LiAlH4

75% yield(5 steps)

2) OTBDMSBrMg66% yield(3 steps)

1) Swern ox.

1) Swern ox.

3) HCl47% yield(2 steps)

Swern ox.

72% yield

81 82

8384

86 87 88

85

61% yield

HOOH

PTSA

56% yield

LDA

Comins' reagent

70% yield

1) Pd(OAc)2 PPh3, CO2) HCl

8990

91 92 (±)-4

2) KOH

O

Me

OH

O

Me

O

SmI2

H

Me

O H

OH

Me

OH

OO

H

H

Me

O

OO

H

H

1) PDC2) K2CO3, Δ

50% yield(2 steps)

Me

OTf

OO

H

HMe

CO2HH

O H

46% yield(2 steps)

HO

Me

O

Me

O

OHMeO

Me

OOTHP

HO

Me

Me

OTHP

OH

OH

3) TBAF



Pd-catalyzedallylicalkylationhasalsobeenusedtogoodeffectfor ring construction towards the synthesis of (±)-4. Tsujidemonstrated an intramolecular allylic alkylation cyclizationprotocol for the construction of the cyclopentanone ring(Scheme 15).46 It should be noted that precise details for thisapproachare limited,withmanyaspectsofreactionconditionsand outcomes not detailed in the report. β-Keto ester 93underwentMichaeladditionwithmethylacrylatetogivediester94. The key Pd-catalyzed intramolecular allylic alkylationwasachievedusingPd(OAc)2 to afford the cyclopentanoneproduct95inexcellentyield.Decarboxylationandacetalformationwasfollowed by alkylation to install the ethyl unit (97).Hydroboration, oxidation, and subsequent esterification gave98.ProtectionthroughacetalformationprecededaDieckmanncondensation to form the 6-membered ring. Reduction of thecyclohexanone and hydrolysis of the ketal also provided thedesired cis-ring junction. POCl3-mediated dehydration gave amixture of (±)-29 and 101, with hydrolysis in acidic mediadelivering(±)-4.

Scheme 15 Tsuji’s allylic alkylation strategy to (±)-4.

Again, the lack of detail communicated about the syntheticsequencedoesnotallowcommentonthesyntheticutilityoftherouteinregardtoyieldsobtainedorscalabilityoftheprocess.

Ring closing metathesis (RCM) was used to construct thecyclohexeneringinBlechert’sapproachto(±)-4(Scheme16).47

Scheme 16 Blechert’s RCM strategy to (±)-4.

Commercially available diallyl adipate 102 underwentDieckmann condensation, followed by alkylation with allylbromide 103, and Pd-catalyzed decarboxylation to forgecyclopentenone 105.48 Michael addition of methyl crotonatethen gave cyclization precursor 107 as a 1:1 mixture ofdiastereoisomers. Attempted RCM on 107 was met with littlesuccess, requiring high catalyst loading or elevatedtemperatures to ultimately afford the desired product in lowyield. Protection of the ketone functionality as the ketal 108allowedefficientRCMusingSchrock’sMocatalysttogiveaccessto bicycle109. This key stepwas carried out on a 0.04mmolscale, and required the use of a glovebox, which reduces thepracticality of the route and its applicability to scale upprocedures. Ketal hydrolysis, base-mediated double bondisomerization, and acid-mediated hydrolysis/epimerizationafforded(±)-4.

Nakayamaetalhavereportedasynthesisof(±)-4 featuringanintramolecular[2+1]cycloaddition(Scheme17).49Startingfromaldehyde 110, the cyclization precursor 112 was obtained inthree steps. Reduction of the aldehyde, was followed bytosylation under phase transfer conditions,50 and finallyalkylationwithmethyl acetoacetate. Treatment of112withp-TsN3 afforded the corresponding diazo compound, whichunderwent thermal decomposition to afford the tricyclicintermediate113. Introduction of the ethyl-unit was achievedthroughalkylationwithexcessethyl iodide.Thedesiredmono-alkylatedproduct114wasobtainedasasinglestereoisomerasconfirmedbyX-raycrystallography;however,itwasnotedthatthe moderately low yield of 53% was obtained as a result ofover alkylation to give the diethyl compound. Reduction withNaBH4 gave115 as amixture of epimers, both ofwhichweresubmitted to tosylation and Grob fragmentation to give aninseparable mixture of methyl esters 116a and 116b.Treatment of this mixture with NaBH4 and dimethyl sulfate,51followedbyoxidationwithH2O2andfurtheroxidationwithPCC,gave CFA methyl ester 29 in low yield from 116a. It wasreportedthat116bwasresistanttothereactionconditions,andcould be separated from the desired product. (±)-4 wassubsequently obtained in 80% yield by acid-mediatedhydrolysis(notshown).

CO2Me

OPh

O

OPh

OCO2Me

CO2MeCO2Me

O

CO2MeCO2Me

98% yieldyield

unreported93 94

95CO2Me

OO

OO

CO2Me

Me

H

H

CO2Me

CO2Me

Me

H

O H

HCO2Me

Me

O

OO

H

HCO2Me

Me

OH

O

HCO2Me

Me

O

HCO2Me

Me

O

1) DemethoxycarbonylationLDA, EtI

89% yield

2) Acetal formation

1) Hydroboration2) Jones

3) Esterification

1) Acetal formation2) KOt-Bu

74% yield (2 steps)

1) NaBH42) Hydrolysis

POCl3

Acid hydrolysis

HCO2H

Me

O

yield unreported

yield unreported

yield unreported

yield unreported

yield unreported

96

97 98

99100

(±)-29 101 (±)-4

Pd(OAc)2, PPh3

H H

H

H

H

H

O

O

O

O

1) NaH, 90 °C

2)

69% yield

O

Pd(OAc)2, PPh3, 90 °C

O Me

MeO2C

Me

MeO2C

OO

OO

Me

CO2Me

Me

CO2H

O

MeMeO

O

HOOH

91% yield

1) HCl2) NaOMe3) HCl, Δ

62% yield1:1 dr

KHMDS

PPTS87% yield

H

H54% yield(3 steps)H

Br

Me, 90 °C

Me

Schrock Mo cat.

102

105

107 108

109(±)-4

103

H

O

104

O

O

Me

85% yield(2 steps)

106



Scheme 17 Nakayama’s [2+1] cycloaddition approach to (±)-4.

The routewas latermodifiedby theNakayamagroup toallowaccessto(+)-4bychromatographicseparationthroughtheuseof l-menthyl esters (Scheme 18).52,53 The synthetic strategyfocused on the separation of the l-menthyl ester derivatives121aand121b.Ester117wasobtainedbyaknownliteratureprocedure,54and theethylunitwas introduced inhighyieldof88%asafirststeptoavoidtheproblematiclatestagealkylationseen in the groups original route to (±)-4.49 Further alkylationgaveβ-ketoester119,whichwascyclizedinmoderateyieldof56% using the previously communicated conditions.49Cyclizationafforded120aand120basamixtureofC6-epimers,whichcouldbeconvergedtothedesired121aand121bupontreatmentwithNaOMe.121a and121b couldbe separatedbycolumn chromatography and, following a final purification byrecrystallization,wereisolatedina1:1ratio.

Scheme 18 Nakayama’s l-menthyl ester enabled approach to (+)-4.

Reductionof l-menthylester121awithZn(BH4)2afforded122asasinglestereoisomer.Thechiralauxiliarywasthenremoved,givingmethylester123in88%yield.Transformationof123to(+)-4 was achieved following the synthetic methodologydeveloped in the same group’s racemic synthesis,49 affording(+)-4 in 1.3% yield over four steps. The authors alsodemonstrated that 121b could be converted to (–)-4 (notshown).Thisapproachwasthefirstreportedsynthesisofbothisomersofopticallyactive4,whichisattractivewithrespecttodevelopingSARforeachenantioseries.53

Intramolecularcyclizationhasalsobeenusedinthesynthesisof(+)-4 by Kobayashi et al (Scheme 19).22 Starting fromenantiopure alcohol 124, which was readily prepared usingliterature methods,55 TBS protected 125 underwent Pd-catalyzed allylic substitution with diethyl malonate.Decarboxylation afforded intermediate 127, which was thenreacted under traditional base-mediated aldol reactionconditions to afford 129 as a mixture of four diastereomers.Aldehyde 128 was prepared by an N-acyl thiazolidinethionechiral auxillary-based literature method.55 The authors’synthetic strategy involved formation of intermediate 134,which bears structural similarity to conjugate additionprecursor 72.35 Both synthetic routes involve mesylateformationandsubsequentelimination;however,inthiscasetheauthors identified an unexpected TBAF-mediated elimination.Desilylationof131wasexpected,however,nodesilylationtookplace and 132 was isolated in moderate yield; the authorshypothesizedthateliminationoftheanti-isomertoaffordtheZ-alkene,wasstericallydisfavoured.Followingketone formation,base-mediated cyclization gave (+)-34b in moderate yield,allowinglatestageformationofthecis-ringjuncture.Unliketheconjugate addition-based approaches, the stereochemistry of

O

H1) LiAlH42) TsCl, NaOH, BTEA

OTs

O

OMe

O

NaH, n-BuLi, 0 °C

Me OMe

OO

1) TsN3, NEt3

NaBH4

66% yield

TsCl, py

1) NaBH4, Me2SO4, 0 °C

76% yield(116a:116b = 1:1)

111not isolated

66% yield(3 steps)

2) P(OMe)3, CuI, Δ

60% yieldOH

CO2Me

EtI, LDA, 0 °C

53% yield

OH

CO2Me

Me

OHH

CO2Me

Me

HCO2Me

Me

HCO2Me

Me

2) H2O2

3) PCC20% yield(3 steps)

HCO2Me

Me

HO

110

112113

114 115

(±)-29 116a 116b

Me

MeMe

O

OO

Me

Me BrNaH, n-BuLi

Me

MeMe

O

OO

Me

TsO

1) NaH, n-BuLi

2)

75% yield

1) TsN3, NEt32) P(OMe)3, CuI, Δ

Zn(BH4)2

1) NaOH2) CH2N2

1) TsCl, pyridine2) BH3•THF, 0 °C

1.3% yield(4 steps)

88% yield

56% yield(2 steps)

O O Me

Me

Me

O

Me

HO O Me

Me

Me

O

Me

H NaOMe

O O Me

Me

Me

O

Me

HO O Me

Me

Me

O

Me

H

O O Me

Me

Me

OH

Me

H

90% yield

CO2Me

OH

Me

H88% yield(2 steps)

3) PCC4) 2.4 M HCl, reflux

CO2H

Me

H

HO

117 118

111

119

120a 120b

75% yield(121a:121b = 1:1)

121a 121b122

123 (+)-4

MeOHreflux

Me

O

OO

Me

Me

Me



the ethyl group was fixed at this point, which allowed theisolation of (+)-34b as a single diastereomer. Acid hydrolysisgaveaccessto(+)-4in85%yield(notshown).Theauthorsthendemonstrated the coupling of (+)-4 with CMA isostere L-isoleucine, lending strength to theapplicabilityof this strategyforthepreparationofCORanalogues.

Scheme 19 Kobayashi’s intramolecular cyclisation approach to (+)-4.

Inasubsequentpublication,Kobayashietalreportedaslightlyshorter synthetic route, albeit with a reduced overall yield(Scheme20).56

Scheme 20 Kobayashi’s shortened route towards (+)-4.

β-Keto ester 135 was prepared in three steps, using chiralauxiliary-based methodology.55 Again, the stereochemistry oftheethylunitwasfixedfromthebeginningofthesynthesis.Theauthors also showed a range of functionality could beincorporatedintothemalonatecondensationstep,which lendsthesyntheticstrategytowardsanaloguepreparation.

Intramolecular cyclization towards the synthesis of4 has alsobeen reportedbyTaber,whodemonstrated the utility of theirapproach towards enantiopure 5,3- and 6,3-carbocyclicscaffoldsbyapplyingthemethodologyto(+)-4(Scheme21).57

Scheme 21 Taber’s menthyl ester-based approach to (+)-4.

Under optimized conditions, diastereoselective Rh-catalyzedcyclopropanation of 137 delivered a 2.5:1 mixture of138a:138b.58 138b was protected as the acetal (139), andreductionofestertothecorrespondingalcoholwasfollowedbyoxidation, and Wittig reaction to give 141. With respect toanalogue synthesis, intermediate 140 is attractive due to thepossibility of incorporating various coupling partners. Underbuffered reaction conditions to prevent acetal deprotection, anovel Fe-mediated cyclocarbonylation then delivered bicycle142 in 38% conversion. On extending the reaction time, theisolatedyieldbegantodecreaseand,therefore,thereactionwashalted at 38% conversion and the starting material 141separated and recycled. The authors reported that the kineticproduct of the reactionwas theβ,γ-unsaturated ketone,whichwas isomerized to the desired enone by the addition of DBU.While the need to separate and recycle the unreacted startingmaterialaddstothesyntheticeffortsrequired,theoverallhighyield of product obtainedmakes this an attractive key step inthe process. Bicycle 142 was then converted to (+)-4 in foursteps. Substrate-controlled facially selective hydrogenation of142 afforded 143 in excellent yield, setting the ethylstereocentre. Methoxycarbonylation and reduction, wasfollowed by mesylation and elimination in 56% yield, and,finally, acetal deprotection and ester hydrolysis under acidicconditionsprovided(+)-4in55%yield.

2.7Oxy-Copeapproaches

An anionic oxy-Cope rearrangement was used in an earlysynthesisof(±)-4,communicatedbyJungetal(Scheme22).59,60Treatment of ketone 146 with lithiated benzofuran deliveredalcohol148,whichunderwent theoxy-Cope rearrangement toafford149 in88%yield.From149, theauthorsaccessed(±)-4in ten steps. Addition of vinyl lithium 150, followed by

TBSCl, imid.

100% yield

Pd(PPh3)4, t-BuOKDMPU/H2OKI, 180 °C

92% yield124 (99% ee)

1) LDA

2) CHO

MeTESO

1) H2, Pd/C2) PPTS

MsClEt3N, DMAP TBAF

63% yield

100% yield

Jones ox.

100% yield

t-BuOK

62% yield

125 126

127128 (96% ee)

129

130 131

132133

134 (+)-34b

HCl

99% yield

79% yield(3 steps)

99% yield

CO2Et

OMsTBSO

H

Me

CO2Et

OMsHO

H

Me

CO2Et

OMsO

H

MeH

HCO2Et

Me

O

OTBS

OAc

OH

OAc

OTBS

CO2EtEtO2C

OTBS

EtO2CCO2Et

OTESTBSO

Me

OH

CO2Et

OHTBSO

Me

OHCO2Et

OMsTBSO

Me

OMs

CO2EtEtO2C67

OTBS

OAc124 (99% ee)

EtO

O O

1) NaBH42) H2, Pd/C

34% yield(5 steps)

Me

OTES135 (99% ee)

Pd(PPh3)4, t-BuOK 3) PPTS

87% yield

136

130

CO2Et

OTESTBSO

Me

O 66% yield(3 steps)

CO2Et

OHTBSO

Me

OH

(+)-34b

H

HCO2Et

Me

O

Me

O

O

N2

O

MeMe

Me

O

O

MeMe

O

Me

O

O

MeMe

ORh2(piv)4

95% yield(138a:138b = 1:2.5)

137 138b138a

Me Me

O

O

Me

MeMe

OO

Me Me1) LiAlH42) DMP

77% yield(2 steps)

OO

Me Me

O

H

Ph3P=CHEt78% yield

OO

Me Me

Me

139

141

1) Fe(CO)5 K2CO3, hv

2) DBU38% conversion

98% yield

H2, Pd/C

144

PTSA

89% yieldOHHO

95% yield1)

45% yield(2 steps)

OO

MeMe

Me

O

H

H

140

142

OO

MeMe

Me

O

H

H143

OO

MeMe

Me

OH

H

HCO2Me

2) NaBH4

MeO

O

OMe, NaH

MsCl, NEt3DBU

56% yield

145

OO

MeMe

MeH

HCO2Me

H

HCO2H

Me

O

HCl55% yield

(±)-4



treatment on silica gel afforded ketal 151. Rh-catalyzedreduction, followed by desilylation gave 152 as a mixture ofolefins. A second Rh-catalyzed reduction, predominantly fromthe less hindered convex face, gave153 as themajor product.Removal of the carboxylate protecting group was achievedthroughozonolysis, followedbyoxidationandhydrolysis.Acidprotection through methyl ester formation preceded POCl3-mediated dehydration to afford (±)-29, and, finally, (±)-4 byacid-mediatedhydrolysisin93%yield(notshown).Thelackofatom economy in this preparation, as well as its overall lowyield (1.7%) limits its attractiveness from a scale upperspective; however, it of synthetic interest as the onlyexampleofanoxy-Copebasedmethodologyforthesynthesisof(±)-4.

Scheme 22 Jung’s oxy-Cope based approach to (±)-4.

Overall, a variety of approaches have been utilised in thesynthesisof4.Diels-Alderreactionshaveproventobeapopularkey step in several syntheses;23,24,26,29,31,32,34 however, theseoften focus on the generation of the same late stage DAprecursor.29,31,32 Conjugate addition approaches andintramolecular cyclization have also been used several times,providing access to both racemic35,45,46 andenantiopure22,36,37,56,574.Despitethevarietyinoverallsyntheticapproaches towards this attractive target, syntheses havetypically been long, linear processes,which are ultimately lowyielding. As previously intimated, the biological activity of 4make it an attractive starting point for analogue synthesis;however,fewofthepublishedsyntheticroutesofferapracticalmethodforpotentialdiversification,particularlywithlatestagemodifications.

3.Totalsynthesisofcoronamicacid(CMA,5)

3.1TotalsynthesisofCFA:Mappingsyntheticstrategies

Natural coronamic acid (5) is present in COR (3) as the (+)-(2S,3S)-isomer.3 Several groups have communicated thesynthesisof(+)-5,aswellasisomers(Figure5).

Figure 5 (+)-5 and its isomers.

Synthetic efforts have also beendirected towards (±)-5. Thereexists a multitude of syntheses towards the synthesis of E-2-alkylaminocyclopropanecarboxylicacids(ACCs)andsyntheticpathways can be categorised into seven strategies, groupedaccording to which ring carbon unit is installed last in thesynthesis:61 final installationofC1,C2,orC3.Table2shows thereported syntheses of 5 in chronological order with theirassociated key step; Figure 6 shows these key steps in moredetail.

Table 2 A summary of the total syntheses of CMA.

Author

(Year)

Key step

(No. steps)

Racemic/

enantiopure

Overal l

Yield (%)

Ref.

Ichihara (1977) C1 (5a) Enantiopure Unknown 62 Stammer

(1983)

C3 (5a) Racemic 18 78

Baldwin (1985) C1 (8b) Racemic 23 69 Williams (1991) C2 (7

a) Enantiopure 51 76

Schollkopf

(1992)

C1 (5b) Enantiopure 14 66

Salaun (1994) C1 (9b) Enantiopure 21 65

Charette

(1995)

C2 (16a) Enantiopure 23 72

Ichihara (1995) C1 (10b) Enantiopure 30 64

Salaun (1995) C1 (3b) Racemic 52c 68

Yamazaki (1995)

C3 (13a) Racemic 9 80

de Meijere

(2000)

C3 (10b) Racemic 30 81

Salaun (2000) C3 (13b) Racemic 32c 82

Cox (2003) C3 (4b) Racemic 17 61

Parsons (2004) C1 (7b) Racemic 28 71 a From a non-commercial starting material. b From commercial starting materials. c Based on an assumed yield from referenced publication.

MeO OMe

O OLi

MeO OMe

HO

O90% yield

1) NaH, Δ

88% yield

146

147

148 149

Li

SiMe3

2) SiO2

77% yield

1) H2, Rh/Al2O32) BF3•OEt2

86% yield(2 steps)

H2, Rh/Al2O3

42% yield

1) O3, AcOH2) aq. H2O2

40% yield(4 steps)

POCl3, Δ61% yield

150

151152

153154

(±)-29

MeOO

O

MeOH

H

H

H

1)

O

MeOH

H

H

H

O

SiMe3

O

H

H

H

H

Me

O

O

H

H

H

H

Me

OH

H

Me

O

OH

CO2Me

3) aq. HO–

4) CH2N2

H

H

Me

O

CO2Me

2) H2O

(+)-(2S,3S)-Coronamic acid (5)

(−)-(2S,3R)-allo-Coronamic acid (156)

(+)-(2R,3S)-allo-Coronamic acid (155)

(−)-(2R,3R)-Coronamic acid (157)

CO2H

NH2

Me

H NH2

CO2H

Me

H

CO2H

NH2

HNH2

CO2H

HMe Me



Figure 6 Map of the key steps towards CMA.

3.2FinalinstallationofC1

Methods for the installation of quaternary C1 to complete thecyclopropaneringtypicallyfocusonthedi-alkylationofglycineanalogues.61 The first reported synthesis of (+)-5 wascommunicatedbyIchiharaetalinthetotalpartialsynthesisof1(Scheme23).62

Scheme 23 Ichihara’s approach towards (+)-5.

The cyclopropane 160 was prepared by the knowncondensation of trans-1,4-dibromo-2-butene and methylmalonate.63 Diimide reduction gave the fully saturated system161, followed by selective amidation of the least stericallyhindered ester to give 162. Hoffmann degradation andhydrolysis then afforded (±)-5. The racematewas resolved byformation of the quinine salt and several fractionalrecrystallizationswererequiredtoobtainenantiomericallypure(+)-5fromthisshortsyntheticsequence.

Ichiharaetal later reported the synthesisof (+)-5 through theuse of optically puremalic acid164 as the source of chirality(Scheme24).64

Commercially available (R)-malic acid 164 was converted toketal165 by reduction of both acids andketal formationwiththe resultant 1,2-diol. Tosylation of the free alcohol wasfollowedby conversion to thealkyl iodide,before reduction toafford 166. Hydrolysis of the ketal gave optically active 167.Sequentialtreatmentof167withSOCl2andRuO4gaveaccesstosulfate ester 168 in quantitative yield. Cyclopropanation wasachieved through treatment of 168 with dibenzyl malonate,whichproceededwithinversionofstereochemistryatC3.

Scheme 24 Ichihara’s malic acid based approach towards (+)-5.

Stereoselective hydrolysis of the less sterically hindered esterwasfollowedbyCurtiusrearrangementtogiveprotectedaminoacid170.Deprotectionandrecrystallizationthenafforded(+)-5in89%yield(notshown).Notably,thisrouteallowedsynthesisof (+)-5 on a preparative scale of 11.4mmol and the authorsalsodemonstratedtheutilityofthesyntheticsequencethroughthe synthesis of all four stereoisomers of5, obtained throughuseof(S)-malicacid.64

SalaunetalappliedtheirgeneralmethodfortheconstructionofE-2-alkyl ACCs to the synthesis of (+)-5, using enzymaticresolution(Scheme25).65

Scheme 25 Salaun’s enzymatic resolution based synthesis of (+)-5.

Enzymatic desymmetrization of 171 gave alcohol 172 inmoderate yield and high ee. It was reported that higher eevalues could be obtained by halting the reaction at 69%conversion, which accounts for the observed isolated yield of65%.Theauthorsdemonstratedtheutilityofthis intermediatebyshowingthat itcanthenbeconvertedtovarious isomersof5.Towardsthesynthesisof(+)-5,alcohol172wasconvertedtointermediate176insevenhighyieldingsteps,withretentionofabsolute stereochemistry throughout the synthetic procedure.Swern oxidation and a multi-step sequence gave access tointermediate 174 as a mixture of diastereomers.Chemoselective tosylation followed by chlorination gave 175,which was then converted to imine 176. The key step in thisroutewasthediastereoselectivecyclizationtoafford177,withthedesireddiastereomer177basthemajorproduct.Attemptedoptimization of the cyclization to improve the

R1O2C NR2R3

R4S

R6

R5

R1O2C NR2R3

N2R4

R1ONR2R3

O

MgBrR4

N2

R1O2C

R2R3

R1O

O

NR2R3

X1R4

X2

R1O2C NR2R3

R4CH2N2

OR7 OR8

R4

Final C3 installation

NH2O

OHMe5

Final C1 installation Final C2 installation

CH2X2

1

2

3

MeO2C

MeO2C

MeO2C

MeO2C Me

H2NOC

MeO2C Me

MeO2CHN

MeO2C Me

H2N

HO2C Me

TsNHNH253% yield

NH3

75% yieldBr2, NaOH

H2O

yield unreported

yield unreported

160

(±)-5

161162

163

BrBr

MeO

O

OMe

O NaOMeyield

unreported158 159

1) BH3, B(OMe)3

2) OMeMeO

EtEtPTSA

93% yield(2 steps)

OH

OO

EtEt 1) TsCl, NEt3

2) NaI

3) LiAlH4

84% yield(3 steps)

MeO

O

EtEt

PTSA

67% yieldMeHO

OH1) SOCl2, Δ2) RuCl3, NaIO4

100% yield

Me

OSO

OO

BnO2C CO2Bn

NaH, Δ93% yield

HBnO2C

BnO2C MeHBocHN

BnO2C Me

164165

166167

168 169 170

1) NaOH2) DPPA t-BuOH, Δ

69% yield(2 steps)

OH

OH O

OHO

Lipase PS, H2O

pH 7.265% yield>88% ee

171 172

1) TMSCN, ZnI2 (cat.)2) Ph2CHNH2, 60 °C

3) K2CO3, MeOH

1) TsCl, NEt3, DMAP

2) LiCl, NMP

t-BuOOHRu2Cl2(PPh3)2

90% yield

N

Cl

Me

NC

Ph2C

74% yield (4 steps)

173

174175

176

K2CO3 or LDA

HCl1) HCl, Δ2) Dowex

177b

177a

178(+)-5

Swern ox.

86% yield(2 steps)

95% yield(177a:177b = 1:3)

NC

NPh2C

N

NCPh2C

HCl•H2N

NC

97% yield98% ee(3 steps)

H2N

HO2C

Me

MeMe

Me

NH

OH

Me

NC

Ph2HCNH

Cl

Me

NC

Ph2HC

CHO

Me

AcO

Me

AcO OH

Me

AcO OAc



diastereoselectivitywas unsuccessful. (+)-5was then obtainedfromhydrolysissteps.

Schöllkopf also reported asymmetric synthetic methodologytowards the synthesis of (+)-5.66 Based on previous work byQuinkert,67 the publication reports a chiral auxiliary-enabledsynthesis(Scheme26).

Scheme 26 Schöllkopf’s chiral auxiliary based methodology towards (+)-5.

Alkylation of 179 delivered 180 with good diastereocontrol(76%de).AnintramolecularalkylationviaSN2’provided181asamixtureoffourdiastereoisomers,whichcouldbeseparatedbychromatography,therebyallowingaccesstoalternativeisomersof5 fromacommonintermediate.Diimidereductionof181 to183 proceeded cleanly, followed by removal of the chiralauxiliary by acid hydrolysis. Further hydrolysis then affordedthefreeaminoacid(+)-5 inreasonableyieldof47%;however,onlyinamoderateeeof68%.

Ina followuptotheirpreviousasymmetricsynthesis,65Salaunetalreportedaracemic,Pd-catalysedallylationstrategyforthesynthesisof(±)-5(Scheme27).68

Scheme 27 Salaun’s synthesis of (±)-5 featuring Pd-catalyzed cyclisation.

Di-electrophile185generated186 inhighyieldandasasinglediastereomervia a highly stereoselective cyclization.The vinylunit of186was then reduced to afford intermediate177b, asemployed in their previous synthesis,66 before final hydrolysistoafford(±)-5.

InareportfromBaldwinetal,69(±)-5waspreparedfollowingashortsyntheticsequence(Scheme28).

Scheme 28 Baldwin’s concise approach to (±)-5.

Tandem intra-/intermolecular dialkylation of di-tert-butylmalonate 187 using dibromide 188 deliveredcyclopropane189ingoodyield.Selectivehydrolysisoftheleasthinderedester,similartoIchihara,62gaveintermediate190.Thecarboxylicacid thenunderwentCurtiusrearrangement,via theacidanhydride,andwasthenconvertedtothemixedanhydride,toafford(±)-5.

Using methodology developed by Baldwin,70 Parsons et alreported a short synthetic sequence towards (±)-5 where thekey step was a radical-based 3-exo-trig cyclisation of 191employingtheirMn-mediatedmethodology(Scheme29).71Theuse of biphasic conditions and the phase transfer catalystbenzyltriethylammonium chloride (BTAC) allowed thepentacarbonylmanganese halide to be washed out of thereactionmixture to improve product isolation. Debrominationusingn-Bu3SnHaffordedintermediate193whichwasadvancedto(±)-5followingtherouteofBaldwin(notshown).70

Scheme 29 Parsons’ radical based methodology for the synthesis of (±)-5.


Methods for the final installation of C2 typically featureSimmons-Smith cyclopropanation or the 1,3-dipolarcycloadditionofdiazo-species.61Charetteetalreportedachiralauxiliary-mediatedsynthesisof3-methanoaminoacids,focusingon5anditsisomers,withthekeystepbeingaSimmons-Smithcyclopropanation(Scheme30).72

Scheme 30 Charette’s chiral auxiliary-based approach to (+)-5.

N

N

OMe

MeO

Me Me

N

N

OMe

MeO

Me Me

Cl

N

N

OMe

MeO

Me Me

N

N

OMe

MeO

Me Me

Me

1) n-BuLi, –70 °C

2) n-BuLi, −70 °C

HCl, Δ

82% yield79% de

84% yield

43% yield

47% yield68% ee

179 180

181183

184 (+)-5H2N

MeO2C MeH2N

HO2C Me

ClCl

182

99% yield

N NCO2K

KO2C

AcOH

HCl

ClCl

NCPh2

Pd(dba)2, PPh3, NaH AcOH, pyridine

185 186

182

177b(±)-5

74% yield

N

NCPh2C

72% yield

N

NC MePh2CH2N

HO2C Me

NCN N

CO2K

KO2C

HCl97% yield

Br

t-BuO Ot-Bu

O OMe

Br

TEBA, NaOH

72% yield

1) TFA, CH2N22) KOH, MeOH

1) HCl2) Ethyl chloroformate DIPEA3) NaN3, H2O4) PhMe, Δ5) HCl, Δ

32% yield(5 steps)

187

188

189

190(±)-5

t-BuO2C

t-BuO2C Me

100% yield

KO2C

MeO2C MeH3N

O2C Me

EtO2C

CO2EtMn2(CO)10CBr4, hv

then DBU orNaOH, BTAC

88% yield191 192

Bu3SnH, Δ

83% yield

193

EtO2C

EtO2C CBr3

EtO2C

EtO2C Me

OBnO

BnOOH

O

BnO TIPSO

H

Et2Zn, CH2ICl

98% yield dr 66:1194 195

1) Tf2O, −20 °C2) Δ

80% yield196

RuCl3, NaIO4 83% yield

1) DPPA, NEt32) t-BuOH, 120 °C3) TBAF, AcOH

75% yield(3 steps)

1) PDC2) KMnO4, NaH2PO4

85% yield(2 steps)

197155

198(+)-199

MeTIPSO

OH

HO2CMeTIPSO

BocHNMeHO

BocHN

HO2C Me

OBnO

BnOOH

O

BnO TIPSO

MeMe

HO2C

H2N Me



Both the E- and Z-glucosides were prepared from a commonstartingalcoholbychangingtheorderofthesyntheticsequence,using methodology previously communicated by the Charettegroup.73,74 Following optimization of the Simmons-Smithreaction,intermediate195wasobtainedinhighyieldandwithgood diastereocontrol, setting the absolute stereochemistry oftheC3position. Formationof the triflate facilitated cleavageofthe chiral auxillary73 and gave cyclopropyl 196 in high yield.Boc-protected (+)-5 was then obtained in six steps. Sharplessoxidation conditions afforded the cyclopropyl acid197, whichcould then be differentiated towards both (+)-5, and (+)-allo-coronamicacid,155.Toobtain(+)-5,197wasconvertedtothecorresponding acyl azide, which underwent Curtiusrearrangement to install the amine functionality. TBAFdeprotection then gave access to 198. The final oxidationreactiontoaffordBoc-protected(+)-5(199)wascarriedoutina two-step process. PDC oxidation allowed access to thecorrespondingaldehyde,whichwasthenfurtheroxidizedtotheacidusingKMnO4,followingtheprocedureofMasamune.75

Williams et al have described the asymmetric synthesis ofseveral ACCs through a phosphonate ester-mediated approach(Scheme31).76 Phosphonate ester201was synthesized in twohigh yielding steps using known chemistry from startingmaterial 200.77 Subsequent Horner-Wadsworth-Emmonsolefination of propionaldehyde provided the E-alkene, 202,exclusively,whichwasconfirmedbyX-raycrystallography.Theauthorshypothesizedthat thisselectivitywasdue to thestericrepulsion of the Boc protecting group and the aldehyde ethylunitinthebetainetransitionstate.Inordertoachieveafaciallyselectivecyclopropanation,a rangeofconditionswasscreenedfor the formation of intermediate 204. Diastereoselectivecyclopropanation using sulfonium ylide 203 gave 204 as asingle diastereomer in excellent yield. Here, the authorshypothesized that this facial selectivity was the result of π-stacking between the aryl ring on the ylide and the phenylsubstitution on the lactone. Treatment of intermediate 204underBirch-like conditions gave theBoc-protected amino acid199,whichwashydrolyzedtoafford(+)-5.OpticalrotationandX-ray analysis proved the retention of absolute configurationthroughoutthesyntheticsequence.

Scheme 31 Williams’ chiral auxillary based methodology towards (+)-5.


Routes which install C3 last typically feature Kulinkovichchemistry or the addition of di-polar species to dehydroaminoacids.61 Stammer et al developed a synthesis of (±)-5, which

featured the addition of a diazonium species to adehydroalaninederivative(Scheme32).78

Scheme 32 Stammer’s amino acid based approach towards (±)-5.

Dehydration of the serine-derived starting material 205 gaveintermediate206,whichcould thenbe treatedwitharangeofdiazonium species to afford the corresponding cyclopropylamino acids via intermediate207, which underwent pyrolysisupon heating in PhMe to give 208 with the desired relativestereochemistry.Hydrolysisof208thenaffordedBocprotected(±)-199.

ImprovedhandlingofthediazospecieswasreportedbyCoxetalwho applied theirmethodology for the in situ generation ofaryl diazomethanes79 to a one-pot diastereoselective synthesisof cyclopropane amino acids.61 Aryldiazomethanes weregenerated in situ from tosylhydrazone derivative 210, whichremovedtheneedtohandlethereactivediazospecies(Scheme33).

Scheme 33 Cox’s diazo-based approach to (±)-5.

Underphasetransferconditions,cyclopropanationof206with210delivered211 asa72:28mixture in favourof thedesireddiastereomer.ReductionofthevinylunitwithconcomitantPNB(p-nitrobenzyl)groupremovalproceededunderhydrogenationconditions,andafinalacid-mediatedBoc-deprotectionafforded(±)-5.

Yamazaki et al have utilised a novel [2+1] cycloaddition,featuringakeySe-enabled1,2-siliconmigrationtoaffordhighlyfunctionalised ACCs, which can then be converted to (±)-5(Scheme34).80

Treatmentof212with213inthepresenceofZnBr2gave[2+2]-adduct 214 and the desired [2+1]-product 215. The leaststerically hindered ester of 215 was reduced to 216 in highyield.Followingprotectionof thealcohol,217wasoxidized toafford 218. Wittig olefination and diimide reduction provided219 in good yield. TBAF deprotection afforded alcohol 220,which was advanced to 221 via oxidation and Curtiusrearrangement. Global deprotection under acid hydrolysisdelivered (±)-5 in 71% yield (not shown).While syntheticallyinteresting, this synthesis is lengthier and, therefore, loweryieldingthanotherpreparationsof(±)-5.

NBoc

OPh

Ph

O

NBoc

OPh

Ph

O

PO

OMeOMe

NBoc

OPh

Ph

OPh S

O

NEt2

CH2

NBoc

OPh

Ph

O

H

BocHN

1) NBS, CCl4, Δ2) P(OMe)3 NaH, EtCHO

Li, NH3

1) HCl2) propylene oxide, Δ

86% yield 92% yield

100% yield64% yield

100% yield

(+)-199

200

(+)-5

201

202

203

204

MeHO2C

H2NMeHO2C

MeMe

DCC, CuCl

80% yield BocHN

p-NBO2CN

N

NHBoc

p-NBO2C59% yield

EtCHN2

NaOH50% yield

205 206 207

208(±)-199

Δ

77% yieldBocHN

p-NBO2C Me

BocHN

HO2C Me

NHBoc

p-NBO2COH Me

O N

HN

Ts

TsNH2NH2

68% yield

1) LiHMDS, −78 °C

2)

36% yield(E:Z = 72:28)

(2 steps)

209 210 211

H2, Pd(OH)2/C

79% yield89% yield199(±)-5

HCl

BocHN

p-NBO2C

BocHN

HO2C MeHCl•H2N

HO2C Me

BnEt3NCl, 40 °CBocHN

p-NBO2C

206



Scheme 34 Yamazaki’s cycloaddition based approach to (±)-5.

deMeijereetalreportedthesynthesisof(±)-5viaTi-mediatedACCformation(Scheme35).81

Scheme 35 de Meijere’s Kulinkovich-de Meijere based approach to (±)-5.

Amide 222 was prepared in three high yielding steps and onkilogram scale from inexpensive starting materials. The keycyclopropanation was achieved through a Kulinkovich-deMeijerereactiontodeliver224inmoderateyieldandfavouringthe undesired diastereomer, despite attempts to optimise.Benzyl deprotection and subsequent Boc protection providedintermediate 225, on which an analogous oxidation to thatcommunicatedbyCharette72wasattempted.WhereasCharetteused conditions developed by Masamune75 in a two-stepprocedureviathealdehyde,Meijerereportedaone-stepprocessusingKMnO4toaccess226asamixtureofdiastereomers.81

SalaunetalalsoapproachedACCsusingaKulinkovichreaction(Scheme 36).82 In this case, the cyclopropanated product 228was obtained in high yield of 92% and with completediastereoselectivity through reaction of ester 227 with n-BuMgBr. Acylation of the free hydroxyl followed by acetaldeprotection gave aldehyde 229. This was then subjected toKnoevanagelcondensationundermicrowaveirradiationtogiveacid230.Followingreductionandmesylateformation,231wasselectivelyreducedtoaffordintermediate232inexcellentyield.Pd-mediated azide incorporation proceeded with retention ofstereochemistry.Thiswasfollowedbyreductionoftheazidetothe free amine following a known procedure.83 Oxidativecleavageofthealkeneunitthenafforded(±)-5.83

Scheme 36 Salaun’s Kulinkovich based approach to (±)-5.

Overall,anumberofwell-establishedmethodologieshavebeenleveragedtoenable thesynthesisofACCssuchas5.Thesecangenerallybegroupedwith regard tooverall synthetic strategy,andtypicallyoffershortroutesto5andanaloguesthereof.Themost synthetically useful of these approaches allow derivativesynthesis from a late stage, common intermediate, which isattractive with respect to generating a structure-activityrelationshiptowardsanovelherbicidalagent.

4.Synthesisofcoronatine

Uedaetalcommunicatedthesynthesisoffourstereoisomersof3,accessedthroughthecondensationofenantiopure(+)-5and(–)-5 with (±)-4 (Scheme 37).26 Boc deprotection of bothenantiomers of 5 was followed by HBTU-mediated amidationwith (±)-4. The free acid was then obtained throughhydrogenationofthebenzylprotectinggroup.Inbothcases,themixture of diastereoisomers was separated by HPLC. Thiscoupling has also been reported usingEDC, again in excellentyield.36,84

Scheme 37 Total synthesis of coronatine.

5.Conclusions

In conclusion, coronatine (1) presents an attractive synthetictarget with significant potential for herbicide generation. The

SePh

Et3Si

CO2t-But-BuO2C

ZnBr2, −30 °C

CO2t-Bu

CO2t-BuPhSe

Et3Si212

213

215214

1) LiAlH42) NaBH4

87% yield(2 steps)

TBDMSClimidazole

95% yield

NaIO4 73% yield

1) Ph3P=CH2

81% yield(2 steps)

TBAF

95% yield

1) RuCl3/NaIO42) DPPA3) t-BuOH

40% yield(3 steps)

216217

218 219

220221

48% yield

CHOt-BuO2C

TBDMSO

t-BuO2C

TBDMSOMe

t-BuO2C

HOMe

BocHN

t-BuO2C Me

2) HN=NH

tBuO2C

t-BuO2CSiEt3SePh

H

t-BuO2CSiEt3SePh

H

HO

t-BuO2CSiEt3SePh

H

TBDMSO

(213:214 = 3:7)

BnONBn2

O

MeTi(Oi-Pr)3

1) Pd/C, H2, HCl

1) KMnO4, t-BuOH, NaOH2) CH2N2

88% yield (2 steps)

Me MgBr

222

223

224

225226

48% yield(anti:syn = 1:5)

Bn2NMeBnO

BocHNMeHO

82% yield(2 steps)

BocHN

MeO2C Me

2) Boc2O Et3N, DMAP

EtO

OEt

CO2Et 92% yield(100% de)

1) Ac2O, DMAP2) HCO2H

96% yield(2 steps)

CH2(CO2H)2SiO2, µW

83% yield70% yield(2 steps)

LiAlH4

99% yield

227 228

229230

231 232

1) Pd(dba)2, PPh32) N3Na, 15-c-5

86% yield100% de

HS(CH2)3SH

97% yield

1) Boc2O, KOH2) RuCl3, NaIO43) HCl, dowex

233234

(±)-5

HOMe

EtO

EtO

AcOMeOHC

AcOMe

HO2C

MsOMe

MsO MsOMe

Me

N3

MeMe

H2NMe

Me

H2N

HO2C Me

n-BuMgBrTi(Oi-Pr)4

1) LiAlH42) MsCl, Et3N

75% yield(3 steps)

BocHN

BnO2C Me

(+)-5 (99.5% ee)

1) TFA2) (±)-CFA, HBTU Et3N, DMAP, 0 °C

3) Pd/C, H2

(+)-1 (99.9% ee) (+)-235 (98.8% ee)

90% yield(3 steps)

BnO2C

BocHN

(−)-5 (99.7% ee)

1) TFA2) (±)-CFA, HBTU Et3N, DMAP, 0 °C

3) Pd/C, H2

(−)-1 (98.6% ee) (−)-236 (99.2% ee)

82% yield(3 steps)

Me

a) Synthesis of (+)-1 and (+)-234.

b) Synthesis of (−)-1 and (−)-234.

Me

H

H

O

OHN

O

OHMe

Me

H

H

O

OHN

O

OHMe

Me

H

H

O

OHN

O

OHMe

Me

H

H

O

OHN

O

OHMe



naturalproductcanbeconsideredascomprisingtwostructuralunits, coronafacicacid (4)andcoronamicacid (5).2Both thesecomponents, particularly 4, pose a synthetic challenge withrespect toamenability toagrochemicaldiscoveryprogrammes.Significanteffortshavebeenmadetodevelopefficientsynthesestowards 4, which must take into consideration thestereochemical requirements and ideally be flexible withregards to analogue generation. Varied synthetic routes havebeencommunicatedtowardsthesynthesisof4,howeverthereexists a need for a less protracted synthetic sequence, ideallyfrom inexpensive and easily accessed starting materials.Cyclopropane amino acids such as 5 have also receivedconsiderable attention froma synthetic viewpoint, and severalclassifications of general methodology amenable to theirsynthesis are known.61 Overall, synthetic efforts towards4,5,and ultimately 1 have made 1 and its analogues a tractablesynthetictargetforherbicidegeneration;however,scopeexistsfor the improvement of these approaches, particularly withrespect to large scale preparations and the amenability of theroutetolatestagediversification.

Acknowledgment

We thank the University of Strathclyde for a studentship (MML) andSyngentaforfinancialandmaterialsupport.

References

(1) Du,M.; Li, X.;Duan, L.; Zhang,M.; Tan,W.; Xu,D.; Li, Z.PLoSOne2014,9,e97652.

(2) Ichihara, A.; Shiraishi, K.; Sato, H.; Sakamura, S.; Nishiyama, K.;Sakai, R.; Furusaki, A.; Matsumoto, T. J. Am. Chem. Soc.1977, 99,636.

(3) Ichihara, A.; Shiraishi, K.; Sakamura, S.; Furusaki, A.; Hashiba, N.;Matsumoto,T.TetrahedronLett.1979,4,365.

(4) Fonseca,S.;Chini,A.;Hamberg,M.;Adie,B.;Porzel,A.;Kramell,R.;Miersch,O.;Wasternack,C.;Solano,R.Nat.Chem.Biol.2009,5,344.

(5) Monte, I.; Hamberg, M.; Chini, A.; Gimenez-Ibanez, S.; García-Casado,G.;Porzel,A.;Pazos,F.;Boter,M.;Solano,R.Nat.Chem.Biol.2014,10,671.

(6) Sheard,L.B.;Tan,X.;Mao,H.;Withers,J.;Ben-Nissan,G.;Hinds,T.R.;Kobayashi,Y.;Hsu,F.-F.;Sharon,M.;Browse,J.;He,S.Y.;Rizo,J.;Howe,G.;Zheng,N.Nature2010,468,400.

(7) Creelman,R.;Mullet, J. E.Annu.Rev. PlantPhysiol. PlantMol. Biol.1997,48,355.

(8) Krumm,T.;Bandemer,K.;Boland,W.FEBSLett.1995,377,523.(9) Yi,H.;Preuss,M.L.;Jez,J.M.Nat.Chem.Biol.2009,5,273.(10) RaoUppalapati,S.;Ayoubi,P.;Weng,H.;Palmer,D.A.;Mitchell,R.

E.;Jones,W.;Bender,C.L.PlantJ.2005,42,201.(11) Ichihara,A.;Sakamura,S.Toxicon1983,187.(12) Sakai,R.Ann.Phytopathol.Soc.Jpn1980,46,499.(13) Feys,B.J.F.;Benedetti,C.E.; Penfold,C.N.;Turner,J.G.PlantCell

1994,6,751.(14) Kenyon,J.S.;Turner,J.G.PlantPhysiol.1992,100,219.(15) Haider,G.;VonSchrader,T.; Füsslein,M.;Blechert, S.;Kutchan,T.

M.Biol.Chem.2000,381,741.(16) Schüler,G.;Mithöfer,A.;Baldwin,I.T.;Berger,S.;Ebel,J.;Santos,J.

G.;Herrmann,G.;Hölscher,D.;Kramell,R.;Kutchan,T.M.;Maucher,H.;Schneider,B.;Stenzel, I.;Wasternack,C.;Boland,W.FEBSLett.2004,563,17.

(17) Okada,M.;Egoshi,S.;Ueda,M.Biosci.Biotechnol.Biochem.2010,74,2092.

(18) Gu,M.;Yan,J.;Bia,Z.;Chen,Y.T.;Lu,W.;Tang,J.;Duan,L.;Xie,D.;Nan,F.J.Bioorg.Med.Chem.2010,18,3012.

(19) Jones,W.; Harvey, D.;Mitchell, R.Food Agric. Immunol.2002,14,301.

(20) Mithöfer,A.;Maitrejean,M.;Boland,W.J.PlantGrowthRegul.2004,23,170.

(21) Blechert,S.;Bockelmann,C.;Füßlein,M.;Schrader,T.V.;Stelmach,B.;Niesel,U.;Weiler,E.W.Planta1999,207,470.

(22) Kosaki,Y.;Ogawa,N.;Wang,Q.;Kobayashi,Y.Org.Lett.2011,13,4232.

(23) Ichihara,A.;Kinura,R.;Moriyasu,K.;Sakamura,S.Tetrahedronlett.1977,194,4331.

(24) Liu,H.J.;Llinas-Brunet,M.Can.J.Chem.1984,62,1747.(25) Sundberg,R.J.;Bukowick,P.A.;Holcombe,F.O.J.Org.Chem.1967,

32,2938.(26) Okada, M.; Ito, S.; Matsubara, A.; Iwakura, I.; Egoshi, S.; Ueda, M.

Org.Biomol.Chem.2009,7,3065.(27) Hale,K.J.;Cai,J.TetrahedronLett.1996,37,4233.(28) Arnold,L.A.;Naasz,R.;Minnaard,A. J.;Feringa,B.L. J.Org.Chem.

2002,67,7244.(29) Ichihara,A.;Kimura,R.;Yamada,S.;Sakamura,S. J.Am.Chem.Soc.

1980,102,6353.(30) Brannock, K. C.; Bell, A.; Burpitt, R. D.; Kelly, C. A. J. Org. Chem.

1964,29,801.(31) Jung,M.E.;Halweg,K.M.TetrahedronLett.1981,22,2735.(32) Moreau, B.; Ginisty, M.; Alberico, D.; Charette, A. B. J. Org. Chem.

2007,72,1235.(33) Inoue, T.; Liu, J. F.; Buske, D. C.; Abiko, A. J. Org. Chem.2002,67,

5250.(34) Yates, P.; Bhamare, N. K.; Granger, T.; Macas, T. S. Can. J. Chem.

1993,71,995.(35) Nara,S.;Toshima,H.;Ichihara,A.TetrahedronLett.1996,37,6745.(36) Nara,S.;Toshima,H.;Ichihara,A.Tetrahedron1997,53,9509.(37) Arai, T.; Sasai, H.; Yamaguchi, K.; Shibasaki, M. J. Am. Chem. Soc.

1998,120,441.(38) Arai, T.; Yamada, Y. M. A.; Yamamoto, N.; Sasai, H.; Shibasaki, M.

Chem.Eur.J.1996,2,1368.(39) Haller,A.;Bauer,E.Compt.Rend.1908,147,824.(40) Mehta,G.;Praveen,M.J.Chem.Soc.,Chem.Commun.1993,1573.(41) Chapman,N.B.;Key,J.M.;Toyne,K.J.J.Org.Chem.1970,35,3860.(42) Schuda,P.F.;Ammon,H.L.;Heimann,M.R.;Bhattacharjee,S.J.Org.

Chem.1982,47,3434.(43) Mehta,G.;Reddy,D.S.TetrahedronLett.1999,40,991.(44) Mehta,G.;Reddy,D.S.J.Chem.Soc.PerkinTrans.12001,4,1153.(45) Sono,M.;Hashimoto,A.;Nakashima,K.;Tori,M.TetrahedronLett.

2000,41,5115.(46) Tsuji,J.PureAppl.Chem.1981,53,2371.(47) Hoelder,S.;Blechert,S.Synlett1996,505.(48) Kataoka, H.; Yamada, T.; Goto, K.; Tsuji, J. Tetrahedron 1987, 43,

4107.(49) Nakayama, M.; Ohira, S.; Okamura, Y.; Soga, S. Chem. Lett. 1981,

731.(50) Szeja,W.Synthesis(Stuttg).1979,822.(51) Bell, H. M.; Vanderslice, C. W.; Spehar, A. J. Org. Chem. 1969, 34,

3923.(52) Ohira,S.Bull.Chem.Soc.Jpn.1984,57,1902.(53) Nakayamaand,M.;Ohira,S.Agric.Biol.Chem.1983,47,1689.(54) Taber, D. F.; Saleh, S. a; Korsmeyer, R.W. J. Org. Chem.1980,45,

4699.(55) Osorio-Lozada,A.;Olivo,H.F.J.Org.Chem.2009,74,1360.(56) Kinouchi,W.;Kosaki,Y.;Kobayashi,Y.TetrahedronLett.2013,54,

7017.(57) Taber,D.F.;Sheth,R.B.;Tian,W.J.Org.Chem.2009,74,2433.(58) Handa,M.;Takata,A.;Nakao,T.;Kasuga,K.;Mikuriya,M.;Kotera,T.

Chem.Lett.1992,10,2085.(59) Hudspeth,J.P.;Jung,M.E.J.Am.Chem.Soc.1980,102,2463.(60) Jung,M.E.;Hudspeth,J.P.J.Am.Chem.Soc.1977,99,5508(61) Adams,L.A.;Aggarwal,V.K.;Bonnert,R.V.;Bressel,B.;Cox,R. J.;

Shepherd,J.;DeVicente,J.;Walter,M.;Whittingham,W.G.;Winn,C.L.J.Org.Chem.2003,68,9433.

(62) Ichihara,A.TetrahedronLett.1977,18,269.(63) Murdock,K.C.;Angier,R.B.J.Org.Chem.1962,27,2395.(64) Toshima,H.;Ichihara,A.Biosci.Biotechnol.Biochem.1995,59,497.



(65) Gaucher,A.;Ollivier, J.;Marguerite, J.;Paugam,R.;Salaün, J.Can. J.Chem.1994,72,1312.

(66) Groth, U.; Schollkopf, U.; Halfbrodt, W. Liebigs Ann. Chem. 1992,351.

(67) Quinkert,G.;Schwartz,U.;Stark,H.;Weber,W.D.;Baier,H.;Adam,F.;Duerner,G.Angew.Chem.1980,92,1062.

(68) Gaucher, A.; Dorizon, P.; Ollivier, J.; Salaün, J. Tetrahedron Lett.1995,36,2979.

(69) Adlington, R. M.; Rawlings, B. J.; Baldwin, J. E. Tetrahedron Lett.1985,26,481.

(70) Baldwin, J. E.; Adlington, R. M.; Rawlings, B. J.; Jones, R. H.TetrahedronLett.1985,26,485.

(71) Huther, N.; McGrail, P. T.; Parsons, A. F. Eur. J. Org. Chem. 2004,1740.

(72) Charette,A.B.;Côté,B.J.Am.Chem.Soc.1995,117,12721.(73) Charette,A.B.;Côté,B.J.Org.Chem.1993,58,933.(74) Charette,A.B.;Côté,B.TetrahedronLett.1993,34,6833.(75) Abiko, A.; Roberts, J. C.; Takemasa, T.; Masamune, S.Tetrahedron

Lett.1986,27,4537.(76) Williams,R.M.;Fegley,G.J.J.Am.Chem.Soc.1991,113,8796.(77) Sinclair,P. J.; Zhai,D.;Reibenspies, J.;Williams,R.M. J.Am.Chem.

Soc.1986,108,1103.

(78) Suzuki,M.;Gooch,E.E.;Stammer,C.H.TetrahedronLett.1983,24,3839.

(79) Aggarwal, V. K.; de Vicente, J.; Bonnert, R. V. Org. Lett. 2001, 3,2785.

(80) Yamazaki,S.;Kataoka,H.;Yamabe,S.J.Org.Chem.1999,64,2367.(81) Kordes,M.;Winsel,H.;Meijere,A.De.Eur.J.Org.Chem.2000,3235.(82) Kozyrkov, Y. Y.; Pukin, A.; Kulinkovich,O. G.; Ollivier, J.; Salaün, J.

TetrahedronLett.2000,41,6399.(83) Atlan,V.;Racouchot,S.;Rubin,M.;Bremer,C.;Ollivier,J.deMeijere,

A.;Salaün,J.TetrahedronAsymm.1998,9,1131.(84) Toshima,H.;Nara,S.;Ichihara,A.Biosci.Biotechnol.Biochem.1997,

61,752.

Biosketches

MairiLittlesonobtainedherMChemdegreeattheUniversityofStrathclydein2014.ShebeganherPh.D.studieswithDrAllanWatsonin2014wheresheisfocusedonthedevelopmentofnewherbicidalagentsbasedonnaturalproductscaffolds.

ClaireJ.RussellcompletedherM.Sci.attheUniversityofStrathclydein2002followedbyPh.D.researchwithProfessorW.J.Kerr(2005)andpostdoctoralworkwithProfessorP.D.MagnusatTheUniversityofTexas,Austin,U.S.(2007).In2007shejoinedSyngentaattheirR&DsiteinJealott'sHill,U.K.,andin2015shemovedtotheSyngentaManufacturingsiteinGrangemouth,U.K.

ElizabethC.FryewasborninStirling,UKin1988.ShestudiedattheUniversityofEdinburgh,completingherMChemdegreein2010.ShereceivedherPh.D.in2013fromtheUniversityofCambridgeunderthesupervisionofProfessorDavidSpring.ShethenjoinedSyngentaattheirJealott’sHillsite,U.K.,wheresheiscurrentlyaSeniorResearchChemist.



KennethLingwasborninAyr,UKin1984.HeobtainedhisMChemdegreefromtheUniversityofOxfordin2005,andhisD.Philfromthesameinstitutionin2009followingdoctoralstudieswithProf.StephenG.Davies.HespentoneyearasaPostdoctoralResearchFellowwithProf.AndrewD.SmithattheUniversityofStAndrewsbeforejoiningtheHerbicideChemistrydepartmentatSyngentain2010whereheiscurrentlyaTeamLeader.

CraigJamiesonobtainedhisB.Sc.(Hons)inChemistryattheUniversityofGlasgowin1996followedbyPh.D.studieswithProfessorR.RamageattheUniversityofEdinburgh(1999)andpostdoctoralresearchwithProfessorS.V.LeyattheUniversityofCambridge.In2001hewasappointedasaPrincipalScientistinGlaxoSmithKline’sDiscoveryMedicinalChemistrygroupworkingonarangeofexploratorymedicinalchemistryprograms.In2004,hejoinedOrganonLaboratories(laterMerckResearchLabs)asaGroupLeaderinMedicinalChemistry.HejoinedtheUniversityofStrathclydein2010wherehisresearchinterestsarewithinsyntheticchemistry,medicinalchemistry,andagrochemistry.

AllanJ.B.WatsoncompletedhisM.Sci.attheUniversityofStrathclydein2004followedbyPh.D.researchwithProfessorW.J.Kerr(2008)andpostdoctoralworkwithProfessorD.W.C.MacMillanatPrincetonUniversity,U.S.(2010).AfteranindustrialpostdoctoralresearchpositionatGlaxoSmithKline,hereturnedtotheUniversityofStrathclydein2011wherehisresearchinterestsarecatalysis,medicinalchemistry,andagrochemistry.

synthetic approaches to coronafacic acid, coronamic acid

Documents