Synthesis of malhamensilipin A exploiting iterative epoxidation/chlorination: experimental and computational analysis of epoxide-derived chloronium ions

Article abstract of DOI:10.1039/c6sc03012b

We report a 12-step catalytic enantioselective formal synthesis of malhamensilipin A (3) and diastereoisomeric analogues from (E)-2-undecenal. The convergent synthesis relied upon iterative epoxidation and phosphorus(v)-mediated deoxydichlorination reactions as well a titanium-mediated epoxide-opening to construct the C11-C16 stereohexad. The latter transformation occurred with very high levels of stereoretention regardless of the C13 configuration of the parent epoxide, implicating anchimeric assistance of either the γ- or δ-chlorine atoms, and the formation of chloretanium or chlorolanium ions, respectively. A computational analysis of the chloronium ion intermediates provided support for the involvement of chlorolanium ions, whereas the potential chloretanium ions were found to be less likely intermediates on the basis of their greater carbocationic character.

Full text of DOI:10.1039/c6sc03012b

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Page 1 of 11
Pleas Ce hꢀ d eo mꢀ ni oc ta ꢀ al dS jcu i se t nꢀ mc ea rginsꢀ
View Article Online
DOI: 10.1039/C6SC03012B
ChemicalꢀScienceꢀ
ꢀ
EDGEꢀARTICLEꢀ
SynthesisꢀofꢀMalhamensilipinꢀAꢀExploitingꢀIterativeꢀ
Epoxidation/Chlorination:ꢀExperimentalꢀandꢀComputationalꢀ
AnalysisꢀofꢀEpoxide-DerivedꢀChloroniumꢀIonsꢀꢀ
Receivedꢀ00thꢀJanuaryꢀ20xx,ꢀ
Acceptedꢀ00thꢀJanuaryꢀ20xxꢀ
a
a
ꢀb*
a*ꢀ
J.ꢀSaska, ꢀW.ꢀLewis, ꢀR.ꢀS.ꢀPaton ꢀandꢀR.M.ꢀDenton
DOI:ꢀ10.1039/x0xx00000xꢀ
www.rsc.org/ꢀ
Weꢀ reportꢀ aꢀ 12-stepꢀ catalyticꢀ enantioselectiveꢀ formalꢀ synthesisꢀ ofꢀ malhamensilipinꢀ Aꢀ (3)ꢀ andꢀ diastereoisomericꢀ
analoguesꢀfromꢀ(E)-2-undecenal.ꢀTheꢀconvergentꢀsynthesisꢀreliedꢀuponꢀiterativeꢀepoxidationꢀandꢀphosphorus(V)-
mediatedꢀ deoxydichlorinationꢀ reactionsꢀ asꢀ wellꢀ aꢀ titanium-mediatedꢀ epoxide-openingꢀ toꢀ constructꢀ theꢀ C11-C16ꢀ
stereohexad.ꢀ Theꢀ latterꢀ transformationꢀ occurredꢀ withꢀ veryꢀ highꢀ levelsꢀ ofꢀ stereoretentionꢀ regardlessꢀ ofꢀ theꢀ C13ꢀ
configurationꢀofꢀtheꢀparentꢀepoxide,ꢀimplicatingꢀanchimericꢀassistanceꢀofꢀeitherꢀtheꢀγ-ꢀorꢀδ-chlorineꢀatoms,ꢀandꢀtheꢀ
formationꢀ ofꢀ chloretaniumꢀ orꢀ chlorolaniumꢀ ions,ꢀ respectively.ꢀ Aꢀ computationalꢀ analysisꢀ ofꢀ theꢀ chloroniumꢀ ionꢀ
intermediatesꢀprovidedꢀsupportꢀforꢀtheꢀinvolvementꢀofꢀchlorolaniumꢀions,ꢀwhereasꢀtheꢀpotentialꢀchloretaniumꢀionsꢀ
wereꢀ foundꢀ toꢀ beꢀ lessꢀ likelyꢀ intermediatesꢀ onꢀ theꢀ basisꢀ ofꢀ theirꢀ greaterꢀ carbocationicꢀ character.ꢀ
ꢀ
ꢀ
ꢀ
(
A) Representative members of the chlorosulfolipid family
Introductionꢀ
SO
3
Cl OSO
3
Cl
Cl
Cl
O
Cl
Cl
Theꢀ chlorosulfolipidsꢀ (Schemeꢀ 1A)ꢀ areꢀ aꢀ familyꢀ ofꢀ bioactiveꢀ
1
Me
OSO
3
Me
5
7
7
7
polychlorinatedꢀ naturalꢀ products ꢀ isolatedꢀ fromꢀ algalꢀ sourcesꢀ
2
Cl Cl Cl
Cl Cl Cl
OSO3
3
andꢀtoxicꢀmussels. ꢀSinceꢀtheꢀoriginalꢀreportsꢀinꢀtheꢀlateꢀ1960s, ꢀ
theꢀfamilyꢀhasꢀgrownꢀandꢀmanyꢀofꢀtheꢀgrossꢀstructuresꢀhaveꢀ
danicalipin A (1)
malhamensilipin A (2)
SO
O Cl
3
Cl
4
beenꢀrefinedꢀtoꢀincludeꢀrelativeꢀandꢀabsoluteꢀstereochemistry. ꢀ
Cl
Me
Theꢀ stereochemicalꢀ challengesꢀ posedꢀ byꢀ theseꢀ uniqueꢀ lipidsꢀ
hasꢀstimulatedꢀtheꢀinterestꢀofꢀsynthesisꢀchemistsꢀaroundꢀtheꢀ
worldꢀ andꢀ theꢀ firstꢀ totalꢀ synthesisꢀ ofꢀ aꢀ chlorosulfolipidꢀ wasꢀ
Cl Cl Cl
mytilipin A (hexachlorosulfolipid)(3)
15 32
C H
SO
3
O
O
Cl
O
Cl OH Cl OH
X
Cl
5
reportedꢀbyꢀtheꢀCarreiraꢀgroupꢀinꢀ2009. ꢀFollowingꢀthisꢀworkꢀ
synthesesꢀ ofꢀ mytilipinꢀ Aꢀ (3),6ꢀ danicalipinꢀ Aꢀ (1),7ꢀ
Me
OH
Cl
Cl Cl Cl Cl
Cl Cl
OH
8
malhamensilipinꢀ Aꢀ (2) ꢀ andꢀ mytilipinꢀ Bꢀ (4) ꢀ wereꢀ reportedꢀ
9
X = OH mytilipin B (4)
X = H mytilipin C (5)
(undecachlorosulfolipids A and B)
(
Schemeꢀ1A).ꢀꢀ
Inꢀ termsꢀ ofꢀ synthesisꢀ strategiesꢀ twoꢀ complementaryꢀ
(
B) Stereoselective dichlorination reactions of alkenes
R2
X
Et NCl Cl
X
4
3
anti dichlorination of Z-alkenes
dichlorinationꢀ reactionsꢀ haveꢀ beenꢀ applied.ꢀ Theꢀ firstꢀ methodꢀ
Schemeꢀ 1B,ꢀ top),ꢀ examinedꢀ inꢀ detailꢀ byꢀ Vanderwalꢀ andꢀ co-
workers,ꢀ involvesꢀ antiꢀ dichlorinationꢀ ofꢀ alkenesꢀ usingꢀ
R1
X=OPg, Cl
R1
R2
(
Cl
TiCl(iOPr)
tBuOCl
3
R2
R2 Cl
catalytic enantioselective
dichlorination
10
tetraethylammoniumꢀtrichloride. ꢀThisꢀdichlorinationꢀreactionꢀ
R1
OH
10-30 mol%
Schiff base
R1
OH
isꢀaꢀfeatureꢀofꢀmanyꢀofꢀtheꢀgroundbreakingꢀsynthesesꢀreportedꢀ
2
R3
Cl
R3
byꢀ bothꢀ theꢀ Vanderwalꢀ andꢀ Carreiraꢀ groups. ꢀ Veryꢀ recentlyꢀ (C) Strereospecific deoxydichlorination reactions of epoxides
Cl
Burnsꢀ andꢀ co-workersꢀ haveꢀ developedꢀ catalyticꢀ
enantioselectiveꢀ chlorinationꢀ reactionsꢀ ofꢀ allylicꢀ alcoholsꢀ andꢀ
appliedꢀ themꢀ inꢀ synthesisꢀ ofꢀ (deschloro)mytilipinꢀ Aꢀ andꢀ
O
NCS
R2
R2
> 2 equiv. of NBS and Ph3P
R1
R1
Ph
3
P
required per epoxide
Cl
ꢀ
11
Schemeꢀ1ꢀ(A)ꢀSelectedꢀchlorosulfolipids.ꢀ(B)ꢀSyntheticꢀmethods.ꢀ
danicalipinꢀAꢀ(2)ꢀ(Schemeꢀ1B,ꢀbottom). ꢀThisꢀwork,ꢀalongꢀwithꢀꢀ
12
13
otherꢀ methodsꢀ developedꢀ byꢀ theꢀ Snyder, ꢀ Nicolaouꢀ and ꢀ
Denmark ꢀ groupsꢀ opensꢀ upꢀ newꢀ approachesꢀ toꢀ
polyhalogenatedꢀ targetꢀ molecules.ꢀ Theꢀ secondꢀ approachꢀ
14
(
Schemeꢀ 1C)ꢀ involvesꢀ deoxydichlorinationꢀ reactionsꢀ ofꢀ
15
epoxides,ꢀreportedꢀbyꢀTanakaꢀandꢀYoshimitsuꢀinꢀ2009. ꢀWhileꢀ
thisꢀreactionꢀhasꢀfoundꢀapplicationꢀinꢀtheꢀsynthesisꢀofꢀmytilipinꢀ
6a,7b
Aꢀ (4)ꢀ andꢀ danicalipinꢀ Aꢀ (2)
quantitiesꢀofꢀorganicꢀwaste.ꢀꢀ
ꢀ itꢀ generatesꢀ stoichiometricꢀ
Thisꢀjournalꢀisꢀ©ꢀTheꢀRoyalꢀSocietyꢀofꢀChemistryꢀ20xxꢀ
J.ꢀName.,ꢀ2013,ꢀ00,ꢀ1-3ꢀ|ꢀ1ꢀꢀ
Pleaseꢀdoꢀnotꢀadjustꢀmarginsꢀ

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ꢀ
View Article Online
DOI: 10.1039/C6SC03012B
(B) Iterative epoxidation/chlorination for chlorosulfolipid synthesis
(A) Catalytic stereospecific deoxydichlorination, ref 16
Cl
Cl
Cl
O
deoxydichlorination
homologation;
epoxidation
R1
O
Cl
Ph
R2
R2
R2
O
P
R2
CO+CO2
R1
R1
R1
Ph
Ph
Cl
Cl
catalytic
in P(V)
deoxydichlorination or
ring-opening with chloride
Cl
X
X
R2
O
P
Cl
X
Cl
R1
n further iterations
R2
R2
(COCl)2
Cl Cl
Cl
R1
R1
n
Ph
Ph
Ph
chlorosulfolipid - all potential
stereoisomers acccessible
Cl Cl
X=Cl or OH
Cl
(
C) THIS WORK: Application to malhamensilipin A and analogs
X=Cl or OH
Cl OH
SO Na
SO3H
3
Vanderwal
deoxydichlorination
sulfation
Cl
O
Cl
Cl
Cl
O
Cl
ref. 8
O
Me
Me
11
Me
1
6
OSO3H
8
OTIPS
7
8
7
7
Cl Cl Cl
OSO3Na
Cl Cl ClCl Cl
Cl Cl
Cl Cl
C11-C12 epoxide (6)
malhamensilipin A-(3)
construction of the C11-C16 stereohexad
via 3-fold epoxidation/chlorination
chlorohydrin
formation
epoxidation
deoxydichlorination
epoxidation
Julia-Kocienski
olefination
O
O
Cl
Cl
O
O
S
Me
N
O
Me
CHO
8
OTIPS
OTIPS
8
Me
CO Et
24
N
7
13
2
7
13
7
N
N
Cl Cl
Cl
Cl Cl
Cl
Ph
C15-C16 epoxide (10)
C12-C24 fragments
a C13-(R) 9b C13-(S)
C1-C11 fragment (8)
C13-C14 epoxide (7)
7a C13-(R) 7b C13-(S)
9
ꢀ
Schemeꢀ 2ꢀ (A)ꢀ Catalyticꢀ deoxydichlorinationꢀ ofꢀ epoxidesꢀ (B)ꢀ Generalꢀ synthesisꢀ strategyꢀ forꢀ chlorosulfolipidsꢀ (C)ꢀ Applicationꢀ toꢀ malhamensilipinꢀ A.
Weꢀreasonedꢀthatꢀaꢀcatalyticꢀdeoxydichlorinationꢀreactionꢀ eitherꢀdiastereoisomericꢀseries,ꢀwereꢀprojectedꢀtoꢀariseꢀfromꢀ
wouldꢀprovideꢀaꢀpowerfulꢀalternativeꢀtoꢀalkeneꢀdichlorinationꢀ enoateꢀ10,ꢀitselfꢀderivedꢀfromꢀE-2-undecenal.ꢀꢀ
andꢀ inꢀ 2011ꢀ weꢀ reportedꢀ aꢀ catalyticꢀ reactionꢀ thatꢀ generatesꢀ
16
CO2ꢀ andꢀ COꢀ asꢀ theꢀ soleꢀ by-productsꢀ (Schemeꢀ 2A). ꢀ Theꢀ
integrationꢀ ofꢀ thisꢀ reactionꢀ intoꢀ anꢀ iterativeꢀ
epoxidation/chlorinationꢀ sequenceꢀ (Schemeꢀ 2B)ꢀ providesꢀ aꢀ
generalꢀ andꢀ systematicꢀ approachꢀ toꢀ theꢀ chlorine-ꢀ andꢀ
hydroxyl-containingꢀ acyclicꢀ stereochemicalꢀ arraysꢀ presentꢀ
withinꢀ theꢀ chlorosulfolipidsꢀ (Schemeꢀ 2B).ꢀ Significantly,ꢀ anyꢀ
stereochemicalꢀ permutationꢀ canꢀ beꢀ accessedꢀ usingꢀ thisꢀ
approachꢀbyꢀcontrolꢀofꢀepoxideꢀconfiguration.ꢀ
ResultsꢀandꢀDiscussionꢀ
Fragmentꢀsynthesisꢀ
Weꢀ beganꢀ withꢀ theꢀ synthesisꢀ ofꢀ theꢀ moreꢀ complexꢀ C12-C24ꢀ
fragmentꢀ (Schemeꢀ 3).ꢀ Thus,ꢀ catalyticꢀ enantioselectiveꢀ
nucleophilicꢀ epoxidationꢀ ofꢀ enalꢀ 11,18 19 ꢀ providedꢀ theꢀ
,
correspondingꢀ epoxideꢀ 12ꢀ inꢀ excellentꢀ yieldꢀ andꢀ 97:3ꢀ
enantiomericꢀratio.ꢀTheꢀconversionꢀofꢀtheꢀepoxideꢀintoꢀenoateꢀ
Hereinꢀ weꢀ demonstrateꢀ theꢀ powerꢀ ofꢀ theꢀ iterativeꢀ
epoxidation/chlorinationꢀstrategyꢀ(Schemeꢀ2B)ꢀwithꢀaꢀcatalyticꢀ
1
reaction,ꢀ whichꢀ providedꢀ theꢀ enoateꢀ withꢀ aꢀ d.r.ꢀ inꢀ excessꢀ ofꢀ
0ꢀ wasꢀ effectedꢀ throughꢀ aꢀ Horner-Wadsworth-Emmonsꢀ
4f
16
enantioselectiveꢀ formalꢀ synthesisꢀ ofꢀ malhamensilipinꢀ A ꢀ (2)ꢀ
andꢀ stereoisomericꢀ analogues.ꢀ Weꢀ alsoꢀ illustrateꢀ theꢀ
2
0:1.ꢀ Phosphorus(V)-mediatedꢀ catalyticꢀ deoxydichlorination ꢀ
ofꢀthisꢀsubstrateꢀaffordedꢀdichlorideꢀ13ꢀwithꢀtheꢀrequiredꢀC15-
C16ꢀsynꢀstereochemistryꢀinꢀ51%ꢀisolatedꢀyield.ꢀBy-productꢀ14ꢀ
accountedꢀforꢀtheꢀremainderꢀofꢀtheꢀmass-balanceꢀandꢀisꢀmostꢀ
1
7
applicabilityꢀofꢀCarreira’sꢀNMRꢀdatabase ꢀforꢀtheꢀassignmentꢀ
ofꢀpolychlorinatedꢀstereotetradsꢀandꢀstereohexads.ꢀFinally,ꢀweꢀ
analyseꢀ ring-openingꢀ reactionsꢀ ofꢀ γ,δ-dichlorovinylꢀ epoxidesꢀ
andꢀreportꢀcomputationalꢀstudiesꢀthatꢀgiveꢀnewꢀinsightsꢀintoꢀ
theꢀstructureꢀofꢀtheꢀchloroniumꢀionꢀintermediatesꢀwhichꢀhaveꢀ
beenꢀproposedꢀtoꢀinterveneꢀinꢀtheseꢀreactions.ꢀ
likelyꢀ derivedꢀ fromꢀ aꢀ competingꢀ eliminationꢀ fromꢀ theꢀ
chloroalkoxyphosphoniumꢀsaltꢀintermediateꢀA.20 ꢀꢀ
SynthesisꢀPlanꢀ
OurꢀretrosyntheticꢀanalysisꢀofꢀmalhamensilipinꢀAꢀ(Schemeꢀ2C)ꢀ
isꢀbasedꢀuponꢀthreeꢀiterationsꢀofꢀtheꢀepoxidation/chlorinationꢀ
sequenceꢀforꢀtheꢀconstructionꢀofꢀtheꢀC11-C16ꢀstereohexadꢀandꢀ
involvesꢀ epoxidesꢀ 10,ꢀ 7ꢀ andꢀ 6ꢀ asꢀ intermediates.ꢀ Whileꢀ theꢀ
stereochemicalꢀ outcomeꢀ ofꢀ theꢀ twoꢀ deoxydichlorinationꢀ
processesꢀ wasꢀ secure,ꢀ theꢀ ringꢀ openingꢀ ofꢀ epoxideꢀ 7ꢀ couldꢀ
occurꢀ withꢀ eitherꢀ retentionꢀ orꢀ inversionꢀ ofꢀ configurationꢀ atꢀ
5
C13 ꢀ andꢀ thereforeꢀ bothꢀ C13ꢀ diastereoisomers,ꢀ 7aꢀ andꢀ 7bꢀ
wereꢀ targeted.ꢀ Disconnectionꢀ ofꢀ theꢀ C11-C12ꢀ E-olefinꢀ wasꢀ
predicatedꢀ uponꢀ theꢀ modifiedꢀ Julia-Kocienskiꢀ olefinationꢀ andꢀ
ledꢀtoꢀsulfoneꢀ8ꢀandꢀaldehydesꢀ9aꢀandꢀ9b.ꢀTheꢀaldehydes,ꢀinꢀ
Thisꢀjournalꢀisꢀ©ꢀTheꢀRoyalꢀSocietyꢀofꢀChemistryꢀ20xxꢀ
J.ꢀName.,ꢀ2013,ꢀ00,ꢀ1-3ꢀ|ꢀ2ꢀꢀ
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Page 3 of 11
Pleas Ce hꢀ d eo mꢀ ni oc ta ꢀ al dS jcu i se t nꢀ mc ea rginsꢀ
ChemicalꢀScienceꢀ
ꢀEDGEꢀARTICLEꢀ
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stereochemicalꢀ differenceꢀ atꢀ C10)ꢀ andꢀ Vanderwal,ꢀ whoꢀ
O
P
Ph
Ph
OTMS
DOI: 10.1039/C6SC03012B
CO2Et
introducedꢀ theꢀ C12ꢀ andꢀ C13ꢀ hydroxylꢀ groupsꢀ afterꢀ
8
dichlorination. ꢀ Inspectionꢀ ofꢀ theꢀ crystalꢀ structureꢀ ofꢀ 15ꢀ
N
H
EtO
a)
b)
OEt
NaH
(
10 mol%), H O
O
2
2
Me
Me
indicatedꢀaꢀgaucheꢀconformationꢀwithꢀrespectꢀtoꢀtheꢀC15ꢀandꢀ
C16ꢀchlorineꢀatomsꢀandꢀthatꢀtheꢀC14ꢀhydroxylꢀandꢀC15ꢀchlorineꢀ
areꢀorientedꢀantiꢀwithꢀrespectꢀtoꢀeachꢀother.ꢀAnalysisꢀofꢀtheꢀ
relevantꢀ vicinalꢀ couplingꢀ constantsꢀ (Schemeꢀ 4)ꢀ revealedꢀ thatꢀ
theꢀmoleculeꢀadoptsꢀtheꢀsameꢀconformationꢀinꢀsolution.ꢀTheꢀ
diastereoisomericꢀepoxideꢀ9bꢀwasꢀpreparedꢀviaꢀreductionꢀofꢀ13ꢀ
toꢀaffordꢀallylicꢀalcoholꢀ17ꢀfollowedꢀbyꢀSharplessꢀepoxidationꢀ
andꢀoxidationꢀwithꢀDess-Martinꢀperiodinane.ꢀ
O
O
(92% >20:1 d.r.)
7
(91%, 97.3 e.r.)
7
1
2
11
c)
Ph PO (15 mol%)
3
Cl
O
O
O
O
(COCl)2 (1.3 equiv.)
Me
Me
Me
OEt
OEt
OEt
7
(51%)
7
Cl
1
0
Ph
Ph
1
3 (51%)
Cl
P
O
Ph
O
1
5
Me
Havingꢀ establishedꢀ reliableꢀ andꢀ selectiveꢀ synthesisꢀ routesꢀ
toꢀtheꢀrequiredꢀC12-C24ꢀaldehydes,ꢀweꢀinvestigatedꢀtheꢀcriticalꢀ
nucleophilicꢀringꢀopeningꢀofꢀtheꢀC13-C14ꢀepoxide.ꢀSimilarꢀringꢀ
openingꢀ reactionsꢀ hadꢀ beenꢀ observedꢀ toꢀ takeꢀ placeꢀ withꢀ
OEt
7
7
H
Cl
via A
Cl
1
4 (45%)
ꢀ
Schemeꢀ3ꢀTowardsꢀtheꢀC12-C24ꢀfragment.ꢀReagentsꢀandꢀconditions:ꢀa)ꢀ10ꢀmol%ꢀ
catalyst,ꢀH ,ꢀCHCl ,ꢀr.t.,ꢀ91%,ꢀ97:3ꢀe.r.;ꢀb)ꢀNaH,ꢀTHFꢀ–78ꢀ°Cꢀtoꢀr.t.,ꢀ92%,ꢀ>20:1ꢀ
PO,ꢀ1.3ꢀequiv.ꢀ(COCl) ,ꢀC ,ꢀ80ꢀ°C,ꢀ51%ꢀ
5,7a
8ꢀ
retention ꢀandꢀinversionꢀofꢀconfigurationꢀatꢀC13. Inꢀtheꢀfirstꢀ
instanceꢀ weꢀ investigatedꢀ chlorohydrinꢀ formationꢀ onꢀ modelꢀ
compoundꢀ 19,ꢀ preparedꢀ fromꢀ aldehydeꢀ 9aꢀ viaꢀ aꢀ Horner-
Wadsworth-Emmonsꢀreactionꢀ(85%,ꢀ>20:1ꢀd.r.,ꢀSchemeꢀ4B).ꢀꢀ
Treatmentꢀ ofꢀ 19ꢀ withꢀ etherealꢀ HClꢀ affordedꢀ chlorohydrinꢀ
2
O
2
3
d.r.;ꢀc)ꢀ15ꢀmol%ꢀPh
ꢀ
3
2
6 6
H
Withꢀ intermediateꢀ 13ꢀ inꢀ hand,ꢀ theꢀ twoꢀ diastereoisomericꢀ
C12-C24ꢀaldehydesꢀ9aꢀandꢀ9bꢀwereꢀpreparedꢀ(Schemeꢀ4A).ꢀAꢀ
sequenceꢀ consistingꢀ ofꢀ diastereoselectiveꢀ Upjohnꢀ
dihydroxylationꢀ (81%,ꢀ 10:1ꢀ d.r.),ꢀ cyclizationꢀ andꢀ reductionꢀ
2
0ꢀasꢀaꢀsingleꢀdiastereoisomer,ꢀtheꢀstereochemistryꢀofꢀwhichꢀ
1
wasꢀ assignedꢀ viaꢀ X-rayꢀ crystallographyꢀ andꢀ Hꢀ NMRꢀ analysisꢀ
(Schemeꢀ4B).ꢀTheseꢀdataꢀconfirmꢀinversionꢀofꢀconfigurationꢀatꢀ
C13ꢀ andꢀ henceꢀ theꢀ formationꢀ ofꢀ theꢀ desiredꢀ syn/anti/synꢀ
stereotetrad.ꢀTheꢀstereochemistryꢀofꢀ20ꢀcouldꢀalsoꢀbeꢀassignedꢀ
2
1
(15→16→9a,ꢀ Schemeꢀ 4)ꢀ affordedꢀ epoxideꢀ 9a. ꢀ Theꢀ
stereochemicalꢀoutcomeꢀofꢀtheꢀdihydroxylationꢀwasꢀconfirmedꢀ
byꢀ anꢀ X-rayꢀ crystalꢀ structureꢀ ofꢀ 15ꢀ andꢀ isꢀ inꢀ agreementꢀ withꢀ
5
resultsꢀpreviouslyꢀobtainedꢀbyꢀCarreira ꢀ(notwithstandingꢀtheꢀ
17a
usingꢀ modelꢀ compoundsꢀ inꢀ Carreira’sꢀ NMRꢀ database.
ꢀ
(
A)
Cl
O
Cl OH
O
Cl
Cl
a) OsO , NMO
b) Tf
O, DBU
O
c) DIBALH
(94%)
O
4
2
Me
Me
Me
Me
OEt
OEt
7
(81%, 10:1 d.r.)
7
(71%)
7
7
Cl
Cl OH
15
Cl
16
CO Et
Cl
9a C13-(R)
2
O
1
3
relevant 1H NMR
data (CDCl
C12-C24 fragment
1
6
)
3
1
4
C16-C15 3JHH=1.8 Hz
C15-C14 3JHH=9.6 Hz
C14-C13 3JHH=0.6 Hz
Cl-C16-C15-Cl 67.8o
1
5
Cl
Cl
Cl
O
d) DIBALH
e) Ti(OiPr) ,(-)-DET,tBuOOH
4
f) Dess-Martin
O 12
Me
Me
Me
24
OH
OH
7
O
(89%)
(64%, >95:5 d.r.)
7
7
Cl
1
Cl
18
Cl
9b C13-(S)
7
C12-C24 fragment
(
B)
a)
O
P
Cl
O
Cl
CO
Et
NaH
Me
O
2
Cl OH
O
Me
EtO
7
b) ethereal HCl
94%)
OEt
85% >20:1 d.r.)
Me
7
Cl
OEt
Cl
(
7
(
O
Cl
Cl
20
CO Et
2
9
a
19
Cl OH
C16-C15 3JHH=1.5 Hz
C15-C14 3JHH=9.4 Hz
C4-C5 3JHH=1.6 Hz
5
3
OH C3-C4 3JHH=9.5 Hz
C2-C3 3JHH=1.2 Hz
Me
16
14
Cl
Cl
C14-C13
3
JHH=1.4 Hz
relevant 1H NMR data (CDCl)3
relevant 1H NMR data (CDCl)3
2
1
20 (malhamensilipin A numbering)
ꢀ
Schemeꢀ4ꢀ(A)ꢀCompletionꢀofꢀtheꢀdiastereoisomericꢀC12-C24ꢀfragmentsꢀ9aꢀandꢀ9bReagentsꢀandꢀconditions:ꢀa)ꢀ5ꢀmol%ꢀOsO
10:1ꢀdr;ꢀb)ꢀTf O,ꢀDABCO,ꢀCH Cl ,ꢀ−78ꢀ°Cꢀtoꢀr.ꢀt.,ꢀ16ꢀh,ꢀ71%;ꢀc)ꢀDIBALH,ꢀtoluene,ꢀ−78ꢀ°C,ꢀ1ꢀh,ꢀ94%;ꢀd)ꢀDIBALH,ꢀtoluene,ꢀ0ꢀ°C,ꢀ15ꢀmin,ꢀ89%;ꢀe)ꢀ(−)-DET,ꢀTi(Oi-Pr)4,ꢀt-
BuOOH,ꢀCH Cl ,ꢀ−20ꢀ°C,ꢀ24ꢀh,ꢀ64%;ꢀf)ꢀDess-Martinꢀperiodinane,ꢀCH Cl ,ꢀr.ꢀt.,ꢀ3ꢀh.ꢀ(B)ꢀOpeningꢀofꢀtheꢀC13-C14ꢀepoxideꢀwithꢀinversionꢀofꢀconfigurationꢀatꢀC13ꢀinꢀaꢀmodelꢀ
4 2
,ꢀNMO,ꢀ2:1ꢀacetone/H O,ꢀr.ꢀt.,ꢀ16ꢀh,ꢀ81%,ꢀ
>
2
2
2
2
2
2
2
2
systemꢀReagentsꢀandꢀconditions:ꢀa)ꢀNaH,ꢀTHF,ꢀ−78ꢀ°Cꢀtoꢀr.ꢀt.,ꢀ2ꢀh,ꢀ85%,ꢀ>20:1ꢀE/Z;ꢀb)ꢀHCl•Et O,ꢀ0ꢀ°Cꢀtoꢀr.ꢀt.,ꢀ16ꢀh,ꢀ94%.ꢀ
ꢀ
ꢀ
Thisꢀjournalꢀisꢀ©ꢀTheꢀRoyalꢀSocietyꢀofꢀChemistryꢀ20xxꢀ
J.ꢀName.,ꢀ2013,ꢀ00,ꢀ1-3ꢀ|ꢀ3ꢀ
Pleaseꢀdoꢀnotꢀadjustꢀmarginsꢀ

Pleas Ce hꢀ d eo mꢀ ni oc ta ꢀ al dS jcu i se t nꢀ mc ea rginsꢀ
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17a
Thus,ꢀ comparisonꢀ ofꢀ 20ꢀ withꢀ referenceꢀ compoundꢀ 21
ꢀ productꢀ 26ꢀ wasꢀ obtainedꢀ inꢀ goodꢀ yieldꢀ andꢀ excellentꢀ
DOI: 10.1039/C6SC03012B
3
revealedꢀ veryꢀ closelyꢀ matchingꢀ JHHꢀ couplingꢀ constants,ꢀ stereoselectivityꢀ(Schemeꢀ6).ꢀWhileꢀthisꢀreagentꢀhasꢀbeenꢀusedꢀ
17aꢀ
highlightingꢀtheꢀutilityꢀofꢀtheꢀdatabaseꢀapproachꢀandꢀgivingꢀusꢀ forꢀ ringꢀ openingꢀ reactionsꢀ ofꢀ hydroxyepoxides; itꢀ hasꢀ notꢀ
confidenceꢀinꢀitsꢀapplicationꢀtoꢀmoreꢀcomplexꢀfragmentsꢀinꢀtheꢀ previouslyꢀ beenꢀ appliedꢀ toꢀ γ-δ-chlorovinylꢀ epoxidesꢀ andꢀ theꢀ
absenceꢀ ofꢀ X-rayꢀ crystallographicꢀ data.ꢀ Followingꢀ thisꢀ highꢀ selectivityꢀ obtainedꢀ isꢀ noteworthy.ꢀ Toꢀ assignꢀ theꢀ
3
encouragingꢀ resultꢀ weꢀ focusedꢀ onꢀ theꢀ synthesisꢀ ofꢀ theꢀ lessꢀ configurationꢀ atꢀ C13ꢀ weꢀ againꢀ comparedꢀ theꢀ JHHꢀ couplingꢀ
complexꢀ C1-C11ꢀ fragmentꢀ (Schemeꢀ 5).ꢀ Toꢀ thisꢀ end,ꢀ PCC- constantsꢀ ofꢀ theꢀ keyꢀ C13-C16ꢀ regionꢀ withꢀ twoꢀ relevantꢀ
mediatedꢀ oxidationꢀ ofꢀ 22ꢀ affordedꢀ aldehydeꢀ 23,ꢀ whichꢀ wasꢀ (enantiomeric)ꢀ fragmentsꢀ fromꢀ Carreira’sꢀ databaseꢀ (Schemeꢀ
17a
subjectedꢀ toꢀ pyrrolidine-catalyzedꢀ α,α-dichlorinationꢀ usingꢀ 6). ꢀWeꢀbeganꢀbyꢀcomparingꢀtheꢀmajorꢀchlorohydrinꢀproductꢀ
8
NCS. ꢀ Theꢀ highlyꢀ sensitiveꢀ aldehydeꢀ soꢀ obtainedꢀ wasꢀ 26ꢀ withꢀ modelꢀ compoundꢀ 21,ꢀ whichꢀ hasꢀ theꢀ relativeꢀ
immediatelyꢀreducedꢀtoꢀtheꢀcorrespondingꢀalcoholꢀtoꢀaffordꢀ24ꢀ stereochemistryꢀ requiredꢀ forꢀ theꢀ naturalꢀ productꢀ andꢀ
inꢀ 93%ꢀ isolatedꢀ yieldꢀ overꢀ theꢀ twoꢀ steps.ꢀ Installationꢀ ofꢀ theꢀ correspondsꢀ toꢀ epoxideꢀ openingꢀ withꢀ inversionꢀ atꢀ C13.ꢀ Aꢀ
3
requiredꢀphenyltetrazolesulfonylꢀgroupꢀwasꢀthenꢀaccomplishedꢀ significantꢀ discrepancyꢀ betweenꢀ theꢀ C13-C14ꢀ andꢀ C2-C3ꢀ JHHꢀ
inꢀtwoꢀstraightforwardꢀstepsꢀafterꢀprotectionꢀofꢀtheꢀalcoholꢀtoꢀ valuesꢀ wasꢀ observed.ꢀ However,ꢀ furtherꢀ comparisonꢀ withꢀ
affordꢀcompoundꢀ8.ꢀ
modelꢀcompoundꢀ27ꢀrevealedꢀveryꢀcloselyꢀmatchingꢀcouplingꢀ
constants.ꢀ Therefore,ꢀ theꢀ stereochemistryꢀ wasꢀ assignedꢀ asꢀ
depictedꢀinꢀstructureꢀ26,ꢀwhichꢀisꢀtheꢀresultꢀofꢀepoxideꢀopeningꢀ
withꢀretentionꢀofꢀstereochemistryꢀatꢀC13.ꢀAsꢀnotedꢀaboveꢀthisꢀ
outcomeꢀ hasꢀ beenꢀ observedꢀ before,ꢀ butꢀ contrastsꢀ withꢀ theꢀ
resultꢀ obtainedꢀ withꢀ modelꢀ compoundꢀ 19ꢀ (Schemeꢀ 4B),ꢀ
pointingꢀtoꢀaꢀpotentialꢀelectronicꢀeffectꢀ(videꢀinfra).ꢀ
a) PCC
80%)
Br
Br
OH
Br
Br
O
8
(
8
2
2
23
b) NCS, pyrrolidine
c) NaBH4
Cl Cl
Cl Cl
d) TIPSOTf
(97%)
OTIPS
OH
N
8
8
(93% 2 steps)
O O
7
2
5
24
N
S
O O
OTIPS
Cl
N
O
1
7
N
N
Cl Cl
Me
S
e) tetrazole sodium thiolate
f) (NH ) Mo O 5 mol%, H O
2
OTIPS
Ph
7
N
11
8
a) KHMDS, 18-C-6
Cl
4
6
7
24
2
N
Cl Cl
N
Ph
Cl
(86% 4:1 E:Z)
O
(96% 2 steps)
7
8
C1-C11 fragment
Me
TIPSO
ꢀ
7
Cl Cl
7a
Cl
Schemeꢀ5ꢀSynthesisꢀofꢀtheꢀC1-C11ꢀfragmentꢀ8.ꢀReagentsꢀandꢀconditions:ꢀa)ꢀPCC,ꢀ
CH Cl ,ꢀr.ꢀt.,ꢀ16ꢀh,ꢀ80%;ꢀb)ꢀNCS,ꢀ20ꢀmol%ꢀpyrrolidine,ꢀ1,2-dichloroethane,ꢀ60ꢀ°C,ꢀ3ꢀ
h;ꢀc)ꢀNaBH ,ꢀEtOH,ꢀ0ꢀ°Cꢀtoꢀr.ꢀt.,ꢀ1ꢀh,ꢀ93%ꢀoverꢀtwoꢀsteps;ꢀd)ꢀTIPSOTf,ꢀ2,6-lutidine,ꢀ
CH Cl ,ꢀr.ꢀt.,ꢀ2ꢀh,ꢀ97%;ꢀe)ꢀsodiumꢀ1-phenyl-1H-tetrazole-5-thiolate,ꢀDMF,ꢀr.ꢀt.,ꢀ4ꢀh,ꢀ
O
9
a
2
2
4
2
2
Cl OH
quantitative;ꢀf)ꢀ5ꢀmol%ꢀammoniumꢀheptamolybdate,ꢀH
h,ꢀ96%.ꢀ
2 2
O ,ꢀEtOH,ꢀ0ꢀ°Cꢀtoꢀr.ꢀt.,ꢀ16ꢀ
7
Me
Me
15
1
3
b) Ti(OiPr)3Cl
OTIPS
7
Cl Cl
Cl Cl
(66% >25:1 d.r.)
ꢀ
FragmentꢀCouplingꢀandꢀChlorohydrinꢀFormationꢀ
2
6
Cl OH
Cl OH
Cl OH
Ourꢀ synthesisꢀ planꢀ (Schemeꢀ 2C)ꢀ isꢀ basedꢀ onꢀ stereospecificꢀ
chlorinationꢀ reactionsꢀ ofꢀ epoxidesꢀ toꢀ constructꢀ theꢀ C11-C16ꢀ
stereohexad.ꢀ Basedꢀ uponꢀ thisꢀ analysis,ꢀ anꢀ E-selectiveꢀ
olefinationꢀ reactionꢀ wasꢀ requiredꢀ forꢀ theꢀ fragmentꢀ couplingꢀ
15
1
3
5
3
5
3
Me
OH
Me
OH
7
Cl Cl
Cl Cl
27
Cl Cl
21
2
6
C16-C15 3JHH=1.5 Hz
C15-C14 3JHH=9.7 Hz
C14-C13 3JHH=2.1 Hz
C5-C4 3JHH=1.8 Hz
C4-C3 3JHH=9.6 Hz
C3-C2 3JHH=2.8 Hz
C5-C4 3JHH=1.6 Hz
C4-C3 3JHH=9.5 Hz
C3-C2 3JHH=1.2 Hz
2
2
andꢀweꢀselectedꢀtheꢀJulia-Kocienskiꢀreactionꢀforꢀthisꢀpurpose. ꢀ
Withꢀtheꢀrequisiteꢀfragmentsꢀavailableꢀinꢀsufficientꢀquantities,ꢀ
weꢀ examinedꢀ theꢀ keyꢀ olefinationꢀ reactionꢀ usingꢀ aldehydeꢀ 9aꢀ
relevant 1H NMR data (CDCl)3
ꢀ
23
Schemeꢀ6ꢀFragmentꢀcouplingꢀandꢀinstallationꢀofꢀC13ꢀchlorineꢀwithꢀretentionꢀofꢀ
configurationꢀReagentsꢀandꢀconditions:ꢀa)ꢀKHMDS,ꢀ18-crown-6,ꢀTHF,ꢀ–78ꢀºCꢀtoꢀ
r.t.,ꢀ30ꢀsec.,ꢀ86%,ꢀ4:1ꢀE:Z;ꢀb)ꢀTiCl(OiPr) ,ꢀC H ,ꢀ–20ꢀºC,ꢀ66%,ꢀ>25:1ꢀd.r.ꢀ
3 6 6
(
Schemeꢀ6).ꢀTheꢀolefinationꢀreactionꢀwasꢀexaminedꢀinꢀdetail ꢀ
beginningꢀ withꢀ theꢀ originalꢀ conditionsꢀ reportedꢀ byꢀ Kocienskiꢀ
beforeꢀinvestigatingꢀconditionsꢀreportedꢀbyꢀJacobsenꢀ(LiHMDS,ꢀ
Inꢀ orderꢀ toꢀ confirmꢀ ourꢀ stereochemicalꢀ assignmentsꢀ andꢀ
investigateꢀ theꢀ finalꢀ epoxidationꢀ andꢀ deoxydichlorinationꢀ
sequence,ꢀcompoundꢀ26ꢀwasꢀtakenꢀforwardꢀ(Schemeꢀ7).ꢀThusꢀ
electrophilicꢀ epoxidationꢀ ofꢀ 26ꢀ withꢀ mCPBAꢀ affordedꢀ aꢀ
separableꢀ1:1ꢀmixtureꢀofꢀepoxidesꢀ28ꢀandꢀ29ꢀ(Schemeꢀ7).ꢀSinceꢀ
itꢀwasꢀnotꢀpossibleꢀtoꢀassignꢀtheꢀconfigurationꢀatꢀC11ꢀorꢀC12ꢀ
theꢀstereochemicalꢀassignmentꢀwasꢀcarriedꢀoutꢀretrospectivelyꢀ
afterꢀsuccessfulꢀdeoxydichlorinationꢀofꢀbothꢀepoxidesꢀ(Schemeꢀ
24
25
DMF/HMPA) ꢀ and,ꢀ finally,ꢀ Popisilꢀ (KHMDS,ꢀ 18-C-6). ꢀ Theꢀ
optimizedꢀ couplingꢀ process,ꢀ fromꢀ whichꢀ alkeneꢀ 7aꢀ wasꢀ
obtainedꢀ inꢀ 86%ꢀ yieldꢀ andꢀ 4:1ꢀ d.r.,ꢀ isꢀ depictedꢀ inꢀ Schemeꢀ 6.ꢀ
Sinceꢀ 7aꢀ wasꢀ inseparableꢀ fromꢀ itsꢀ Z-isomer,ꢀ theꢀ keyꢀ epoxideꢀ
openingꢀandꢀintroductionꢀofꢀtheꢀC13ꢀchlorineꢀsubstituentꢀwasꢀ
investigatedꢀ usingꢀ theꢀ crudeꢀ product.ꢀ Afterꢀ someꢀ
2
3
experimentationꢀwithꢀalternativeꢀreagents, ꢀnamely,ꢀetherealꢀ
HClꢀ andꢀ thionylꢀ chloride,ꢀ weꢀ discoveredꢀ thatꢀ chlorotitaniumꢀ
isopropoxideꢀ inꢀ tolueneꢀ wasꢀ aꢀ veryꢀ effectiveꢀ reagentꢀ forꢀ theꢀ
conversionꢀofꢀγ-δ-chlorovinylꢀepoxidesꢀintoꢀchlorohydrinsꢀandꢀ
7
).
Thisꢀjournalꢀisꢀ©ꢀTheꢀRoyalꢀSocietyꢀofꢀChemistryꢀ20xxꢀ
J.ꢀName.,ꢀ2013,ꢀ00,ꢀ1-3ꢀ|ꢀ4ꢀꢀ
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DOI: 10.1039/C6SC03012B
Cl OH
Cl OH Cl
O
b) Ph PO, (COCl)
3 2
7
7
Me
Me
13
Me
Me
13
OTIPS
OTIPS
OTIPS
OTIPS
7
11
7
Cl Cl
Cl Cl
Cl Cl Cl Cl Cl
30 (28%)
Cl OH
7
a) mCPBA
28 (35%)
Me
OTIPS
7
Cl OH
Cl OH Cl
Cl Cl
Cl Cl
O
1
3
7
c) Ph
PO, (COCl)
3
2
13
7
2
6
7
11
7
Cl Cl
Cl Cl
9 (35%)
Cl Cl Cl Cl Cl
2
31 (35%)
Cl OH Cl
H
H
Cl OH Cl
H
R2
R2
Cl
Cl
Cl
7
7
Me
13
Me
13
OTIPS
OTIPS
7
R1
7
R1
Cl
Cl Cl Cl Cl Cl
0 C12-C13 3JHH = 6.0 Hz
Cl Cl Cl Cl Cl
31 C12-C13 3J = 10.5 Hz
H
3
5.8-8.2 Hz syn
8.0-10.5 Hz anti
HH
ꢀ
Schemeꢀ7ꢀFinalꢀepoxidation/deoxydichlorinationꢀandꢀsynthesisꢀofꢀdiastereoisomericꢀanalogsꢀReagentsꢀandꢀconditions:ꢀa)ꢀmCPBA,ꢀCH
yield,ꢀ1:1ꢀ29ꢀandꢀ30;ꢀb)ꢀ1.5ꢀequiv.ꢀPh PO,ꢀ1.5ꢀequiv.ꢀ(COCl) ,ꢀtoluene,ꢀ90ꢀ°C,ꢀ3ꢀh,ꢀ27%;ꢀc)ꢀ1.5ꢀequiv.ꢀPh PO,ꢀ1.5ꢀequiv.ꢀ(COCl) ,ꢀtoluene,ꢀ90ꢀ°C,ꢀ3ꢀhꢀ,ꢀ35%.ꢀ
2
Cl ,ꢀ0ꢀ°Cꢀtoꢀr.t.,ꢀ70%ꢀcombinedꢀ
ꢀ
2
3
2
3
2
Thisꢀ transformationꢀ occurredꢀ inꢀ 28%ꢀ andꢀ 36%ꢀ isolatedꢀ yieldꢀ forꢀ
epoxidesꢀ 28ꢀ andꢀ 29ꢀ respectively.ꢀ Inꢀ eachꢀ caseꢀ by-productsꢀ arisingꢀ
fromꢀ eliminationꢀ wereꢀ alsoꢀ observed.ꢀ Givenꢀ thatꢀ theꢀ
deoxydichlorinationꢀ reactionꢀ takesꢀ placeꢀ withꢀ inversionꢀ ofꢀ
configurationꢀatꢀbothꢀstereogenicꢀcentersꢀofꢀtheꢀepoxide,ꢀtheꢀC11-
C12ꢀ relativeꢀ stereochemistryꢀ inꢀ bothꢀ compoundsꢀ wasꢀ assumedꢀ toꢀ
beꢀ syn.ꢀ Toꢀ determineꢀ theꢀ relativeꢀ configurationꢀ betweenꢀ theꢀ
ꢀ
ꢀ
O O
S
7
N
OTIPS
N
N
Cl Cl
N
Ph
Cl
Cl
8
a) KHMDS, 18-C-6
O
3
15
7
Me
chlorinesꢀatꢀC12ꢀandꢀC13ꢀtheꢀ JHHꢀcouplingꢀconstantsꢀwereꢀexaminedꢀ
OTIPS
(48% 7:1 E:Z)
7
1
7a
(
Schemeꢀ7).ꢀꢀBasedꢀuponꢀCarreira’sꢀpreviousꢀstudy, ꢀaꢀvalueꢀofꢀ6.0ꢀ
Cl
Cl Cl
O
12
Me
Hzꢀ isꢀ indicativeꢀ ofꢀ aꢀ synꢀ relationshipꢀ betweenꢀ C13ꢀ andꢀ C12ꢀ and,ꢀ
therefore,ꢀ compoundꢀ 30ꢀ wasꢀ assignedꢀ asꢀ havingꢀ aꢀ
syn,anti,anti,syn,synꢀ stereohexad.ꢀ Theꢀ higherꢀ valueꢀ ofꢀ 10.5ꢀ Hzꢀ isꢀ
characteristicꢀ ofꢀ anꢀ antiꢀ relationshipꢀ betweenꢀ theꢀ C13ꢀ andꢀ C12ꢀ
chlorineꢀ substituentsꢀ andꢀ henceꢀ aꢀ syn,anti,anti,anti,synꢀ
stereohexad,ꢀasꢀdepictedꢀinꢀstructureꢀ31.ꢀWhileꢀnotꢀprovidingꢀtheꢀ
correctꢀ stereochemistryꢀ requiredꢀ forꢀ malhamensilipinꢀ A,ꢀ theseꢀ
studiesꢀestablishedꢀtheꢀviabilityꢀofꢀourꢀsynthesisꢀplanꢀbasedꢀuponꢀaꢀ
threefoldꢀ epxoditation/chlorinationꢀ approach.ꢀ Weꢀ nextꢀ soughtꢀ toꢀ
correctꢀtheꢀstereochemistryꢀatꢀC13ꢀinꢀorderꢀtoꢀcompleteꢀaꢀsynthesisꢀ
ofꢀmalhamensilipinꢀA.ꢀ
O
2
4
7
7b
Cl
9
b
Cl OH
1
3
7
b) Ti(OiPr)3Cl
71% >25:1 d.r.)
Me
15
OTIPS
7
(
Cl Cl
Cl Cl
3
2
Cl OH
Cl OH
Cl OH
15
1
3
Me
5
3
5
3
Me
OH
Me
OH
7
Cl Cl
Cl Cl
21
Cl Cl
27
3
2
C16-C15 3JHH=1.5 Hz
C15-C14 3JHH=9.4 Hz
C14-C13 3JHH=1.3 Hz
C5-C4 3JHH=1.6 Hz
C4-C3 3JHH=9.5 Hz
C3-C2 3JHH=1.2 Hz
C5-C4 3JHH=1.8 Hz
C4-C3 3JHH=9.6 Hz
C3-C2 3JHH=2.8 Hz
CompletionꢀofꢀtheꢀSynthesisꢀ
Givenꢀ thatꢀ theꢀ C13ꢀ epoxideꢀ openingꢀ hadꢀ beenꢀ observedꢀ toꢀ
takeꢀ placeꢀ withꢀ stereoretentionꢀ usingꢀ TiCl(OiPr)3,ꢀ weꢀ
relevant 1H NMR data (CDCl)3
ꢀ
progressedꢀtheꢀalternativeꢀC12-C24ꢀfragmentꢀ9bꢀwithꢀinvertedꢀ Schemeꢀ8ꢀSynthesisꢀofꢀtheꢀcarbonꢀskeletonꢀwithꢀinvertedꢀconfigurationꢀatꢀC13ꢀ
Reagentsꢀ andꢀ conditions:ꢀ a)ꢀ KHMDS,ꢀ 18-crown-6,ꢀ THF,ꢀ −78ꢀ °C,ꢀ 30ꢀs,ꢀ thenꢀ 10b,ꢀ
C13ꢀstereochemistryꢀ(Schemeꢀ8).ꢀToꢀthisꢀend,ꢀcouplingꢀwithꢀtheꢀ
−
3
78ꢀ°Cꢀtoꢀr.ꢀt.,ꢀ16ꢀh,ꢀ48%ꢀfromꢀ19,ꢀ7:1ꢀE/Z;ꢀb)ꢀTiCl(Oi-Pr) ,ꢀtoluene,ꢀ–20ꢀºC,ꢀ2ꢀh,ꢀ
C1-C11ꢀ sulfoneꢀ 8ꢀ underꢀ theꢀ previouslyꢀ identifiedꢀ conditionsꢀ 71%,ꢀ>25:1ꢀd.r.ꢀ
affordedꢀintermediateꢀ7bꢀwithꢀimprovedꢀselectivityꢀ(7:1ꢀd.r.),ꢀ
butꢀinꢀlowerꢀyieldꢀ–ꢀaꢀconsequenceꢀofꢀtheꢀrelativeꢀinstabilityꢀofꢀ
aldehydeꢀ 9bꢀ comparedꢀ toꢀ 9a.ꢀ Theꢀ criticalꢀ epoxideꢀ openingꢀ
reactionꢀwasꢀthenꢀinvestigatedꢀ(Schemeꢀ8).ꢀWeꢀassumedꢀthatꢀ
inꢀthisꢀstereochemicalꢀseriesꢀtheꢀepoxideꢀopeningꢀwouldꢀagainꢀ
takeꢀplaceꢀwithꢀretentionꢀofꢀconfigurationꢀatꢀC13ꢀwhenꢀusingꢀ
TiCl(OiPr)3ꢀandꢀthisꢀwasꢀconfirmedꢀbyꢀcomparisonꢀofꢀ32ꢀwithꢀ
Thisꢀ finalꢀ deoxydichlorinationꢀ processꢀ isꢀ noteworthyꢀ forꢀ
twoꢀ reasons:ꢀ (a)ꢀ theꢀ reactionꢀ isꢀ chemoselectiveꢀ –ꢀ theꢀ C14ꢀ
hydroxylꢀ groupꢀ doesꢀ notꢀ undergoꢀ deoxychlorination;ꢀ andꢀ (b)ꢀ
theꢀintroductionꢀofꢀchlorineꢀatꢀC12ꢀoccursꢀdespiteꢀtheꢀpresenceꢀ
ofꢀtheꢀflankingꢀchlorinesꢀatꢀC13ꢀandꢀC11.ꢀTheseꢀobservationsꢀ
demonstrateꢀ thatꢀ aꢀ combinationꢀ ofꢀ stericꢀ andꢀ electronicꢀ
effectsꢀ preventsꢀ activationꢀ ofꢀ theꢀ C14ꢀ hydroxylꢀ groupꢀ byꢀ theꢀ
electrophilicꢀchlorophosphoniumꢀsalt.ꢀꢀ
17a
modelꢀ compoundsꢀ 21ꢀ andꢀ 27 ꢀ (Schemeꢀ 8).ꢀ Subsequentꢀ
epoxidationꢀofꢀ32ꢀwithꢀmCPBAꢀ(Schemeꢀ9)ꢀgaveꢀtwoꢀseparableꢀ
epoxidesꢀ 6aꢀ andꢀ 6bꢀ inꢀ aꢀ 2:1ꢀ ratio.ꢀ Again,ꢀ stereochemicalꢀ
assignmentsꢀ ofꢀ theseꢀ keyꢀ intermediatesꢀ wereꢀ performedꢀ
retrospectivelyꢀ afterꢀ theꢀ introductionꢀ ofꢀ theꢀ finalꢀ twoꢀ
chlorines.ꢀ First,ꢀ weꢀ subjectedꢀ theꢀ minorꢀ diastereoisomerꢀ toꢀ
deoxydichlorinationꢀ andꢀ obtainedꢀ theꢀ correspondingꢀ
heptachlorinatedꢀcompoundꢀ33ꢀinꢀgoodꢀyieldꢀ(Schemeꢀ9).ꢀ
ꢀ
Theꢀconfigurationꢀofꢀ33ꢀwasꢀdeducedꢀbyꢀcomparisonꢀwithꢀ
17a
modelsꢀ 21ꢀ andꢀ 37, ꢀ whichꢀ containꢀ matchingꢀ stereotriadsꢀ
highlightedꢀinꢀblueꢀandꢀred).ꢀ
(
ꢀ
ꢀ
Thisꢀjournalꢀisꢀ©ꢀTheꢀRoyalꢀSocietyꢀofꢀChemistryꢀ20xxꢀ
J.ꢀName.,ꢀ2013,ꢀ00,ꢀ1-3ꢀ|ꢀ5ꢀꢀ
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Page 6 of 11
ꢀEDGEꢀARTICLEꢀ
ChemicalꢀScienceꢀ
View Article Online
DOI: 10.1039/C6SC03012B
Cl OH
Cl OH Cl
O
b)Ph3PO, (COCl)2
7
7
Me
Me
Me
Me
OTIPS
OTIPS
7
11
7
Cl OH
Cl Cl
Cl Cl
Cl Cl Cl Cl Cl
33 (60%)
7
a) mCPBA
Me
b
(29%)
6
OTIPS
7
Cl Cl
Cl Cl
Cl OH
Cl OH Cl
c)
Ph3PO, (COCl)2
O
3
2
7
7
OTIPS
OTIPS
7
11
7
Cl Cl
Cl Cl
Cl Cl Cl Cl Cl
6
a
(45%)
3
4 (64%)
SO H
3
SO Na
3
Cl
Cl
O
Cl
OSO H
3
Cl OH Cl
OH
Cl
O
Cl
Vanderwal
ref.8
e)SO3 py
d) TBAF
7
7
7
Me
Me
Me
Me
7
7
7
Cl Cl Cl Cl Cl
35 (>95%)
Cl Cl Cl
malhamensilipin A-(3)
OSO Na
3
Cl Cl Cl Cl Cl
36 (68%)
Cl OH Cl
Cl OH
OH Cl
Cl OH Cl
Cl OH Cl
13
Me
1
3
Me
13
HO
Me
Me
Me
5
3
OH
5
3
7
7
7
7
Cl Cl Cl
Cl Cl
21
Cl Cl
Cl Cl Cl
Cl Cl Cl
3
3
37
38
34
C16-C15 3JHH=1.6 Hz
C5-C4 3JHH=1.6 Hz
C4-C3 3JHH=9.5 Hz
C3-C2 3JHH=1.2 Hz
C16-C15 3JHH=1.3 Hz
C16-C15 3JHH=1.4 Hz
C15-C14 3JHH=9.5 Hz
C14-C13 3JHH=1.1 Hz
C13-C12 3JHH=10.3 Hz
C15-C14 3JHH=9.2 Hz
C14-C13 3JHH=1.0 Hz
C13-C12 3JHH=8.6 Hz
C15-C14 3JHH=9.3 Hz
C14-C13 3JHH=0.9 Hz
C13-C12 3JHH=8.6 Hz
C3-C2 3JHH=1.0 Hz
C4-C3 3JHH=10.3 Hz
C5-C4 3JHH=1.4 Hz
C12-C11 3JHH=1.4 Hz
C12-C11 3JHH=2.3 Hz
C12-C11 3JHH=2.1 Hz
ꢀ
Schemeꢀ9ꢀCompletionꢀofꢀaꢀformalꢀsynthesisꢀofꢀmalhamensilipinꢀAꢀReagentsꢀandꢀconditions:ꢀa)ꢀmCPBA,ꢀCH2Cl2,ꢀ0ꢀ°Cꢀtoꢀr.ꢀt.,ꢀ24ꢀh,ꢀ74%,ꢀ2:1ꢀ7a:7b;ꢀb)ꢀ1.5ꢀeq.ꢀPh
3
PO,ꢀ
.5ꢀeq.ꢀ(COCl) ,ꢀtoluene,ꢀ90ꢀ°C,ꢀ3ꢀh,ꢀ64%;ꢀc)ꢀ1.5ꢀeq.ꢀPh PO,ꢀ1.5ꢀeq.ꢀ(COCl) ,ꢀtoluene,ꢀ90ꢀ°C,ꢀ3ꢀhꢀ60%ꢀd)ꢀTBAF,ꢀAcOH,ꢀTHF,ꢀr.ꢀt.,ꢀ16ꢀh,ꢀquantitative;ꢀe)ꢀSO -pyridine,ꢀDMF,ꢀ
1
r.ꢀt.,ꢀ1ꢀh,ꢀ68%.ꢀꢀꢀꢀꢀ
2
3
2
3
ꢀ
Stereoretentiveꢀ Ringꢀ Openingꢀ Reactionsꢀ ofꢀ γ-ꢀ andꢀ δ-
Dichlorovinylepoxides:ꢀ Theꢀ Intermediacyꢀ ofꢀ Chloroniumꢀ
IonꢀIntermediates.ꢀꢀ
Theꢀ closeꢀ matchꢀ ofꢀ theꢀ relevantꢀ vicinalꢀ couplingꢀ
constantsꢀ areꢀ congruousꢀ withꢀ theꢀ non-naturalꢀ
syn/anti/syn/anti/synꢀstereochemistryꢀdepictedꢀinꢀstructureꢀ
Theꢀsynthesisꢀdescribedꢀinꢀtheꢀpreviousꢀsections,ꢀalongꢀwithꢀ
severalꢀ otherꢀ chlorosulfolipidꢀ syntheses,ꢀ reliedꢀ uponꢀ
3
3.ꢀ Withꢀ thisꢀ analysisꢀ inꢀ mind,ꢀ deoxydichlorinationꢀ ofꢀ theꢀ
majorꢀepoxideꢀ6aꢀwasꢀundertakenꢀwithꢀtheꢀexpectationꢀthatꢀ
theꢀ correctꢀ syn/anti/syn/syn/synꢀ stereochemistryꢀ wouldꢀ
result.ꢀ Theꢀ heptachlorinatedꢀ materialꢀ 34ꢀ wasꢀ obtainedꢀ inꢀ
goodꢀ yieldꢀ andꢀ comparedꢀ veryꢀ favourablyꢀ withꢀ modelꢀ
nucleophilicꢀ
openingꢀ
ofꢀ
γ,δ-dichlorovinylepoxideꢀ
intermediatesꢀ forꢀ theꢀ introductionꢀ ofꢀ theꢀ chlorohydrinꢀ
motif.ꢀ Theꢀ stereochemicalꢀ outcomeꢀ ofꢀ suchꢀ reactionsꢀ hasꢀ
beenꢀ shownꢀ toꢀ occurꢀ withꢀ bothꢀ retentionꢀ (e.g.ꢀ 7a→26,ꢀ
Schemeꢀ 6ꢀ andꢀ 7b→32,ꢀ Schemeꢀ 8)ꢀ andꢀ inversionꢀ (e.g.ꢀ
19→20,ꢀ Schemeꢀ 4B).ꢀ Stereoretentiveꢀ reactionsꢀ wereꢀ firstꢀ
observedꢀandꢀdocumentedꢀbyꢀCarreiraꢀduringꢀtheꢀsynthesisꢀ
4fꢀ
compoundꢀ 38,ꢀ whichꢀ containsꢀ anꢀ identicalꢀ stereohexad.
Furtherꢀ spectroscopicꢀ comparisonꢀ ofꢀ 34ꢀ withꢀ Vanderwal’sꢀ
8
TBDMSꢀ protectedꢀ analogue ꢀ confirmedꢀ theꢀ desiredꢀ
5
stereochemistry.ꢀ
ofꢀ mytilipinꢀ A ꢀ andꢀ haveꢀ subsequentlyꢀ beenꢀ observedꢀ byꢀ
7a
Inꢀ orderꢀ toꢀ completeꢀ aꢀ formalꢀ totalꢀ synthesisꢀ ofꢀ
malhamensilipinꢀ Aꢀ theꢀ silylꢀ etherꢀ protectingꢀ groupꢀ wasꢀ
removedꢀ inꢀ excellentꢀ yieldꢀ usingꢀ TBAFꢀ toꢀ affordꢀ diolꢀ 35,ꢀ
whichꢀ wasꢀ subsequentlyꢀ convertedꢀ intoꢀ diacidꢀ 36ꢀ usingꢀ
sulfurꢀ trioxideꢀ pyridineꢀ complex.ꢀ Compoundꢀ 36ꢀ hadꢀ
previouslyꢀ beenꢀ preparedꢀ byꢀ Vanderwalꢀ andꢀ wasꢀ theꢀ
penultimateꢀ intermediateꢀ inꢀ hisꢀ totalꢀ synthesisꢀ ofꢀ theꢀ
Vanderwal. ꢀ Carreiraꢀ hasꢀ proposedꢀ thatꢀ retentionꢀ ofꢀ
configurationꢀ occursꢀ asꢀ aꢀ resultꢀ ofꢀ aꢀ doubleꢀ inversionꢀ
processꢀinꢀwhichꢀanchimericꢀassistanceꢀfromꢀeitherꢀtheꢀγ-ꢀorꢀ
δ-chlorineꢀ substituentꢀ affordsꢀ aꢀ chloroniumꢀ ionꢀ
intermediate,ꢀ whichꢀ itselfꢀ undergoesꢀ subsequentꢀ
5
nucleophilicꢀ substitution. ꢀ Carreira’sꢀ analysisꢀ canꢀ beꢀ
transferredꢀ toꢀ theꢀ ringꢀ openingꢀ reactionsꢀ thatꢀ wereꢀ
discussedꢀinꢀtheꢀpreviousꢀsectionꢀofꢀthisꢀArticleꢀ(Schemeꢀ10).ꢀ
8
naturalꢀ product. ꢀ Allꢀ spectroscopicꢀ dataꢀ forꢀ 36ꢀ wereꢀ inꢀ
excellentꢀ agreementꢀ withꢀ thoseꢀ previouslyꢀ reported,ꢀ
therebyꢀ completingꢀ aꢀ 12-stepꢀ formalꢀ synthesisꢀ ofꢀ
malhamensilipinꢀAꢀ(3).ꢀ
ꢀ
ꢀ
Thisꢀjournalꢀisꢀ©ꢀTheꢀRoyalꢀSocietyꢀofꢀChemistryꢀ20xxꢀ
J.ꢀName.,ꢀ2013,ꢀ00,ꢀ1-3ꢀ|ꢀ6ꢀ
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Page 7 of 11
ChemicalꢀScienceꢀ
Pleas Ce ꢀhd eo mꢀ ni oc taꢀ al dS j cu ise t nꢀ mc ea rginsꢀ
ꢀEDGEꢀARTICLEꢀ
26
chlorineꢀsubstituentꢀonꢀC13ꢀinꢀeitherꢀaꢀ5ꢀorꢀ4-fused ꢀ(endo)ꢀ
(
A)
Cl
O
View Article Online
sense,ꢀ respectively.ꢀ Twoꢀ furtherꢀ possibleꢀ chloroniumꢀ ionsꢀ
DOI: 10.1039/C6SC03012B
Me
Cl OH
OTIPS
7
Ti(OiOPr)3Cl
7
Cl
Me
arisingꢀ fromꢀ attackꢀ atꢀ C12ꢀ inꢀ eitherꢀ aꢀ 4-ꢀ orꢀ 3-spiroꢀ (exo)ꢀ
cyclisationꢀmodesꢀhaveꢀnotꢀbeenꢀconsideredꢀasꢀtheꢀproductsꢀ
arisingꢀ fromꢀ theseꢀ modesꢀ ofꢀ attackꢀ wereꢀ notꢀ isolated,ꢀ
presumablyꢀ asꢀ aꢀ resultꢀ ofꢀ theꢀ alkeneꢀ activatingꢀ C13ꢀ withꢀ
7
OTIPS
7
Cl Cl
26 (66% >25:1 d.r.)
Cl Cl
7
a
via:
M Cl
OM
Cl
4-fused
R1
H
Cl
O
H
R1
27
R2
respectꢀ toꢀ nucleophilicꢀ attack. ꢀ ꢀ Theꢀ observedꢀ retentionꢀ
Cl
C13-(S)
Cl
Cl OH
withꢀbothꢀ7aꢀandꢀ7bꢀcoupledꢀwithꢀnumerousꢀelegantꢀstudiesꢀ
28 ,29
onꢀchloroniumꢀspecies,ꢀincludingꢀcyclicꢀstructures, ꢀmakesꢀ
R2
13
R2
chloretanium 1
R1
M = Ti(OiPr)3
Cl Cl
Cl
OH
C13-(S)
thisꢀ aꢀ compellingꢀ explanation.ꢀ Moreꢀ recentꢀ workꢀ byꢀ
30
Carreira ꢀonꢀtheꢀringꢀopeningꢀreactionsꢀofꢀaꢀcollectionꢀofꢀγ-ꢀ
Cl
M
Cl
Cl
O
5-fused
R1
R2
R1
Cl
H
Cl
H
andꢀδ-chloroꢀvinylꢀepoxidesꢀhasꢀprovidedꢀfurtherꢀresultsꢀthatꢀ
C13-(S)
R2
areꢀconsistentꢀwithꢀtheꢀinterventionꢀofꢀfour-(chloretanium)ꢀ
chlorolanium 1
andꢀ five-(chlorolanium)ꢀ memberedꢀ ringꢀ ions.ꢀ Inꢀ comparingꢀ
28,29
(
B)
Cl
TIPSO
7
Cl OH
OTIPS
O
Ti(OiOPr)3Cl
7
Me
Me
theꢀearlyꢀworkꢀofꢀPetersonꢀandꢀOlah
ꢀwithꢀrecentꢀstudiesꢀ
7
7
Cl
Cl Cl
Cl Cl
32 (71% >25:1 d.r.)
Cl Cl
weꢀ notedꢀ thatꢀ allꢀ ofꢀ theꢀ substratesꢀ thatꢀ haveꢀ beenꢀ
investigatedꢀinꢀtheꢀcontextꢀofꢀchlorosulfolipidꢀsynthesisꢀareꢀ
vinylꢀepoxides.ꢀGivenꢀthatꢀtheꢀalkeneꢀsubstituentꢀwouldꢀbeꢀ
expectedꢀ toꢀ influenceꢀ theꢀ structureꢀ ofꢀ anyꢀ derivedꢀ
chloroniumꢀ ionꢀ intermediatesꢀ weꢀ carriedꢀ outꢀ aꢀ theoreticalꢀ
studyꢀ toꢀ investigateꢀ theꢀ structuresꢀ andꢀ energiesꢀ ofꢀ ꢀ theꢀ
7
b
via:
M Cl
OM
Cl
4-fused
Cl
O
R1
R2
R2
R1
H
H
Cl
Cl
Cl OH
1
3
R2
C13-(R)
chloretanium 2
R1
M = Ti(OiPr)3
Cl Cl
31
unsaturatedꢀcyclicꢀchloroniumꢀionsꢀdepictedꢀinꢀSchemeꢀ10. ꢀꢀ
Weꢀ beganꢀ ourꢀ computationalꢀ investigationꢀ withꢀ aꢀ
comparisonꢀ ofꢀ theꢀ simpleꢀ dipropylꢀ substitutedꢀ chloroniumꢀ
ionꢀ 39ꢀ withꢀ itsꢀ unsaturatedꢀ analogyꢀ 40.ꢀ Equilibriumꢀ
geometriesꢀ forꢀ theseꢀ twoꢀ speciesꢀ wereꢀ optimizedꢀ usingꢀ aꢀ
varietyꢀ ofꢀ methodsꢀ atꢀ theꢀ wavefunctionꢀ andꢀ densityꢀ
functionalꢀlevelꢀofꢀtheoryꢀ(Tableꢀ1),ꢀwithꢀimplicitꢀsolvationꢀbyꢀ
C13-(R)
Cl
M
Cl
OH
Cl
Cl
O
5-fused
R1
R1
H
R2
Cl
Cl
C13-(R)
R2
H
chlorolanium 2
ꢀ
Schemeꢀ10ꢀInterventionꢀofꢀchloroniumꢀionsꢀinꢀepoxideꢀopeningꢀreactionsꢀofꢀ
aꢀandꢀ7b.ꢀ
7
Inꢀ eachꢀ caseꢀ thereꢀ areꢀ twoꢀ potentialꢀ chloroniumꢀ ionꢀ
intermediatesꢀ arisingꢀ fromꢀ attackꢀ ofꢀ eitherꢀ theꢀ γ-orꢀ δ-
32
anꢀSMDꢀdescriptionꢀofꢀtoluene. ꢀꢀ
Tableꢀ1.ꢀComparisonꢀofꢀalkylꢀandꢀallylꢀsubstitutedꢀchloroniumꢀionsꢀ(BS1ꢀ=ꢀdef2-TZVPP;ꢀBS2ꢀ=ꢀdef2-QZVPP).ꢀ
model chloronium ions equilibrium geometries
1.85 1.47
rC-allyl
1.80
1.47
rC-alkyl
rC-alkyl
Cl
Cl
Me
Me
Me
3
9
40
1.89
1.33
2.54
1.33
4
0 (M06-2X/def-TZVPP)
40 (M11-L/def-TZVPP)
ꢀ
Entry
Level of theory
B3YLP/BS1
B3LYP-D3/BS1
ωB97XD/BS1
M06-2X/BS1
M11/BS1
M11-L/BS1
MP2/BS1
B2-PLYP-D3/BS1 1.87
B3LYP/BS2
B3LYP-D3/BS2
ωB97XD/BS2
M06-2X/BS2
M11/BS2
r
C-Cl 39 (Å)
r
C-allyl 40 (Å)
r
C-alkyl 40 (Å)
∆r (Å)
∆E (kcal/mol)
11.2
14.8
14.9
16.8
16.2
8.1
-
-
-
-
-
-
-
-
1
2
3
4
5
6
7
8
9
1.89
1.89
1.85
1.85
-
2.00
1.98
1.90
1.89
1.89
2.54
1.87
1.93
2.01
1.99
1.90
1.89
1.90
1.94
1.88
1.88
1.85
1.85
1.85
1.80
1.84
1.86
1.88
1.88
1.85
1.85
1.85
1.83
0.12
0.10
0.05
0.04
0.04
0.74
0.03
0.07
0.13
0.11
0.05
0.04
0.05
0.11
1.83
1.84
1.89
1.89
1.86
1.86
-
1
1
1
1
1
0
1
2
3
4
M11-L/BS2
1.84
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
Thisꢀjournalꢀisꢀ©ꢀTheꢀRoyalꢀSocietyꢀofꢀChemistryꢀ20xxꢀ
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ꢀEDGEꢀARTICLEꢀ
ChemicalꢀScienceꢀ
Aꢀ recentꢀ studyꢀ byꢀ Stoyanovꢀ andꢀ Reed,ꢀ inꢀ whichꢀ X-rayꢀ
structuresꢀ ofꢀ dimethylꢀ andꢀ diethylꢀ chloroniumꢀ saltsꢀ wereꢀ
fragmentsꢀ (∆E,ꢀ Tableꢀ 1)ꢀ isꢀ positiveꢀ byꢀ atꢀ leastꢀ 8ꢀ kcal/mol,ꢀ
View Article Online
signifyingꢀaꢀstabilizingꢀinteractionꢀbetweenꢀtheꢀchlorineꢀandꢀ
DOI: 10.1039/C6SC03012B
3
3
obtained, ꢀ allowedꢀ usꢀ toꢀ compareꢀ computedꢀ andꢀ
experimentallyꢀ determinedꢀ C-Clꢀ bondꢀ lengths.ꢀ Theꢀ
experimentalꢀ C-Clꢀ lengthꢀ inꢀ theꢀ diethylchloroniumꢀ ionꢀ isꢀ
theꢀallylicꢀcarbonꢀatomꢀevenꢀinꢀtheꢀstructuresꢀwithꢀlongerꢀ(C-
allyl)ꢀdistances.ꢀꢀ
Weꢀreturnedꢀtoꢀtheꢀringꢀopeningꢀreactionsꢀofꢀepoxidesꢀ
7aꢀ andꢀ 7bꢀ (Schemeꢀ 10).ꢀ Takingꢀ epoxideꢀ 7aꢀ first,ꢀ weꢀ
optimizedꢀ theꢀ SMD-M06-2X/def-TZVPPꢀ geometriesꢀ forꢀ
truncatedꢀ analoguesꢀ ofꢀ theꢀ twoꢀ putativeꢀ chloroniumꢀ ionꢀ
intermediates,ꢀ chloretaniumꢀ 1ꢀ andꢀ chlorolaniumꢀ 1ꢀ (Figureꢀ
1A)ꢀderivedꢀfromꢀanchimericꢀassistanceꢀofꢀeitherꢀtheꢀγ-ꢀorꢀδ-
chlorineꢀ substituents,ꢀ respectively.ꢀ Inspectionꢀ ofꢀ theꢀ
geometryꢀ ofꢀ chloretaniumꢀ 1ꢀ reveals:ꢀ ꢀ (a)ꢀ aꢀ longꢀ Cl-allylꢀ
distanceꢀ ofꢀ 2.69ꢀ Å;ꢀ (b)ꢀ similarꢀ bondꢀ lengthsꢀ ofꢀ 1.39ꢀ Åꢀ andꢀ
1.36ꢀ Åꢀ withinꢀ theꢀ allylicꢀ fragment;ꢀ andꢀ (c)ꢀ planarꢀ allylicꢀ
carbonꢀ atoms,ꢀ asꢀ quantifiedꢀ byꢀ theꢀ extentꢀ ofꢀ
pyramidalization.ꢀTheseꢀdataꢀareꢀconsistentꢀwithꢀaꢀdistortedꢀ
chloretaniumꢀionꢀwithꢀsignificantꢀcarbocationicꢀcharacter.ꢀInꢀ
contrast,ꢀchlorolaniumꢀ1ꢀhasꢀaꢀsubstantiallyꢀshorterꢀcarbon-
chlorineꢀ bondꢀ lengthꢀ (1.90ꢀ Å)ꢀ andꢀ substantialꢀ
pyramidalizationꢀ ofꢀ theꢀ allylicꢀ carbon,ꢀ consistentꢀ withꢀ aꢀ
cyclicꢀ chloroniumꢀ ion.ꢀ Theꢀ sameꢀ patternꢀ wasꢀ seenꢀ withꢀ
chloretaniumꢀ 2ꢀ andꢀ chlorolaniumꢀ 2,ꢀ whichꢀ ariseꢀ fromꢀ theꢀ
diastereoisomericꢀ epoxideꢀ 7b.ꢀ Theꢀ relativeꢀ energyꢀ ofꢀ theꢀ
carbocation-likeꢀchloretaniumꢀstructuresꢀwas,ꢀinꢀeachꢀcase,ꢀ
significantlyꢀ higherꢀ byꢀ moreꢀ thanꢀ 8ꢀ kcal/molꢀ comparedꢀ toꢀ
theꢀcorrespondingꢀchlorolaniumꢀionꢀ(Figureꢀ1).ꢀꢀ
1
.840ꢀÅ.ꢀAꢀsurveyꢀofꢀdifferentꢀmethodsꢀandꢀbasisꢀsetsꢀ(BS1ꢀ=ꢀ
def2-TZVPP,ꢀ BS2ꢀ =ꢀ def2-QZVPP)ꢀ foundꢀ thatꢀ B3LYP,ꢀ B3LYP-
D3,ꢀ B2PLYPꢀ overestimateꢀ thisꢀ distance.ꢀ However,ꢀ ωB97XDꢀ
andꢀtheꢀMinnesotaꢀfunctionalsꢀprovideꢀaꢀgoodꢀdescriptionꢀofꢀ
theꢀ chloroniumꢀ structure.ꢀ Theꢀ MP2/BS1ꢀ andꢀ M11-L/BS2ꢀ
derivedꢀbondꢀlengthsꢀofꢀ1.84ꢀÅꢀwereꢀinꢀexcellentꢀagreementꢀ
withꢀexperiment.ꢀSmallerꢀbasisꢀsets,ꢀsuchꢀasꢀ6-31+G(d)ꢀgaveꢀ
routinelyꢀ worseꢀ resultsꢀ (seeꢀ SI).ꢀ Weꢀ nextꢀ examinedꢀ theꢀ
unsymmetricalꢀ allyl/propylꢀ chloroniumꢀ ionꢀ usingꢀ theꢀ sameꢀ
theoreticalꢀmodelsꢀ(Tableꢀ1).ꢀꢀThisꢀmodelꢀcompoundꢀallowsꢀ
forꢀ aꢀ comparisonꢀ ofꢀ C-Clꢀ bondꢀ lengths,ꢀ and,ꢀ therefore,ꢀ toꢀ
establishꢀ theꢀ extentꢀ ofꢀ chloroniumꢀ versusꢀ carbocationicꢀ
characterꢀinꢀtheseꢀstructures.ꢀAllꢀofꢀtheꢀtheoreticalꢀmethodsꢀ
testedꢀ showꢀ thatꢀ theꢀ allylicꢀ groupꢀ interactsꢀ moreꢀ weaklyꢀ
thanꢀtheꢀalkylꢀgroup,ꢀbasedꢀonꢀaꢀlongerꢀC-Clꢀbondꢀdistance.ꢀ
Theꢀ computedꢀ variationꢀ betweenꢀ alkylꢀ andꢀ allylꢀ distancesꢀ
rangesꢀ fromꢀ 0.04-0.13ꢀ Å.ꢀ Theꢀ M11-L/def2-TZVPPꢀ (entryꢀ 6)ꢀ
optimizedꢀ structureꢀ isꢀ anꢀ outlier,ꢀ consistentꢀ withꢀ aꢀ
carbocationꢀ(seeꢀFigureꢀ2A)ꢀwithꢀaꢀrꢀ(C-allyl)ꢀdistanceꢀ2.54Åꢀ
andꢀ bondꢀ lengthsꢀ ofꢀ 1.35ꢀ Åꢀ andꢀ 1.39ꢀ Åꢀ inꢀ theꢀ allylicꢀ
fragment.ꢀ However,ꢀ allꢀ otherꢀ methodsꢀ generatedꢀ aꢀ
chloroniumꢀ likeꢀ structure.ꢀ Atꢀ allꢀ levelsꢀ theꢀ calculatedꢀ
dissociationꢀenergyꢀofꢀ40ꢀintoꢀallylꢀcationꢀandꢀpropylchlorideꢀ
ꢀ
(A) M06-2X/def-TZVPP geometries of truncated choretanium ion and chlorolanium ions derived from epoxide 7a
dC-C1.36
dC-C1.33
Cl
OH
Cl
Cl
OH
H
O
Me
H
Me
7
Me
Cl
H
Cl
Cl
H
dC-C1.39
dC···Cl 2.69
OTIPS
7
dC-C1.48
dC ·· · Cl1.90
Δ = 0.3 Å
dC-Cl1.80
Δ = 0.0 Å
carbocation-like Lewis structure
ΔE= -8.2 kcal/mol (chloretanium1 vs chorolanium1)
dC-Cl1.89
7
a
chlorolanium1
chloretanium1
chloronium ion-like Lewis structure
(B) M06-2X/def-TZVPP geometries of truncated choretanium ion and chlorolanium ions derived from epoxide 7b
dC-C1.39
dC-C1.33
Cl
OH
Cl
OH
Cl
OTIPS
O
7
Me
Me
Me
H
7
H
H
Cl
Cl
Cl Cl
Cl
H
dC-C1.36
dC···Cl 2.70
dC-C1.47
dC ·· · Cl1.94
Δ = 0.3 Å
chloronium ion-like Lewis structure
dC-Cl1.80
Δ = 0.1 Å
dC-Cl1.88
7
b
chloretanium 2
chlorolanium 2
carbocation-like Lewis structure
ΔE= -9.2 kcal/mol (chloretanium 2 vs chorolanium 2)
ΔEact= 3.5 kcal/mol (chloretanium1 chloretanium 2)
ꢀ
Figꢀ1ꢀSMD-M06-2X/def2-TZVPPꢀoptimizedꢀstructuresꢀofꢀmodelꢀchloroniumꢀions.ꢀBondꢀdistancesꢀandꢀpyramidalizationꢀ(Δ)ꢀinꢀÅ,ꢀwithꢀNCIꢀisosurfaceꢀshownꢀforꢀtheꢀ
chloretaniumꢀstructures.ꢀ
Thisꢀjournalꢀisꢀ©ꢀTheꢀRoyalꢀSocietyꢀofꢀChemistryꢀ20xxꢀ
J.ꢀName.,ꢀ2013,ꢀ00,ꢀ1-3ꢀ|ꢀ8ꢀ
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Whileꢀ chloretaniumꢀ intermediatesꢀ wereꢀ foundꢀ toꢀ beꢀ lessꢀ reactionsꢀ ofꢀ γ,δ-dichloroꢀ vinylꢀ epoxides. ꢀD SOp I :e 1c 0i f. 1i c0 a3 9l l /yC, ꢀ6 wS Ce 0ꢀ 3h 0 a1 v2 eB ꢀ
stable,ꢀ withꢀ greaterꢀ carbocationicꢀ characterꢀ thanꢀ theꢀ corroboratedꢀtheꢀinterventionꢀofꢀchloroniumꢀionꢀintermediatesꢀ
chlorolaniumꢀ species,ꢀ thereꢀ isꢀ stillꢀ anꢀ interactionꢀ betweenꢀ Clꢀ bothꢀ experimentallyꢀ andꢀ computationally.ꢀ Furthermore,ꢀ theꢀ
andꢀ theꢀ allylicꢀ carbon.ꢀ Theꢀ C-Clꢀ distanceꢀ inꢀ theseꢀ intermediateꢀchloretaniumꢀionsꢀhaveꢀbeenꢀshownꢀtoꢀbeꢀhighlyꢀ
unsymmetricalꢀ intermediatesꢀ (2.69ꢀ -ꢀ 2.70ꢀ Å)ꢀ isꢀ considerablyꢀ distortedꢀ withꢀ pronouncedꢀ carbocationicꢀ character,ꢀ makingꢀ
shorterꢀthanꢀtheꢀsumꢀofꢀvanꢀderꢀWaalsꢀradiiꢀofꢀ3.45ꢀÅꢀ(Bondi)ꢀ themꢀ lessꢀ stableꢀ thanꢀ theꢀ chlorolaniums.ꢀ Despiteꢀ this,ꢀ
orꢀ3.52ꢀÅꢀ(Pauling).ꢀTheꢀpresenceꢀofꢀaꢀthrough-space,ꢀweaklyꢀ computationsꢀdoꢀsupportꢀtheꢀexistenceꢀofꢀaꢀweaklyꢀattractiveꢀ
attractiveꢀC-Clꢀinteractionꢀinꢀtheꢀchloretaniumꢀisꢀalsoꢀapparentꢀ C-Clꢀ interactionꢀ inꢀ theꢀ four-memberedꢀ intermediate.ꢀ Theꢀ
34
fromꢀaꢀNBO-computedꢀWibergꢀbondꢀorder ꢀofꢀ0.06,ꢀandꢀtheꢀ structuresꢀofꢀbothꢀcyclicꢀintermediatesꢀexistꢀalongꢀaꢀcontinuumꢀ
35
Non-Covalentꢀ Interactionꢀ (NCI)ꢀ isosurfaceꢀ shownꢀ inꢀ Fig.ꢀ 1. ꢀ ofꢀLewisꢀstructuresꢀfromꢀfreeꢀcarbocationꢀtoꢀchloronium,ꢀsuchꢀ
Thisꢀinteractionꢀisꢀmuchꢀweakerꢀthanꢀtheꢀcorrespondingꢀbondꢀ thatꢀanchimericꢀassistanceꢀcanꢀoccurꢀinꢀbothꢀcases.ꢀ
orderꢀobtainedꢀforꢀtheꢀchlorolaniumꢀspeciesꢀ(0.89-0.92),ꢀandꢀaꢀ
fairlyꢀsmallꢀbarrierꢀofꢀ3.5ꢀkcal/molꢀtoꢀrotateꢀaboutꢀtheꢀC13-C14ꢀ
bondꢀwasꢀfoundꢀforꢀchloretaniumꢀ1.ꢀItꢀisꢀfairꢀtoꢀsummiseꢀthatꢀ
theꢀ fourꢀ andꢀ five-memberedꢀ chloroniumꢀ intermediatesꢀ lieꢀ
Acknowledgementsꢀ
RMDꢀ acknowledgesꢀ financialꢀ supportꢀ fromꢀ theꢀ Schoolꢀ ofꢀ
alongꢀ aꢀ continuumꢀ fromꢀ freeꢀ carbocationꢀ toꢀ chloronium-likeꢀ
Chemistry,ꢀ Universityꢀ ofꢀ Nottinghamꢀ (Studentshipꢀ toꢀ JS)ꢀ andꢀ
Lewisꢀstructures,ꢀratherꢀthanꢀanꢀabruptꢀshiftꢀinꢀtheꢀnatureꢀofꢀ
bonding.ꢀꢀ
theꢀ supportꢀ ofꢀ analyticalꢀ servicesꢀ withinꢀ theꢀ Schoolꢀ ofꢀ
Chemistry.ꢀ RSPꢀ acknowledgesꢀ theꢀ useꢀ ofꢀ theꢀ EPSRCꢀ UKꢀ
Withꢀtheseꢀcomputationalꢀdataꢀinꢀmind,ꢀweꢀreturnꢀtoꢀtheꢀ
stereoretentiveꢀ titanium-mediatedꢀ epoxideꢀ ringꢀ openingꢀ
Nationalꢀ Serviceꢀ forꢀ Computationalꢀ Chemistryꢀ Softwareꢀ
(
CHEM773).ꢀ
reactionsꢀ depictedꢀ inꢀ Schemeꢀ 10.ꢀ Weꢀ suggestꢀ thatꢀ theseꢀ
reactionsꢀ takeꢀ placeꢀ throughꢀ aꢀ pairꢀ ofꢀ diastereoisomericꢀ
chlorolanium-likeꢀ intermediatesꢀ (chlorolaniumꢀ 1ꢀ andꢀ Notesꢀandꢀreferencesꢀ
chlorolaniumꢀ 2,ꢀ Schemeꢀ 10)ꢀ ratherꢀ thanꢀ theꢀ higherꢀ energyꢀ
ꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀ
distortedꢀ chloretaniumꢀ ions.ꢀ Basedꢀ uponꢀ theꢀ computedꢀ
geometriesꢀ ofꢀ theꢀ truncatedꢀ analoguesꢀ theꢀ chlorolanium-likeꢀ
1
ꢀ
Forꢀ aꢀ comprehensiveꢀ reviewꢀ onꢀ halogen-containingꢀ naturalꢀ
products,ꢀ see:ꢀ (a)ꢀ G.W.ꢀ Gribble,ꢀ Progressꢀ inꢀ theꢀ Chemistryꢀ ofꢀ
intermediatesꢀareꢀlikelyꢀtoꢀhaveꢀunequalꢀcarbon-chlorineꢀbondꢀ OrganicꢀNaturalꢀProducts,ꢀ2010,ꢀ91,ꢀ1–613.ꢀForꢀotherꢀrecentꢀelegantꢀ
distancesꢀ andꢀ exhibitꢀ aꢀ degreeꢀ ofꢀ carbocationicꢀ characterꢀ atꢀ studiesꢀonꢀhalogenatedꢀnaturalꢀproducts,ꢀseeꢀ(b)ꢀS.ꢀA.ꢀSnyder,ꢀA.ꢀP.ꢀ
Brucks,ꢀ D.ꢀ S.ꢀ Treitler,ꢀ andꢀ I.ꢀ Moga,ꢀ J.ꢀ Am.ꢀ Chem.ꢀ Soc.,ꢀ 2012,ꢀ 134,ꢀ
C13.ꢀWeꢀnoteꢀthatꢀtheꢀepoxideꢀopeningꢀofꢀmodelꢀcompoundꢀ
19ꢀ (Schemeꢀ 4B),ꢀ whichꢀ containedꢀ anꢀ electronꢀ withdrawingꢀ
esterꢀgroupꢀtookꢀplaceꢀwithꢀinversionꢀofꢀstereochemistry.ꢀThisꢀ
1
7714;ꢀ(c)ꢀD.ꢀC.ꢀBraddock,ꢀA.ꢀX.ꢀGao,ꢀA.ꢀJ.ꢀP.ꢀWhiteꢀandꢀM.ꢀWhyte,ꢀ
Chem.ꢀCommun.ꢀ2014,ꢀ50,ꢀ13725–13728;ꢀ(d)ꢀD.ꢀC.ꢀBraddockꢀandꢀD.ꢀ
T.ꢀ Sbircea,ꢀ Chem.ꢀ Commun.ꢀ 2014,ꢀ 50,ꢀ 12691–12693;ꢀ (e)ꢀ H.ꢀ M.ꢀ
resultꢀ corroboratesꢀ theꢀ developmentꢀ ofꢀ partialꢀ cationicꢀ Sheldrake,ꢀC.ꢀJamieson,ꢀS.ꢀI.ꢀPascaꢀandꢀJ.ꢀW.ꢀBurton,ꢀOrg.ꢀBiomol.ꢀ
characterꢀ atꢀ C13ꢀ duringꢀ reactionsꢀ thatꢀ takeꢀ placeꢀ withꢀ Chem.,ꢀ2009,ꢀ7,ꢀ232–234.ꢀ
2
ꢀ
Forꢀreviewsꢀtheꢀchlorosulfolipidꢀfamilyꢀofꢀnaturalꢀproducts,ꢀsee:ꢀ(a)ꢀ
retentionꢀofꢀconfiguration.ꢀFinally,ꢀitꢀshouldꢀbeꢀnotedꢀthatꢀhighꢀ
levelsꢀ ofꢀ stereoretentionꢀ haveꢀ beenꢀ observedꢀ inꢀ systemsꢀ inꢀ
whichꢀtheꢀformationꢀofꢀaꢀchlorolaniumꢀionꢀisꢀnotꢀpossibleꢀe.g.ꢀ
D.ꢀK.ꢀBedkeꢀandꢀC.ꢀD.ꢀVanderwal,ꢀNat.ꢀProd.ꢀRep.,ꢀ2011,ꢀ28,ꢀ15–25;ꢀ
b)ꢀC.ꢀNilewskiꢀandꢀE.ꢀM.ꢀCarreira,ꢀEur.ꢀJ.ꢀOrg.ꢀChem.,ꢀ2012,ꢀ1685–
698;ꢀ(c)ꢀT.ꢀUmezawaꢀandꢀF.ꢀMatsuda,ꢀTetrahedronꢀLett.,ꢀ2014,ꢀ55,ꢀ
(
1
30
δ-chloroꢀvinylꢀepoxides. ꢀInꢀsuchꢀcasesꢀitꢀisꢀlikelyꢀthatꢀdistortedꢀ 3003–3012;ꢀ W.ꢀ –J.ꢀ Chungꢀ andꢀ C.ꢀ D.ꢀ Vanderwal,ꢀ Acc.ꢀ Chem.ꢀ Res.,ꢀ
chloretaniumꢀ ionsꢀ areꢀ involvedꢀ andꢀ thatꢀ theꢀ chlorineꢀ 2014,ꢀ47,ꢀ718–728.ꢀ
3
ꢀ
(a)ꢀJ.ꢀElovsonꢀandꢀP.ꢀRꢀVagelos,ꢀProc.ꢀNatl.ꢀAcad.ꢀSoc.ꢀUSA,ꢀ1969,ꢀ
substituentꢀ blocksꢀ oneꢀ faceꢀ ofꢀ theꢀ allylicꢀ subunitꢀ leadingꢀ toꢀ
highꢀlevelsꢀofꢀstereoretention.ꢀ
6
2,ꢀ 957–963;ꢀ (b)ꢀ T.ꢀ H.ꢀ Haines,ꢀ M.ꢀ Pousada,ꢀ B.ꢀ ꢀ Sternꢀ andꢀ G.ꢀ L.ꢀ
Mayers,ꢀ Biochem.ꢀ J.,ꢀ 1969,ꢀ 113,ꢀ 565–566;ꢀ (c)ꢀ T.ꢀ H.ꢀ Haines,ꢀ M.ꢀ
Pousada,ꢀB.ꢀSternꢀandꢀG.ꢀL.ꢀMayersꢀBiochem.ꢀJ.,ꢀ1969,ꢀ113,ꢀ565–566;ꢀ
(
d)ꢀJ.ꢀElovsonꢀandꢀP.ꢀR.ꢀVagelos,ꢀBiochemistry,ꢀ1970,ꢀ89,ꢀ3110–3126;ꢀ
Conclusionꢀ
(e)ꢀ J.ꢀ Elovson,ꢀ Biochemistry,ꢀ 1974,ꢀ 13,ꢀ 2105–2109;ꢀ (f)ꢀ J.ꢀ Elovson,ꢀ
Biochemistry,ꢀ 1974,ꢀ 13,ꢀ 3483–3487;ꢀ (g)ꢀ C.ꢀ L.ꢀ Mooney,ꢀ E.ꢀ M.ꢀ
Mahoney,ꢀ M.ꢀ Pousadaꢀ andꢀ T.ꢀ H.ꢀ Haines,ꢀ Biochemistry,ꢀ 1972,ꢀ 11,ꢀ
Inꢀ summary,ꢀ weꢀ haveꢀ accomplishedꢀ aꢀ 12-stepꢀ convergent,ꢀ
enantioselectiveꢀ formalꢀ synthesisꢀ ofꢀ malhamensilipinꢀ Aꢀ fromꢀ
4
839–4844;ꢀ(h)ꢀC.ꢀL.ꢀMooneyꢀandꢀT.ꢀH.ꢀHaines,ꢀBiochemistry,ꢀ1973,ꢀ
commercialꢀ(E)-2-undecenal.ꢀTheꢀsynthesisꢀstrategyꢀwasꢀbasedꢀ 12,ꢀ 4469–4472;ꢀ (i)ꢀ G.ꢀ Thomasꢀ andꢀ E.ꢀ I.ꢀ Mercer,ꢀ Phytochemistry,ꢀ
1
ꢀ
974,ꢀ12,ꢀ4469–4472.ꢀ
(a)ꢀP.ꢀCiminiello,ꢀE.ꢀFattorusso,ꢀM.ꢀForino,ꢀM.ꢀDiꢀRosa,ꢀA.ꢀIanaroꢀ
uponꢀ anꢀ iterativeꢀ epoxidation/deoxydichlorinationꢀ sequence,ꢀ
whichꢀ demonstratesꢀ theꢀ powerꢀ ofꢀ phosphorus(V)-mediatedꢀ
deoxydichlorinationꢀ reactionsꢀ ofꢀ epoxidesꢀ forꢀ theꢀ
stereospecificꢀ andꢀ chemoselectiveꢀ constructionꢀ ofꢀ chlorine-
4
andꢀR.ꢀPoletti,ꢀJ.ꢀOrg.ꢀChem.,ꢀ2001,ꢀ66,ꢀ578–582;ꢀ(b)ꢀP.ꢀCiminiello,ꢀCꢀ
Dell’Aversano,ꢀ E.ꢀ Fattorusso,ꢀ M.ꢀ Forino,ꢀ S.ꢀ Magno,ꢀ M.ꢀ Diꢀ Rosa,ꢀ Aꢀ
IanaroꢀandꢀR.ꢀPoletti,ꢀJ.ꢀAm.ꢀChem.ꢀSoc.,ꢀ2002,ꢀ124,ꢀ13114–13120;ꢀ
containingꢀ stereochemicalꢀ arrays.ꢀ Inꢀ additionꢀ toꢀ theꢀ formalꢀ (c)ꢀ P.ꢀ Ciminiello,ꢀ C.ꢀ Dell’Aversano,ꢀ E.ꢀ Fattorusso,ꢀ M.ꢀ Forino,ꢀ Sꢀ
Magno,ꢀP.ꢀDiꢀMeglio,ꢀA.ꢀIanaroꢀandꢀR.ꢀPoletti,ꢀTetrahedron,ꢀ2004,ꢀ
synthesis,ꢀ weꢀ haveꢀ preparedꢀ threeꢀ furtherꢀ diastereoisomericꢀ
heptachlorinatedꢀ analogsꢀ andꢀ demonstratedꢀ theꢀ utilityꢀ ofꢀ
Carreira’sꢀNMRꢀdatabaseꢀforꢀtheꢀstereochemicalꢀassignmentꢀofꢀ
complexꢀ polychlorinatedꢀ entities.ꢀ Ourꢀ computationalꢀ analysisꢀ
6
0,ꢀ7093–7098;ꢀ(d)ꢀT.ꢀKawahara,ꢀY.ꢀKumaki,ꢀT.ꢀKamada,ꢀT.ꢀIshiiꢀandꢀTꢀ
Okino,ꢀ J.ꢀ Org.ꢀ Chem.ꢀ 2009,ꢀ 74,ꢀ 6016–6024;ꢀ (e)ꢀ J.ꢀ L.ꢀ Chen,ꢀ P.ꢀ J.ꢀ
Proteau,ꢀM.ꢀA.ꢀRobertsꢀandꢀW.ꢀH.ꢀGerwick,ꢀJ.ꢀNat.ꢀProd.,ꢀ1994,ꢀ57,ꢀ
5
24–527ꢀ (f)ꢀ A.ꢀ R.ꢀ Pereira,ꢀ T.ꢀ Byrum,ꢀ M.ꢀ Shibuya,ꢀ C.ꢀ D.ꢀ Vanderwalꢀ
hasꢀprovidedꢀnewꢀinsightꢀintoꢀtheꢀstereoretentiveꢀring-openingꢀ andꢀW.H.ꢀGerwick,ꢀJ.ꢀNat.ꢀProd.ꢀ2010,ꢀ73,ꢀ279–283;ꢀ(g)ꢀC.-H.ꢀChao,ꢀ
Thisꢀjournalꢀisꢀ©ꢀTheꢀRoyalꢀSocietyꢀofꢀChemistryꢀ20xxꢀ
J.ꢀName.,ꢀ2013,ꢀ00,ꢀ1-3ꢀ|ꢀ9ꢀꢀ
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Pleas Ce hꢀ d eo mꢀ ni oc ta ꢀ al dS jcu i se t nꢀ mc ea rginsꢀ
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ChemicalꢀScienceꢀ
ꢀEDGEꢀARTICLEꢀ
ꢀ
ꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀ ꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀ ꢀꢀꢀ ꢀꢀ ꢀꢀꢀ
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6
DOI: 10.1039/C6SC03012B
H.ꢀ–C.ꢀHuang,ꢀG.ꢀH.ꢀWang,ꢀZ.ꢀ–H.ꢀWen,ꢀW.ꢀ–H.ꢀWang,ꢀI.ꢀ–MꢀChenꢀandꢀ
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5
ꢀ
5
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(a)ꢀ T.ꢀ Yoshimitsu,ꢀ N.ꢀ Fukumoto,ꢀ R.ꢀ Nakatani,ꢀ N.ꢀ Kojimaꢀ andꢀ T.ꢀ 1189–1192.ꢀ Thisꢀ terminologyꢀ avoidsꢀ confusionꢀ sinceꢀ theꢀ carbon-
6
Tanaka,ꢀJ.ꢀOrg.ꢀChem.,ꢀ2010,ꢀ75,ꢀ5425–5437;ꢀ(b)ꢀW.ꢀ–J.ꢀChung,ꢀJ.ꢀS.ꢀ oxygenꢀbondꢀbreaksꢀoutsideꢀtheꢀringꢀinꢀbothꢀtheꢀendoꢀandꢀexoꢀringꢀ
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7
1
5
ꢀ
35
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4,ꢀ 696–702;ꢀ forꢀ theꢀ originalꢀ reaction,ꢀ seeꢀ (b)ꢀ N.ꢀ S.ꢀ Isaacsꢀ andꢀ D.ꢀ
ꢀ(a)ꢀJ.ꢀContreras-Garcia,ꢀE.ꢀR.ꢀJohnson,ꢀS.ꢀKeinan,ꢀR.ꢀChaudret,ꢀJ.ꢀ–P.ꢀ
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4
678–4681;ꢀ(b)ꢀForꢀaꢀreviewꢀonꢀcatalyticꢀvariantsꢀofꢀphosphorus(V)- Garcia,ꢀA.ꢀCohenꢀandꢀW.ꢀYang,ꢀJ.ꢀAm.ꢀChem.ꢀSoc.ꢀ2010,ꢀ132,ꢀ6498.ꢀ
mediatedꢀreactions,ꢀseeꢀ(a)ꢀS.P.ꢀMarsdenꢀin:ꢀDunn,ꢀP.ꢀJ.;ꢀHii,ꢀK.ꢀK.;ꢀ
Krische,ꢀM.ꢀJ.;ꢀWilliams,ꢀM.ꢀT.ꢀSustainableꢀCatalysis:ꢀChallengesꢀandꢀ
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17
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2
0
ꢀ
Theꢀ competingꢀ eliminationꢀ hasꢀ beenꢀ observedꢀ inꢀ relatedꢀ
reactionsꢀ byꢀ usꢀ (referenceꢀ 16)ꢀ asꢀ wellꢀ asꢀ Tanakaꢀ andꢀ Yoshimitsuꢀ
referenceꢀ15a).ꢀ
(
2
1
ꢀ
Epoxideꢀ9aꢀhadꢀbeenꢀpreviouslyꢀdescribedꢀbyꢀVanderwalꢀandꢀco-
workersꢀ duringꢀ theꢀ firstꢀ totalꢀ synthesisꢀ ofꢀ malhamensilipinꢀ A,ꢀ seeꢀ
referenceꢀ8.ꢀ
2
2
ꢀ
P.ꢀR.ꢀBlakemore,ꢀW.ꢀJ.ꢀCole,ꢀP.ꢀJ.ꢀKocienskiꢀandꢀA.ꢀMorley,ꢀSynlett,ꢀ
1
998,ꢀ1,ꢀ26–28.ꢀ
2
2
3
ꢀ
ꢀ
FullꢀdetailsꢀcanꢀbeꢀfoundꢀinꢀtheꢀSupportingꢀInformation.ꢀ
P.ꢀLiu.ꢀandꢀE.ꢀN.ꢀJacobsen,ꢀJ.ꢀAm.ꢀChem.ꢀSoc.,ꢀ2001,ꢀ123,ꢀ10772–
4
1
0773.ꢀ
2
5
ꢀ
J.ꢀPospisil,ꢀTetrahedronꢀLett.,ꢀ2011,ꢀ52,ꢀ2348–2352.ꢀ
Thisꢀjournalꢀisꢀ©ꢀTheꢀRoyalꢀSocietyꢀofꢀChemistryꢀ20xxꢀ
J.ꢀName.,ꢀ2013,ꢀ00,ꢀ1-3ꢀ|ꢀ10ꢀ
Pleaseꢀdoꢀnotꢀadjustꢀmarginsꢀ

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