A Short Synthesis of Delavatine A Unveils New Insights into Site-Selective Cross-Coupling of 3,5-Dibromo-2-pyrone

Article abstract of DOI:10.1021/jacs.8b13012

The recognition of latent symmetry in delavatine A has enabled a short synthesis of the natural product starting from 3,5-dibromo-2-pyrone. The concise synthetic route features a cascade process involving a 6p electrocyclization to construct the indane co

Full text of DOI:10.1021/jacs.8b13012

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Article
A short synthesis of delavatine A unveils new insights
into site-selective cross-coupling of 3,5-dibromo-2-pyrone
Vignesh Palani, Cedric L Hugelshofer, Ilia Kevlishvili, Peng Liu, and Richmond Sarpong
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.8b13012 • Publication Date (Web): 15 Jan 2019
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Journal of the American Chemical Society
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A short synthesis of delavatine A unveils new insights into site-selec-
tive cross-coupling of 3,5-dibromo-2-pyrone
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VigneshꢀPalani, ꢀCedricꢀL.ꢀHugelshofer, ꢀIliaꢀKevlishvili, ꢀPengꢀLiu,* ꢀandꢀRichmondꢀSarpong* ꢀ
†
ꢀDepartmentꢀofꢀChemistry,ꢀUniversityꢀofꢀCalifornia,ꢀBerkeley,ꢀCAꢀ94720ꢀ(USA)ꢀ
§
ꢀ
DepartmentꢀofꢀChemistry,ꢀUniversityꢀofꢀPittsburgh,ꢀPittsburgh,ꢀPAꢀ15260ꢀ(USA)ꢀ
SupportingꢀInformationꢀPlaceholder
ABSTRACT:ꢀTheꢀrecognitionꢀofꢀlatentꢀsymmetryꢀinꢀdelavatineꢀAꢀhasꢀenabledꢀaꢀshortꢀsynthesisꢀofꢀtheꢀnaturalꢀproductꢀstartingꢀfromꢀ
3
,5-dibromo-2-pyrone.ꢀTheꢀconciseꢀsyntheticꢀrouteꢀfeaturesꢀaꢀcascadeꢀprocessꢀinvolvingꢀaꢀ6pꢀelectrocyclizationꢀtoꢀconstructꢀtheꢀ
indaneꢀcoreꢀofꢀdelavatineꢀA.ꢀInꢀaddition,ꢀweꢀhaveꢀconductedꢀdetailedꢀexperimentalꢀandꢀcomputationalꢀstudiesꢀtoꢀgainꢀin-depthꢀ
understandingꢀofꢀtheꢀmechanismꢀofꢀtheꢀobservedꢀsite-selectiveꢀcross-couplingꢀofꢀ3,5-dibromo-2-pyrone.ꢀThisꢀinsightꢀmayꢀprovideꢀ
newꢀavenuesꢀtoꢀachieveꢀtheꢀselectiveꢀcross-couplingꢀofꢀmultiply-halogenatedꢀheteroarenes.
Introductionꢀ
Schemeꢀ1.ꢀRetrosyntheticꢀplanꢀandꢀsite-selectiveꢀcross-cou-
plingꢀofꢀ3,5-dibromo-2-pyroneꢀ
PlantsꢀofꢀtheꢀIncarvilleaꢀgenus,ꢀnativeꢀtoꢀtheꢀHimalayasꢀandꢀ
Southwestꢀ China,ꢀ haveꢀ attractedꢀ considerableꢀ interestꢀ be-
causeꢀofꢀtheirꢀuseꢀinꢀtraditionalꢀherbalꢀmedicine. Incarvilleaꢀ
delavayiꢀhasꢀbeenꢀusedꢀasꢀaꢀmedicinalꢀplantꢀtoꢀtreatꢀanemia,ꢀ
rheumatismꢀandꢀdizziness. ꢀRecently,ꢀaꢀstructurallyꢀuniqueꢀal-
kaloid,ꢀ delavatineꢀ Aꢀ (1,ꢀ Schemeꢀ 1a)ꢀ wasꢀ isolatedꢀ fromꢀ I.ꢀ
delavayiꢀbyꢀZhangꢀandꢀco-workers. Thisꢀunusualꢀisoquinoline-
containingꢀ alkaloidꢀ displaysꢀ micromolarꢀ antitumorꢀ activityꢀ
a) previous work - Li, Zhang, and coworkers, Ref. 4a
1ꢀ
•
asymmetric hydrogenation
• triflamide directed C–H olefination
Me
2
Me
H
Me
NHTf
H
NHTf
N
ꢀ
H
CO Me
2
3
CHO
againstꢀaꢀnumberꢀofꢀhumanꢀcancerꢀcellꢀlines. ꢀNotꢀsurprisingly,ꢀ
MeO
MeO
theꢀuniqueꢀarchitectureꢀandꢀnovelꢀbiologicalꢀactivityꢀofꢀ1ꢀhasꢀ
madeꢀitꢀanꢀattractiveꢀsyntheticꢀtarget.ꢀAnꢀelegantꢀtotalꢀsynthe-
sisꢀofꢀ1ꢀwasꢀrecentlyꢀreportedꢀbyꢀLiꢀetꢀal.ꢀthatꢀfeaturedꢀanꢀasym-
metricꢀhydrogenationꢀofꢀanꢀindenylꢀolefinꢀgroupꢀasꢀwellꢀasꢀtheꢀ
applicationꢀ ofꢀ aꢀ triflamide-directedꢀ C–Hꢀ olefinationꢀ methodꢀ
Me
delavatine A
1
2
3
b) our work - latent symmetry inspired retrosynthetic analysis
Me
O
Me
4
aꢀ
Me
O
R1
O
(Schemeꢀ1a).
CHO
R1
O
Biosynthetically,ꢀitꢀhasꢀbeenꢀproposedꢀthatꢀdelavatineꢀAꢀ(1)ꢀisꢀ
derivedꢀfromꢀtrisaldehydeꢀ4ꢀ(Schemeꢀ1b). ꢀOnꢀthisꢀbasis,ꢀourꢀ
6π
E/Z
3
CHO
R2
1
O
R2
syntheticꢀdesignꢀtargetedꢀaꢀfinalꢀstage,ꢀbioinspired,ꢀcondensa-
tionꢀofꢀ4ꢀwithꢀanꢀammoniaꢀsourceꢀtoꢀyieldꢀtheꢀisoquinolineꢀmoi-
etyꢀinꢀ1.ꢀFurthermore,ꢀweꢀrecognizedꢀtheꢀlatentꢀsymmetryꢀinꢀ4ꢀ
(seeꢀhighlightedꢀcyclopentenyls),ꢀwhichꢀweꢀenvisionedꢀcouldꢀ
translateꢀintoꢀanꢀelegantꢀandꢀpowerfulꢀretrosyntheticꢀdiscon-
nection.ꢀ Leveragingꢀ molecularꢀ symmetryꢀ (bothꢀ hiddenꢀ andꢀ
overt)ꢀinꢀtotalꢀsynthesisꢀisꢀespeciallyꢀpowerfulꢀasꢀitꢀmayꢀfacili-
tateꢀtheꢀidentificationꢀofꢀradicallyꢀsimplifiedꢀprecursors,ꢀandꢀinꢀ
O
O
O
CHO
4
Me
Me
Me
5
6
biosynthetic precursor
c) experimental/computational studies related to site selective cross-coupling
of 3,5-dibromo-2-pyrone
5
ꢀ
R
O
O
3
Me
thisꢀwayꢀenhanceꢀsyntheticꢀefficiency.
O
[
Pd], RX
9-R
Byꢀ takingꢀ advantageꢀ ofꢀ theꢀ latentꢀ symmetryꢀ ofꢀ 4,ꢀ weꢀ alsoꢀ
soughtꢀtoꢀdeviseꢀaꢀmodularꢀandꢀconvergentꢀsyntheticꢀrouteꢀtoꢀ
4ꢀthroughꢀanꢀambitiousꢀcascadeꢀsequenceꢀstartingꢀfromꢀpseu-
dosymmetricꢀ pyroneꢀ 7.ꢀ Moreꢀ specifically,ꢀ itꢀ wasꢀ anticipatedꢀ
thatꢀtheꢀindaneꢀcoreꢀofꢀ4ꢀwouldꢀbeꢀforgedꢀbyꢀ6pꢀelectrocycliza-
tion ꢀofꢀcross-conjugatedꢀdienolateꢀ5,ꢀwhichꢀinꢀturnꢀwouldꢀariseꢀ
fromꢀ theꢀ highlyꢀ conjugatedꢀ polyeneꢀ 6.ꢀ Givenꢀ theꢀ inherentꢀ
pseudosymmetryꢀofꢀpyroneꢀ7,ꢀthisꢀintermediateꢀwasꢀtracedꢀꢀ
R1
O
C3-coupling
Br
Br
O
O
Br
3
O
5
8
R3
Br
O
O
6
[Pd], RX
O
10-R
Me
C5-coupling
7
5
R
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Journal of the American Chemical Society
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backꢀtoꢀknownꢀ3,5-dibromo-2-pyroneꢀ(8) ꢀandꢀtheꢀcorrespond-
ingꢀcyclopentenylꢀcouplingꢀpartnersꢀ(highlightedꢀinꢀblueꢀinꢀpy-
roneꢀ7)ꢀthroughꢀsite-selectiveꢀcross-couplingꢀreactions.ꢀ
Tableꢀ1.ꢀSuzukiꢀcouplingsꢀwithꢀ3,5-dibromo-2-pyroneꢀ
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
O
O
O
O
Br
PhB(OH)2
Ph
Br
Ph
O
O
O
O
3
3
,5-Dibromo-2-pyroneꢀ(8)ꢀisꢀanꢀa-pyroneꢀderivedꢀpolyhalogen-
atedꢀ heterocycleꢀ bearingꢀ twoꢀ chemicallyꢀ inequivalentꢀ C–Brꢀ
bonds. ꢀSite-selectiveꢀmodificationsꢀofꢀ8,ꢀleadingꢀtoꢀconstitu-
tionalꢀisomericꢀproducts,ꢀhaveꢀbeenꢀdemonstratedꢀbyꢀChoꢀandꢀ
+
+
conditions
5
8
Br
Br
Ph
Ph
8
9
10
11
9
–11
co-workersꢀinꢀvariousꢀcross-couplingꢀprocesses. ꢀWhileꢀcer-
tainꢀexperimentalꢀconditionsꢀhaveꢀbeenꢀestablishedꢀthatꢀena-
bleꢀsite-selectiveꢀcouplingꢀinꢀ8,ꢀtheꢀmechanisticꢀrationaleꢀforꢀ
thisꢀ observedꢀ selectivityꢀ hasꢀ notꢀ beenꢀ unequivocallyꢀ estab-
yieldb (%) 9:10:11
rt (w/ CuI)
nd:12:nd
nd:18:nd
tr:32:nd
εa
Solvent
Δ
(w/o CuI)
Δ (w/ CuI)
8:13:nd
4
7
DMSO
DMF
—c
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
3
8.25
tr:nd:nd
53:nd:nd
70:nd:nd
47:nd:19
52:nd:nd
18 b
15:37:nd
16:29:nd
58:tr:11
ꢀ
lished. Site-selectiveꢀcross-couplingꢀreactionsꢀofꢀpolyhalogen-
1
2
21.01
0.42
7.52
.38
acetone
DCE
atedꢀ heterocycles ꢀ allowꢀ highlyꢀ efficientꢀ retrosyntheticꢀ dis-
connectionsꢀ andꢀ haveꢀ evolvedꢀ toꢀ beꢀ invaluableꢀ transfor-
1
57:13:nd
27:8:nd
1
3
THF
49:17:nd
56:tr:tr
mationsꢀforꢀbothꢀacademicꢀandꢀindustrialꢀresearchers. ꢀWhileꢀ
severalꢀstudiesꢀaimedꢀatꢀunderstandingꢀtheꢀbasisꢀofꢀsite-selec-
2
toluene
55:tr:nd
1
4
a
1
tiveꢀcouplingsꢀhaveꢀemergedꢀoverꢀtheꢀpastꢀdecade, ꢀpredictingꢀ
andꢀ rationalizingꢀ theꢀ selectivityꢀ outcomeꢀ hasꢀ oftentimesꢀ re-
Dielectricꢀconstantꢀatꢀ20ꢀ°C. ꢀ Determinedꢀbyꢀ HꢀNMRꢀanalysisꢀ
usingꢀ1,1,2,2-tetrachloroethaneꢀasꢀanꢀinternalꢀstandard.ꢀ Decom-
positionꢀ ofꢀ 8.ꢀ Conditions:ꢀ PhB(OH) ꢀ (1.2ꢀ equiv),ꢀ Pd(PPh ) ꢀ (10ꢀ
2 3
mol%),ꢀCuIꢀ(1.0ꢀequiv),ꢀK CO ꢀ(2.0ꢀequiv),ꢀsolventꢀ(0.1ꢀM).ꢀndꢀ=ꢀnotꢀ
c
8
,12a
mainedꢀ challenging. ꢀ Inꢀ someꢀ polyhaloaromaticꢀ com-
2
3 4
1
pounds,ꢀconsiderationꢀofꢀ HꢀNMRꢀchemicalꢀshiftsꢀofꢀtheꢀC–Hꢀ
bondsꢀinꢀtheꢀcorrespondingꢀnon-halogenatedꢀaromaticꢀcom-
poundsꢀ canꢀ guideꢀ theꢀ predictionꢀ ofꢀ site-selectiveꢀ transfor-
detectable,ꢀtrꢀ=ꢀtrace.ꢀꢀ
Inꢀ polarꢀ solventsꢀ (DMF),ꢀ weꢀ observedꢀ theꢀ formationꢀ ofꢀ 12ꢀ
whenꢀtheꢀreactionꢀwasꢀconductedꢀinꢀtheꢀabsenceꢀofꢀCuI,ꢀwhileꢀ
C5-Pdꢀ complexꢀ 13ꢀ wasꢀ formedꢀ asꢀ theꢀ majorꢀ productꢀ inꢀ theꢀ
presenceꢀofꢀCuI.ꢀTheꢀstructuresꢀofꢀ12ꢀandꢀ13ꢀwereꢀunambigu-
1
5
mations. ꢀHowever,ꢀtheꢀcross-couplingꢀofꢀ3,5-dibromo-2-py-
roneꢀ(8)ꢀgivesꢀriseꢀtoꢀproductsꢀthatꢀareꢀcontraryꢀtoꢀthisꢀpre-
8
dictedꢀoutcome. ꢀHence,ꢀweꢀsoughtꢀtoꢀgatherꢀfurtherꢀmecha-
nisticꢀinsightꢀtoꢀguideꢀpredictable,ꢀsite-selectiveꢀcouplingsꢀinꢀ8.ꢀ
19
ouslyꢀ confirmedꢀ byꢀ single-crystalꢀ X-rayꢀ analysis. ꢀ Notably,ꢀ
ꢀ
theseꢀ oxidativeꢀ additionꢀ experimentsꢀ areꢀ alsoꢀ supportedꢀ byꢀ
theꢀobservedꢀpositionꢀselectivityꢀinꢀSuzukiꢀcouplingꢀofꢀ8ꢀ(Tableꢀ
1),ꢀwhereꢀtheꢀC5-coupledꢀproductꢀ(10)ꢀwasꢀonlyꢀformedꢀinꢀpo-
larꢀsolventsꢀandꢀinꢀtheꢀpresenceꢀofꢀCuI.ꢀ
MechanisticꢀStudiesꢀ
Onꢀ theꢀ basisꢀ ofꢀ previousꢀ studiesꢀ conductedꢀ byꢀ Choꢀ andꢀ co-
workers,ꢀweꢀrecognizedꢀthatꢀsolventꢀchoice,ꢀtemperature,ꢀandꢀ
additionꢀofꢀcopperꢀiodideꢀappearedꢀtoꢀhaveꢀaꢀmarkedꢀinfluenceꢀ
Tableꢀ2.ꢀOxidativeꢀadditionꢀexperimentsꢀ
9
–11
onꢀtheꢀobservedꢀcouplingꢀselectivityꢀinꢀ8. ꢀTableꢀ1ꢀsumma-
rizesꢀourꢀresultsꢀofꢀtheꢀsite-selectiveꢀSuzukiꢀcouplingꢀofꢀ8ꢀandꢀ
O
O
O
Br
Pd(PPh3)4 (10 mol%)
3
PdL X
Br
2
10
O
O
O
3
phenylꢀboronicꢀacid.ꢀConsistentꢀwithꢀtheꢀresultsꢀofꢀChoꢀetꢀal., ꢀ
weꢀ foundꢀ thatꢀ inꢀ non-polarꢀ solvents,ꢀ suchꢀ asꢀ 1,2-dichloro-
ethane,ꢀtetrahydrofuran,ꢀandꢀtoluene,ꢀC3-coupledꢀproductꢀ9ꢀ
wasꢀprimarilyꢀformed.ꢀInꢀtheseꢀsolvents,ꢀneitherꢀtheꢀadditionꢀ
ofꢀCuIꢀnorꢀconductingꢀtheꢀreactionꢀatꢀelevatedꢀtemperatureꢀaf-
fectedꢀtheꢀobservedꢀsite-selectivity.ꢀInterestingly,ꢀinꢀmoreꢀpo-
larꢀsolvents,ꢀsuchꢀasꢀdimethylꢀsulfoxide,ꢀdimethylformamide,ꢀ
andꢀacetone,ꢀC5-coupledꢀproductꢀ10ꢀwasꢀgenerallyꢀformedꢀasꢀ
theꢀmajorꢀproduct.ꢀHowever,ꢀ9ꢀwasꢀformedꢀinꢀtheꢀabsenceꢀofꢀ
+
conditions
5
5
Br
Br
PdL X
2
L = PPh3
X = Br
8
12
13
yielda (%) 12:13
Solvent
rt (w/o CuI)
Δ
(w/o CuI)
rt (w/ CuI)
Δ (w/ CuI)
14:23
DMF
31:nd
32:nd
39:nd
50:nd
11:20
29:nd
toluene
50:nd
1
6
CuIꢀandꢀwhenꢀtheꢀreactionꢀwasꢀconductedꢀinꢀacetone. ꢀInꢀcon-
1
1
trastꢀtoꢀtheꢀobservationsꢀofꢀChoꢀetꢀal., ꢀweꢀdidꢀnotꢀobserveꢀaꢀ
switchꢀinꢀtheꢀsite-selectivityꢀuponꢀincreasingꢀtheꢀreactionꢀtem-
peratureꢀfromꢀ23ꢀ°Cꢀtoꢀ50ꢀ°C.ꢀOverall,ꢀweꢀfoundꢀtheꢀselectivityꢀ
ofꢀ theꢀ cross-couplingꢀ reactionsꢀ toꢀ beꢀ non-temperatureꢀ de-
pendent,ꢀandꢀtoꢀproceedꢀpredominantlyꢀatꢀtheꢀC3-positionꢀinꢀ
non-polarꢀsolvents,ꢀwhileꢀcouplingꢀisꢀfavoredꢀatꢀtheꢀC5ꢀpositionꢀ
inꢀpolarꢀsolventsꢀinꢀtheꢀpresenceꢀofꢀCuI.ꢀ
1
2-trans [X-ray]
13-trans [X-ray]
ꢀ
ToꢀgainꢀmoreꢀinsightꢀintoꢀtheꢀeffectꢀofꢀCuIꢀinꢀtheseꢀcross-cou-
plingꢀreactions,ꢀweꢀchoseꢀtoꢀrevisitꢀseveralꢀoxidativeꢀadditionꢀ
a
1
Determinedꢀbyꢀ HꢀNMRꢀanalysisꢀusingꢀ1,1,2,2-tetrachloroethaneꢀ
10,11
experimentsꢀpreviouslyꢀconductedꢀbyꢀChoꢀandꢀco-workers,
andꢀanalyzeꢀtheꢀrelativeꢀstabilitiesꢀofꢀtheꢀresultingꢀC3ꢀandꢀC5-
ꢀ
asꢀanꢀinternalꢀstandard.ꢀTheꢀNMRꢀyieldsꢀwereꢀcalculatedꢀwithꢀre-
spectꢀ toꢀ theꢀ amountꢀ ofꢀ Pd(PPh ꢀ usedꢀ (10ꢀ mol%).ꢀ Conditions:ꢀ
Pd(PPh ꢀ(10ꢀmol%),ꢀCuIꢀ(1.0ꢀequiv),ꢀsolventꢀ(0.1ꢀM).ꢀndꢀ=ꢀnotꢀde-
tectable.ꢀ
3 4
)
17ꢀ
Pdꢀcomplexesꢀ(12ꢀandꢀ13,ꢀTableꢀ2). Weꢀobservedꢀthatꢀwhenꢀ
3 4
)
theꢀ oxidativeꢀ additionꢀ wasꢀ conductedꢀ inꢀ non-polarꢀ solventsꢀ
(
toluene)ꢀonlyꢀC3-Pdꢀcomplexꢀ12ꢀwasꢀformed,ꢀirrespectiveꢀofꢀ
Next,ꢀtheꢀoxidativeꢀadditionꢀexperimentsꢀwereꢀcarriedꢀoutꢀatꢀ
differentꢀreactionꢀtemperaturesꢀinꢀtheꢀpresenceꢀofꢀCuIꢀwithꢀ
theꢀreactionꢀtemperatureꢀorꢀwhetherꢀCuIꢀwasꢀadded.ꢀꢀꢀꢀ
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DMFꢀasꢀtheꢀsolventꢀ(Figureꢀ1).ꢀItꢀwasꢀobservedꢀthatꢀC5ꢀPdꢀoxi-
ismꢀwithꢀaꢀdifferentꢀactiveꢀPdꢀcatalyst.ꢀBecauseꢀpreviousꢀcom-
putationalꢀstudiesꢀhaveꢀsuggestedꢀaꢀbis-phosphineꢀligatedꢀPdꢀ
complexꢀisꢀmoreꢀfavoredꢀforꢀoxidativeꢀadditionꢀwithꢀPPh ꢀasꢀ
ligand, ꢀ theꢀ oxidativeꢀ additionꢀ inꢀ theꢀ absenceꢀ ofꢀ CuIꢀ isꢀ ex-
pectedꢀtoꢀoccurꢀviaꢀtri-coordinatedꢀ(PPh Pd(0)-pyroneꢀcom-
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
dativeꢀadductꢀ13ꢀwasꢀfavoredꢀatꢀlowerꢀtemperaturesꢀwhereasꢀ
atꢀ elevatedꢀ temperature,ꢀ C3ꢀ Pdꢀ oxidativeꢀ adductꢀ 12ꢀ wasꢀ
formedꢀasꢀtheꢀmajorꢀproduct.ꢀFurtherꢀexperimentsꢀrevealedꢀ
thatꢀC5ꢀPdꢀoxidativeꢀadductꢀ13ꢀconvertsꢀtoꢀC3ꢀPdꢀoxidativeꢀad-
ductꢀ12ꢀinꢀDMFꢀinꢀtheꢀpresenceꢀofꢀCuIꢀatꢀelevatedꢀtempera-
3
2
3
3 2
)
plexꢀ14ꢀ(Schemeꢀ2).ꢀAdditionally,ꢀonꢀtheꢀbasisꢀofꢀempiricallyꢀes-
20
turesꢀandꢀoverꢀprolongedꢀreactionꢀperiods. ꢀꢀ
tablishedꢀprecedentꢀsupportingꢀtheꢀabilityꢀofꢀCuIꢀtoꢀpromoteꢀ
2
4
phosphineꢀligandꢀexchangeꢀatꢀPd, ꢀweꢀhypothesizedꢀthatꢀCuIꢀ
couldꢀhaveꢀaꢀsimilarꢀeffectꢀinꢀthisꢀsystem.ꢀInꢀthisꢀway,ꢀCuIꢀcouldꢀ
promoteꢀ phosphineꢀ ligandꢀ dissociationꢀ fromꢀ 14ꢀ toꢀ formꢀ aꢀ
mono-phosphineꢀligatedꢀPdꢀcomplexꢀ(16ꢀorꢀ17,ꢀSchemeꢀ2)ꢀasꢀ
theꢀ operativeꢀ intermediateꢀ inꢀ theꢀ catalyticꢀ cycle,ꢀ whichꢀ hasꢀ
beenꢀreportedꢀtoꢀbeꢀrelativelyꢀmoreꢀreactiveꢀtowardꢀoxidativeꢀ
1
00%
8
6
4
0%
0%
0%
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
5
addition. ꢀIndeed,ꢀourꢀDFTꢀcalculationsꢀshowꢀthatꢀexchangingꢀ
oneꢀ ofꢀ theꢀ PPh ꢀ ligandsꢀ inꢀ 14ꢀ withꢀ (DMF) CuIꢀ (15)ꢀ toꢀ formꢀ
mono-phosphineꢀ ligatedꢀ Pdꢀ complexesꢀ 17ꢀ andꢀ 16ꢀ areꢀ bothꢀ
20%
3
2
0
%
0 °C
23 °C
50 °C
70 °C
100 °C
2
6
thermodynamicallyꢀ feasible, ꢀ indicatingꢀ anꢀ equilibriumꢀ be-
tweenꢀtheꢀbis-ꢀandꢀmono-phosphineꢀligatedꢀPdꢀcomplexesꢀbe-
foreꢀtheꢀoxidativeꢀadditionꢀstep.ꢀFurthermore,ꢀinꢀtheꢀabsenceꢀ
ofꢀCuI,ꢀformationꢀofꢀtheꢀmono-phosphineꢀligatedꢀPdꢀcomplexesꢀ
temperature (°C)
C3-Pd complex 12
C5-Pd complex 13
ꢀꢀ
Figureꢀ1.ꢀInfluenceꢀofꢀtemperatureꢀonꢀratiosꢀofꢀC3-ꢀtoꢀC5-Pdꢀ
complexes.ꢀConditions:ꢀPd(PPh ꢀ(10ꢀmol%),ꢀCuIꢀ(1.0ꢀequiv),ꢀ
DMFꢀ(0.1ꢀM).
Interestingly,ꢀwhenꢀaꢀmixtureꢀofꢀPdꢀoxidativeꢀadductsꢀ12ꢀandꢀ
3ꢀwasꢀtreatedꢀwithꢀtributylphenylstannaneꢀinꢀDMF,ꢀonlyꢀtheꢀ
C5-coupledꢀproductꢀ(10)ꢀwasꢀformed, ꢀindicatingꢀthatꢀ12ꢀcanꢀ
alsoꢀinterconvertꢀtoꢀ13ꢀpriorꢀtoꢀcross-coupling.ꢀInꢀsummary,ꢀourꢀ
observationsꢀindicateꢀthatꢀC5-Pdꢀcomplexꢀ13ꢀisꢀtheꢀkineticꢀoxi-
dativeꢀ adductꢀ whereasꢀ C3-Pdꢀ complexꢀ 12ꢀ isꢀ theꢀ thermody-
namicꢀoxidativeꢀadduct.ꢀMoreover,ꢀ12ꢀandꢀ13ꢀcanꢀinterconvert,ꢀ
andꢀtheꢀrateꢀofꢀtransmetallation/reductiveꢀeliminationꢀisꢀfasterꢀ
forꢀC5-Pdꢀcomplexꢀ13ꢀwhenꢀcomparedꢀtoꢀthatꢀofꢀC3-Pdꢀcom-
20
isꢀhighlyꢀendergonicꢀ(ΔGꢀ≥ꢀ13ꢀkcal/mol), ꢀindicatingꢀtheꢀbis-
3 4
)
phosphineꢀligatedꢀPdꢀcomplexꢀ14ꢀisꢀoperativeꢀunderꢀtheseꢀcon-
ꢀ
ditions.
ꢀ
Schemeꢀ2.ꢀComputedꢀligandꢀexchangeꢀenergiesꢀfromꢀtheꢀbis-
phosphineꢀligatedꢀPdꢀcomplexꢀ14ꢀtoꢀformꢀmono-phosphineꢀli-
gatedꢀPdꢀcomplexesꢀ16ꢀandꢀ17.ꢀ
1
2
0
O
Br
DMF
O
Pd PPh3
DMF
+
Cu
I
ΔG = 3.1 kcal/mol
Ph P
3
O
Br
O
Br
DMF
Cu
17
18
O
Pd PPh3
PPh3
+
2
1
plexꢀ12.ꢀThisꢀdescribesꢀaꢀCurtin–Hammettꢀscenario ꢀwhereinꢀ
rapidꢀinterconversionꢀofꢀtheꢀPd-complexesꢀ(12ꢀandꢀ13)ꢀoccurs,ꢀ
andꢀwhereꢀtheꢀratioꢀofꢀtheꢀresultingꢀcross-coupledꢀproductsꢀ
i.e.,ꢀ9:10)ꢀisꢀsolelyꢀdependentꢀonꢀtheꢀenergyꢀdifferenceꢀbe-
tweenꢀ theꢀ twoꢀ respectiveꢀ rate-limitingꢀ transitionꢀ statesꢀ ofꢀ
DMF
I
Br 14
15
Br
DMF
–
+
DMF
DMF
O
Pd PPh3
+
(
Cu
I
Ph P
3
ΔG = –0.1 kcal/mol
Br
1
6
18
transmetallation/reductiveꢀelimination.
ꢀ
ꢀꢀ
ꢀ
Therefore,ꢀweꢀcomputedꢀtheꢀoxidativeꢀadditionꢀpathwaysꢀfromꢀ
complexesꢀ14ꢀ(Figureꢀ2A),ꢀ16ꢀ(Figureꢀ2B),ꢀandꢀ17ꢀ(FigureꢀS3Aꢀinꢀ
theꢀSupportingꢀInformation).ꢀInterestingly,ꢀtheꢀoxidativeꢀaddi-
tionsꢀ ofꢀ 14ꢀ andꢀ 16ꢀ haveꢀ veryꢀ differentꢀ site-selectivityꢀ out-
comes.ꢀInꢀtheꢀbis-phosphineꢀligatedꢀPdꢀcomplexꢀpathway,ꢀtheꢀ
barrierꢀforꢀtheꢀoxidativeꢀadditionꢀatꢀC3ꢀ(TS1;ꢀFigureꢀ2A)ꢀisꢀ3.5ꢀ
kcal/molꢀlowerꢀthanꢀthatꢀatꢀC5ꢀ(TS2).ꢀFollowingꢀcis/transꢀisom-
erizationꢀofꢀtheꢀphosphineꢀligandsꢀonꢀtheꢀoxidativeꢀadditionꢀ
complexesꢀ(i.e.,ꢀ12-cisꢀandꢀ13-cis,ꢀrespectively),ꢀtheꢀC3ꢀadductꢀ
ComputationalꢀInsightꢀ
Weꢀsoughtꢀtoꢀgainꢀadditionalꢀinsightꢀintoꢀtheꢀoriginsꢀofꢀtheꢀef-
fectsꢀofꢀCuIꢀandꢀsolventꢀonꢀtheꢀkineticꢀandꢀthermodynamicꢀse-
lectivitiesꢀ ofꢀ theꢀ oxidativeꢀ additionꢀ throughꢀ computationalꢀ
studies.ꢀDensityꢀfunctionalꢀtheoryꢀ(DFT)ꢀcalculationsꢀwereꢀper-
formedꢀatꢀtheꢀM06/6-311+G(d,p)-SDD/SMD(DMF)//B3LYP/6-
20
3
1G(d)-SDDꢀlevelꢀofꢀtheory. ꢀWeꢀfirstꢀcomputationallyꢀconsid-
eredꢀtheꢀLewis-acidꢀactivationꢀofꢀtheꢀpyroneꢀthroughꢀcoordina-
tionꢀofꢀCuIꢀorꢀcationicꢀ(DMF)Cu ꢀtoꢀtheꢀcarbonylꢀgroupꢀofꢀ8.ꢀ
However,ꢀtheseꢀresultsꢀindicatedꢀthatꢀtheꢀCuIꢀorꢀCu ꢀcoordina-
+
(
12-trans)ꢀisꢀslightlyꢀ(0.3ꢀkcal/mol)ꢀmoreꢀstableꢀthanꢀtheꢀC5ꢀad-
+
ductꢀ(13-trans).ꢀTheseꢀresultsꢀareꢀconsistentꢀwithꢀtheꢀexperi-
mentallyꢀobservedꢀC3-selectivityꢀforꢀoxidativeꢀadditionꢀinꢀDMFꢀ
andꢀtolueneꢀinꢀtheꢀabsenceꢀofꢀCuIꢀ(seeꢀTableꢀ2).ꢀToꢀunderstandꢀ
theꢀfactorsꢀgoverningꢀtheꢀC3ꢀsite-selectivity,ꢀweꢀperformedꢀaꢀ
distortion/interactionꢀanalysisꢀtoꢀinvestigateꢀtheꢀdistortionꢀen-
ergiesꢀofꢀtheꢀcatalystꢀ(∆Edist-cat)ꢀandꢀtheꢀpyroneꢀsubstrateꢀ(∆Edist-
sub)ꢀtoꢀreachꢀtheirꢀtransitionꢀstateꢀgeometriesꢀasꢀwellꢀasꢀtheꢀsta-
bilizingꢀinteractionꢀenergyꢀ(∆Eint)ꢀbetweenꢀtheꢀtwoꢀfragmentsꢀ
tionꢀhasꢀaꢀminimalꢀimpactꢀonꢀtheꢀsite-selectivityꢀofꢀoxidativeꢀ
20
addition, ꢀ andꢀ thusꢀ cannotꢀ explainꢀ theꢀ experimentallyꢀ ob-
servedꢀsite-selectivityꢀtrendꢀunderꢀtheꢀdifferentꢀconditions.ꢀAd-
ditionally,ꢀweꢀconsideredꢀtheꢀpathwayꢀinvolvingꢀoxidativeꢀad-
22
‡
ditionꢀofꢀpyroneꢀ8ꢀtoꢀCuI ꢀ(∆G ꢀ=ꢀ27.2ꢀkcal/mol,ꢀwithꢀrespectꢀ
toꢀtheꢀpyrone-CuIꢀπ-complex).ꢀThisꢀpathwayꢀrequiresꢀaꢀhigherꢀ
barrierꢀthanꢀtheꢀoxidativeꢀadditionꢀtoꢀPd(0)ꢀandꢀdoesꢀnotꢀsup-
portꢀtheꢀobservedꢀreversalꢀofꢀꢀsite-selectivityꢀinꢀtheꢀpresenceꢀ
2
7
(Figureꢀ2A). ꢀAlthoughꢀtheꢀC3-oxidativeꢀadditionꢀhasꢀanꢀearlierꢀ
transitionꢀstate,ꢀasꢀevidencedꢀbyꢀtheꢀsmallerꢀsubstrateꢀdistor-
tionꢀenergyꢀ(DEdist-sub)ꢀandꢀtheꢀshorterꢀC−Brꢀbondꢀdistanceꢀinꢀ
TS1,ꢀtheꢀinteractionꢀbetweenꢀtheꢀcatalystꢀandꢀtheꢀsubstrateꢀinꢀ
(20)
ofꢀCuI. ꢀAsꢀsuch,ꢀweꢀsurmisedꢀthatꢀinꢀtheꢀpresenceꢀofꢀCuIꢀtheꢀ
oxidativeꢀadditionꢀmayꢀoccurꢀthroughꢀanꢀalternativeꢀmechan-
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 4 of 11
TS1ꢀ(∆Eint)ꢀisꢀstillꢀstrongerꢀthanꢀthatꢀinꢀTS2ꢀbyꢀ2.6ꢀkcal/mol.ꢀTheꢀ observedꢀempiricallyꢀinꢀtheꢀpresenceꢀofꢀCuIꢀinꢀDMFꢀ(Tableꢀ2).ꢀ
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
strongerꢀcatalyst-substrateꢀinteractionꢀisꢀdueꢀtoꢀaꢀmoreꢀfavor-
ableꢀfrontierꢀmolecularꢀorbitalꢀ(FMO)ꢀinteractionꢀbetweenꢀtheꢀ
Distortion/interactionꢀanalysisꢀofꢀTS3ꢀandꢀTS4ꢀrevealsꢀthatꢀTS3ꢀ
hasꢀaꢀmoreꢀfavorableꢀinteractionꢀenergyꢀasꢀcomparedꢀtoꢀTS4.ꢀ
However,ꢀTS3ꢀisꢀaꢀlaterꢀtransitionꢀstateꢀwithꢀgreaterꢀdistortionꢀ
penaltyꢀofꢀtheꢀsubstrateꢀ(DEdist-sub),ꢀwhichꢀcompensatesꢀforꢀtheꢀ
interactionꢀenergyꢀdifferenceꢀandꢀleadsꢀtoꢀsimilarꢀbarriersꢀforꢀ
theꢀtwoꢀoxidativeꢀadditionꢀtransitionꢀstates.ꢀInꢀthisꢀmono-phos-
phineꢀligatedꢀPdꢀcomplexꢀpathway,ꢀPdꢀisꢀlessꢀnucleophilicꢀdueꢀ
toꢀaꢀlower-lyingꢀHOMO. ꢀTherefore,ꢀtheꢀFMOꢀinteractionꢀbe-
tweenꢀtheꢀPdꢀcenterꢀandꢀtheꢀsubstrateꢀisꢀlessꢀprominentꢀandꢀ
theꢀpreferenceꢀforꢀtheꢀC3ꢀoxidativeꢀadditionꢀselectivityꢀisꢀdi-
minished.
1
4a
LUMO(π*)ꢀofꢀ8ꢀandꢀtheꢀHOMOꢀ(dxy)ꢀofꢀtheꢀPdꢀinꢀTS1. ꢀTheꢀ
computedꢀLUMOꢀofꢀ8ꢀshowedꢀaꢀmuchꢀlargerꢀcoefficientꢀatꢀtheꢀ
2
8
C3-positionꢀthanꢀatꢀtheꢀC5ꢀpositionꢀ(Figureꢀ2Aꢀinset). ꢀꢀ
InꢀtheꢀpresenceꢀofꢀCuI,ꢀtheꢀC3ꢀandꢀC5ꢀoxidativeꢀadditionsꢀofꢀtheꢀ
mono-phosphineꢀligatedꢀPdꢀcomplexꢀ16ꢀ(TS3ꢀandꢀTS4,ꢀrespec-
tively,ꢀFigureꢀ2B)ꢀbothꢀrequireꢀlowerꢀbarriersꢀasꢀcomparedꢀtoꢀ
thoseꢀ ofꢀ bis-phosphineꢀ ligatedꢀ Pdꢀ complexꢀ 14.ꢀ Notably,ꢀ theꢀ
mono-phosphineꢀ ligatedꢀ Pdꢀ complexꢀ oxidativeꢀ additionꢀ noꢀ
longerꢀkineticallyꢀfavorsꢀtheꢀformationꢀofꢀC3-Pdꢀcomplexꢀ12ꢀ
andꢀtheꢀbarriersꢀforꢀTS3ꢀandꢀTS4ꢀareꢀcomparable.ꢀThisꢀisꢀcon-
sistentꢀwithꢀtheꢀlowꢀselectivityꢀforꢀtheꢀsiteꢀofꢀoxidativeꢀadditionꢀ
2
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
3
5
TS1
TS2
TS3
TS4
Figureꢀ2.ꢀA)ꢀOxidativeꢀadditionꢀofꢀtheꢀbis-phosphineꢀligatedꢀPdꢀcomplexꢀ14ꢀatꢀtheꢀC3-ꢀ(shownꢀinꢀblue)ꢀandꢀC5-ꢀ(inꢀred)ꢀpositionsꢀofꢀ
,5-dibromo-2-pyroneꢀ8ꢀinꢀtheꢀabsenceꢀofꢀCuI.ꢀB)ꢀOxidativeꢀadditionꢀofꢀtheꢀmono-phosphineꢀligatedꢀPdꢀcomplexꢀ16ꢀinꢀtheꢀpresenceꢀ
ofꢀCuI.ꢀTheꢀdistortionꢀenergiesꢀofꢀtheꢀPdL ꢀcatalystꢀ(DEdist-cat)ꢀandꢀtheꢀpyroneꢀsubstrateꢀ(DEdist-sub),ꢀandꢀtheꢀinteractionꢀenergiesꢀbe-
3
n
tweenꢀtheseꢀtwoꢀfragmentsꢀinꢀtheꢀoxidativeꢀadditionꢀtransitionꢀstatesꢀ(∆Eint)ꢀareꢀprovided.ꢀAllꢀenergiesꢀinꢀFigureꢀ2Aꢀareꢀwithꢀrespectꢀ
toꢀ14.ꢀAllꢀenergiesꢀinꢀFigureꢀ2Bꢀareꢀwithꢀrespectꢀtoꢀ16,ꢀ18,ꢀandꢀDMF.
ACS Paragon Plus Environment

Page 5 of 11
Journal of the American Chemical Society
Furthermore,ꢀweꢀrepeatedꢀtheꢀoxidativeꢀadditionꢀstudiesꢀinꢀtheꢀ
Weꢀ alsoꢀ consideredꢀ theꢀ oxidativeꢀ additionsꢀ ofꢀ theꢀ DMF-
20
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
coordinatedꢀmono-phosphineꢀligatedꢀPdꢀcomplexꢀ17.ꢀFromꢀ17,ꢀ
theꢀselectivityꢀbetweenꢀtheꢀC3ꢀandꢀC5ꢀoxidativeꢀadditionꢀtran-
sitionꢀstatesꢀisꢀalsoꢀdiminishedꢀ(∆∆G ꢀ=ꢀ0.8ꢀkcal/mol). ꢀOverall,ꢀ
theseꢀ resultsꢀ highlightꢀ aꢀ significantꢀ effectꢀ ofꢀ theꢀ numberꢀ ofꢀ
presenceꢀofꢀotherꢀphosphineꢀligands. ꢀWeꢀobservedꢀaꢀprefer-
enceꢀforꢀtheꢀformationꢀofꢀC5-Pdꢀcomplexꢀ13ꢀwhenꢀtheꢀoxida-
tiveꢀadditionꢀwasꢀcarriedꢀoutꢀusingꢀbulkyꢀphosphineꢀligands.ꢀ
ThisꢀobservationꢀsupportsꢀtheꢀrationaleꢀthatꢀtheꢀC5-Pdꢀcom-
plexꢀ13ꢀisꢀgeneratedꢀwhenꢀtheꢀoxidativeꢀadditionꢀproceedsꢀviaꢀ
aꢀ mono-phosphineꢀ ligatedꢀ Pdꢀ complex,ꢀ whichꢀ isꢀ favoredꢀ atꢀ
‡
20
3
PPh ꢀligandsꢀonꢀtheꢀselectivityꢀofꢀoxidativeꢀaddition.ꢀWhileꢀoxi-
dativeꢀ additionꢀ ofꢀ bis-phosphineꢀ ligatedꢀ Pdꢀ complexꢀ 14ꢀ isꢀ
stronglyꢀpreferredꢀatꢀC3,ꢀtheꢀsite-selectivityꢀisꢀdiminishedꢀinꢀre-
actionsꢀwithꢀtheꢀmono-phosphineꢀligatedꢀPdꢀcomplexesꢀ(16ꢀorꢀ
3
lowerꢀPPh ꢀconcentrationsꢀorꢀinꢀtheꢀpresenceꢀofꢀbulkierꢀphos-
phineꢀligands.ꢀTheꢀconclusionsꢀdrawnꢀfromꢀtheseꢀexperimentsꢀ
areꢀinꢀgoodꢀagreementꢀwithꢀourꢀcomputationally-derivedꢀre-
sults.ꢀ
1
7).ꢀꢀ
Followingꢀoxidativeꢀaddition,ꢀtheꢀmoreꢀelectron-deficientꢀPd(II)ꢀ
adductꢀbindsꢀanotherꢀPPh ꢀthroughꢀligandꢀexchangeꢀwithꢀtheꢀ
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
3
Weꢀnextꢀsoughtꢀtoꢀgainꢀcomputationalꢀinsightꢀintoꢀtheꢀoriginꢀofꢀ
C5-site-selectivityꢀofꢀtheꢀStilleꢀcouplingꢀreactionsꢀunderꢀcondi-
tionsꢀwhereꢀoxidativeꢀadditionꢀhasꢀbeenꢀestablishedꢀtoꢀbeꢀre-
CuI-phosphineꢀcomplexꢀtoꢀformꢀtetracoordinatedꢀPd(II)ꢀcom-
plexesꢀ12ꢀandꢀ13ꢀ(Figureꢀ2B).ꢀTheꢀcisꢀisomerꢀofꢀtheꢀC3ꢀadductꢀ
(12-cis)ꢀcanꢀbindꢀtoꢀCuIꢀtoꢀformꢀaꢀrelativelyꢀstableꢀternaryꢀCuꢀ
complexꢀ(19)ꢀinꢀwhichꢀtheꢀCuꢀcenterꢀisꢀcoordinatedꢀtoꢀbothꢀtheꢀ
pyroneꢀcarbonylꢀoxygenꢀandꢀtheꢀbromideꢀattachedꢀtoꢀtheꢀPdꢀ
center.ꢀ Itꢀ shouldꢀ beꢀ notedꢀ thatꢀ similarꢀ chelatingꢀ complexesꢀ
cannotꢀbeꢀformedꢀfromꢀ13-cis,ꢀorꢀeitherꢀofꢀtheꢀtrans-isomers. ꢀ
Becauseꢀofꢀtheꢀgreaterꢀstabilityꢀofꢀ19ꢀcomparedꢀtoꢀotherꢀC3ꢀandꢀ
C5ꢀadducts,ꢀtheꢀC3ꢀoxidativeꢀadditionꢀpathwayꢀisꢀthermody-
30
versibleꢀ (seeꢀ Tableꢀ S6ꢀ forꢀ experimentalꢀ details). ꢀ Inꢀ theseꢀ
cases,ꢀtheꢀselectivityꢀisꢀexpectedꢀtoꢀbeꢀdeterminedꢀinꢀtheꢀsub-
sequentꢀtransmetallationꢀorꢀreductiveꢀeliminationꢀsteps.ꢀWeꢀ
calculatedꢀ theꢀ C3-ꢀ andꢀ C5-selectiveꢀ pathwaysꢀ forꢀ theꢀ
transmetallationꢀandꢀreductiveꢀeliminationꢀstepsꢀfromꢀtheꢀoxi-
dativeꢀadductsꢀ12ꢀandꢀ13ꢀusingꢀtrimethylphenylstannaneꢀasꢀaꢀ
modelꢀ couplingꢀ partnerꢀ (Figureꢀ 4).ꢀ Weꢀ locatedꢀ theꢀ cyclicꢀ
transmetallationꢀ transitionꢀ statesꢀ whereꢀ theꢀ substrateꢀ andꢀ
bromideꢀareꢀeitherꢀcis-ꢀorꢀtrans-ꢀdisposed.ꢀInꢀaccordanceꢀwithꢀ
20
(20)
namicallyꢀmoreꢀfavorable. ꢀThisꢀisꢀconsistentꢀwithꢀtheꢀexper-
imentallyꢀobservedꢀtrendꢀthatꢀincreasingꢀtemperatureꢀleadsꢀtoꢀ
theꢀC3ꢀadductꢀasꢀtheꢀmajorꢀproductꢀ(Figureꢀ1).ꢀ
3
1
previousꢀ computationalꢀ studies, ꢀ theꢀ trans-transmetallationꢀ
transitionꢀstatesꢀ(TS5ꢀandꢀTS6)ꢀareꢀaboutꢀ5-6ꢀkcal/molꢀmoreꢀfa-
vorableꢀthanꢀtheꢀcorrespondingꢀcis-TS.ꢀTheꢀtransitionꢀstateꢀas-
sociatedꢀwithꢀtheꢀtransmetallationꢀofꢀtheꢀC5-adductꢀ(TS6)ꢀisꢀ2.0ꢀ
kcal/molꢀmoreꢀfavorableꢀthanꢀthatꢀofꢀtheꢀC3-adductꢀ(TS5)ꢀ(Fig-
ureꢀ4A).ꢀꢀ
WithꢀcomputationalꢀresultsꢀinꢀhandꢀthatꢀexplainꢀtheꢀroleꢀofꢀCuIꢀ
inꢀfacilitatingꢀformationꢀofꢀaꢀmono-phosphineꢀligatedꢀPdꢀcom-
plexꢀ(16ꢀorꢀ17)ꢀwhichꢀinꢀturnꢀkineticallyꢀfavorsꢀtheꢀformationꢀofꢀ
C5-Pdꢀcomplexꢀ13,ꢀweꢀsoughtꢀexperimentalꢀevidenceꢀtoꢀsup-
portꢀthisꢀpathway.ꢀTowardꢀthisꢀend,ꢀweꢀanalyzedꢀtheꢀratioꢀofꢀ
theꢀgeneratedꢀC3ꢀtoꢀC5-Pdꢀcomplexesꢀwhenꢀtheꢀoxidativeꢀad-
ditionꢀ wasꢀ carriedꢀ outꢀ withꢀ varyingꢀ concentrationsꢀ ofꢀ tri-
phenylphosphineꢀ (Figureꢀ 3).ꢀ Interestingly,ꢀ weꢀ observedꢀ thatꢀ
whenꢀtheꢀconcentrationꢀofꢀtriphenylphosphineꢀwasꢀincreased,ꢀ
C3-Pdꢀcomplexꢀ12ꢀwasꢀpredominantlyꢀformed.ꢀHence,ꢀweꢀpos-
Theseꢀcomputationalꢀresultsꢀareꢀconsistentꢀwithꢀtheꢀempiri-
callyꢀobservedꢀpreferableꢀcouplingꢀofꢀ13ꢀoverꢀ12,ꢀwhenꢀthisꢀ
20
mixtureꢀisꢀexposedꢀtoꢀtributylphenylstannane. ꢀToꢀbetterꢀun-
derstandꢀtheꢀoriginꢀofꢀthisꢀpreference,ꢀweꢀconsideredꢀtheꢀpo-
larityꢀofꢀtheꢀtransmetallationꢀtransitionꢀstates.ꢀWeꢀhypothe-
sizedꢀthatꢀsinceꢀTS6ꢀisꢀsignificantlyꢀmoreꢀpolarꢀthanꢀTS5ꢀdueꢀtoꢀ
theꢀgreaterꢀseparationꢀofꢀtheꢀpartialꢀpositiveꢀ(onꢀPd)ꢀandꢀneg-
ativeꢀ(onꢀtheꢀpyroneꢀcarbonylꢀoxygen)ꢀcharges,ꢀmoreꢀfavorableꢀ
stabilizationꢀofꢀthisꢀtransitionꢀstateꢀwouldꢀoccurꢀinꢀaꢀpolarꢀsol-
vent.ꢀInꢀsupportꢀofꢀthisꢀhypothesis,ꢀweꢀcalculatedꢀtheꢀgasꢀphaseꢀ
energiesꢀforꢀTS5ꢀandꢀTS6.ꢀTheseꢀcalculationsꢀshowꢀthatꢀtheꢀrel-
ativeꢀstabilityꢀisꢀreversedꢀinꢀtheꢀgasꢀphase,ꢀwhereꢀTS5ꢀisꢀfavoredꢀ
byꢀ2.6ꢀkcal/molꢀ(Figureꢀ4B).ꢀTherefore,ꢀtheꢀpolarꢀsolventꢀplaysꢀ
anꢀimportantꢀroleꢀinꢀdeterminingꢀtheꢀselectivityꢀforꢀtransmetal-
3
tulatedꢀthatꢀhigherꢀconcentrationsꢀofꢀPPh ꢀfavorꢀtheꢀoxidativeꢀ
additionꢀpathwayꢀinvolvingꢀaꢀbis-phosphineꢀligatedꢀPdꢀcomplexꢀ
whichꢀleadsꢀtoꢀformationꢀofꢀC3-Pdꢀcomplexꢀ12,ꢀinꢀconcertꢀwithꢀ
ourꢀcomputationalꢀstudies.ꢀꢀ
ꢀ
1
00%
80%
60%
40%
20%
0%
lation.ꢀTheꢀtransmetallationꢀandꢀsubsequentꢀligandꢀexchangeꢀ
II
withꢀCuI(PPh
3
)(DMF)ꢀ18ꢀleadsꢀtoꢀaꢀfour-coordinateꢀPd ꢀspeciesꢀ
(
20ꢀorꢀ21),ꢀwhichꢀthenꢀundergoesꢀreductiveꢀeliminationꢀviaꢀei-
therꢀ aꢀ bis-phosphineꢀ orꢀ mono-phosphineꢀ ligatedꢀ transitionꢀ
0
0.5
1
2
20ꢀ
stateꢀtoꢀformꢀcouplingꢀproductsꢀ9ꢀandꢀ10.
PPh (equiv)
3
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
C3-Pd complex 12
C5-Pd complex 13
ꢀ
Figureꢀ3.ꢀEffectꢀofꢀPPh
complex.ꢀ Conditions:ꢀ Pd(PPh )
PPh ,ꢀDMFꢀ(0.1ꢀM),ꢀ23ꢀ°C.ꢀ
3
3
ꢀonꢀtheꢀobservedꢀratioꢀofꢀC3-ꢀtoꢀC5-Pdꢀ
ꢀ (10ꢀ mol%),ꢀ CuIꢀ (1.0ꢀ equiv),ꢀ
3 4
ꢀ
ꢀ
ꢀ
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 6 of 11
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
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3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
TS5
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
TS6
Figureꢀ4.ꢀA)ꢀTransmetallationꢀandꢀreductiveꢀeliminationꢀstepsꢀinꢀtheꢀPd-catalyzedꢀStilleꢀcross-couplingꢀreactionꢀofꢀ3,5-dibromo-2-
pyrone.ꢀTheꢀC3-ꢀandꢀC5-selectiveꢀpathwaysꢀareꢀshownꢀinꢀblueꢀandꢀinꢀred,ꢀrespectively.ꢀB)ꢀRelativeꢀactivationꢀenergiesꢀofꢀtransmetal-
lationꢀinꢀanꢀimplicitꢀsolventꢀ(∆∆G DMF)ꢀandꢀinꢀtheꢀgasꢀphaseꢀ(∆∆G gas).ꢀAllꢀenergiesꢀinꢀFigureꢀ4Aꢀareꢀwithꢀrespectꢀtoꢀ19,ꢀtwoꢀDMFꢀ
‡
‡
molecules,ꢀandꢀPhSnMe
3
.ꢀTheꢀenergiesꢀinꢀFigureꢀ4BꢀareꢀwithꢀrespectꢀtoꢀTS5.ꢀ
ꢀ
a) Conditions to obtain site-selective cross coupling in 3,5-dibromo-2-pyrone
Summaryꢀofꢀcross-couplingꢀstudiesꢀ
O
O
O
Schemeꢀ3aꢀprovidesꢀanꢀoverviewꢀofꢀourꢀobservationsꢀregardingꢀ
theꢀ site-selectiveꢀ cross-couplingꢀ inꢀ 3,5-dibromopyrone.ꢀ Inꢀ
summary,ꢀcross-couplingꢀofꢀ8ꢀgaveꢀriseꢀtoꢀtheꢀC3-coupledꢀprod-
uctꢀ (9)ꢀ asꢀ theꢀ majorꢀ productꢀ inꢀ non-polarꢀ solventsꢀ (withꢀ orꢀ
withoutꢀCuI)ꢀandꢀinꢀpolarꢀsolventsꢀinꢀtheꢀabsenceꢀofꢀCuI.ꢀTheꢀ
formationꢀofꢀC5-coupledꢀproductꢀ10ꢀwasꢀfavoredꢀbyꢀconduct-
ingꢀtheꢀreactionꢀinꢀpolarꢀsolventsꢀinꢀtheꢀpresenceꢀofꢀCuI.ꢀUnderꢀ
theseꢀconditions,ꢀitꢀwasꢀdeterminedꢀthatꢀC5ꢀPdꢀcomplexꢀ13-cisꢀ
isꢀkineticallyꢀfavoredꢀandꢀgivesꢀriseꢀtoꢀC5-coupledꢀproductꢀ10ꢀ
followingꢀaꢀrelativelyꢀlowꢀbarrierꢀforꢀtransmetallation.ꢀꢀ
Ph
C3-coupling
Br
C5-coupling
Br
O
O
O
3
3
non-polar solvents
w/ & w/o CuI)
polar solvents
(w/o CuI)
polar solvents
(w/ CuI)
5
5
(
Br
Br
Ph
9
8
10
b) Summary of rationale behind the observed C5-coupling in polar solvents in
the presence of CuI.
9
8
10
higher
transmetallation
barrier
lower
transmetallation
barrier
Pd(PPh3)4
CuI assisted
PPh3 dissociation
Thisꢀlatterꢀselectivityꢀwasꢀcomputationallyꢀestablishedꢀtoꢀariseꢀ
fromꢀ anꢀ initialꢀ CuI-assistedꢀ PPh ꢀ dissociationꢀ fromꢀ bis-phos-
3
CuI, DMF
phineꢀligatedꢀPdꢀcomplexꢀ14ꢀtoꢀgiveꢀmono-phosphineꢀligatedꢀ
Pdꢀcomplexꢀ16ꢀorꢀ17ꢀ(Schemeꢀ3b),ꢀwhichꢀhasꢀaꢀlowerꢀactivationꢀ
barrierꢀtoꢀfurnishꢀtheꢀC5ꢀPdꢀcomplexꢀ13-cis.ꢀInꢀaddition,ꢀwhenꢀ
theꢀcouplingꢀisꢀconductedꢀinꢀpolarꢀsolventsꢀinꢀtheꢀpresenceꢀofꢀ
CuI,ꢀtheꢀisomericꢀPdꢀcomplexesꢀwereꢀfoundꢀtoꢀinterconvert.ꢀ
TheꢀC3ꢀPdꢀcomplexꢀ19ꢀwasꢀestablishedꢀtoꢀbeꢀtheꢀthermody-
namicꢀoxidativeꢀadductꢀandꢀpossessesꢀaꢀhigherꢀtransmetalla-
tionꢀbarrierꢀcomparedꢀtoꢀitsꢀC5ꢀanalogꢀ13-cis.ꢀ
I
O
O
O
Cu
Br
O
O
Br
Br
Pd PPh3
Pd PPh3
(DMF)
n = 0,1
O
3
5
PPh
n
3
Ph P Pd Br
3
Br
PPh3
Br
19
16 or 17
13-cis
thermodynamically
mono-phosphine
ligated intermediate
kinetically
favored
ꢀ
favored
ꢀ
Schemeꢀ3.ꢀSummaryꢀofꢀexperimental/computationalꢀresultsꢀ
thatꢀrationalizesꢀtheꢀobservedꢀsite-selectivityꢀinꢀ3,5-dibromo-
ꢀ
ꢀ
2
-pyroneꢀ
ACS Paragon Plus Environment

Page 7 of 11
TotalꢀSynthesisꢀofꢀdelavatineꢀAꢀ
Journal of the American Chemical Society
esterꢀ28ꢀdirectlyꢀfromꢀ8ꢀinꢀaꢀsingleꢀpotꢀandꢀinꢀcomparableꢀover-
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
allꢀyield.ꢀAꢀnumberꢀofꢀconditionsꢀwereꢀnextꢀinvestigatedꢀtoꢀcon-
vertꢀ28ꢀintoꢀaꢀsuitableꢀdienolate-likeꢀspeciesꢀ(cf.ꢀ5,ꢀSchemeꢀ1).ꢀ
Whileꢀdeprotonationꢀofꢀtheꢀg-hydrogenꢀofꢀenalꢀ28ꢀusingꢀstrongꢀ
basesꢀwasꢀunsuccessful,ꢀsofterꢀenolizationꢀconditionsꢀcleanlyꢀ
convertedꢀ28ꢀtoꢀsilylꢀenolꢀetherꢀ29,ꢀprovidingꢀaꢀprecursorꢀforꢀ
theꢀ envisionedꢀ 6p-electrocyclization.ꢀ Theꢀ majorꢀ olefinꢀ dia-
stereomerꢀinꢀ29ꢀwasꢀestablishedꢀasꢀtheꢀEꢀisomer.ꢀWeꢀthenꢀbe-
ganꢀ exploringꢀ conditionsꢀ forꢀ theꢀ 6p-electrocyclizationꢀ andꢀ
wereꢀ delightedꢀ toꢀ findꢀ thatꢀ theꢀ desiredꢀ transformationꢀ oc-
curredꢀatꢀelevatedꢀtemperatureꢀinꢀtheꢀpresenceꢀofꢀ1,8-diazabi-
cyclo(5.4.0)undec-7-eneꢀ(DBU)ꢀtoꢀfurnishꢀtheꢀdesiredꢀcyclizedꢀ
productꢀ(30).ꢀTheꢀentireꢀsequenceꢀ(silylꢀenolꢀetherꢀformation,ꢀ
E/Zꢀisomerization,ꢀ6p-electrocyclization,ꢀdesilylation,ꢀandꢀaro-
matization)ꢀcanꢀbeꢀcarriedꢀoutꢀinꢀaꢀsingleꢀpotꢀtoꢀdirectlyꢀdeliverꢀꢀ
Ourꢀenhancedꢀmechanisticꢀunderstandingꢀofꢀtheꢀsite-selectiveꢀ
cross-couplingꢀofꢀ3,5-dibromo-2-pyroneꢀ(8)ꢀpositionedꢀusꢀwellꢀ
toꢀcompleteꢀaꢀsynthesisꢀofꢀdelavatineꢀAꢀ(Schemeꢀ4).ꢀInꢀaꢀfirstꢀ
32
step,ꢀknownꢀvinylꢀtriflate ꢀ22ꢀwasꢀsubjectedꢀtoꢀMiyauraꢀboryla-
33
tion ꢀtoꢀfurnishꢀvinylꢀboronateꢀesterꢀ23ꢀinꢀhighꢀyield.ꢀNext,ꢀtheꢀ
conditionsꢀinitiallyꢀestablishedꢀbyꢀChoꢀetꢀal.ꢀforꢀtheꢀsite-selec-
tiveꢀSuzukiꢀcouplingꢀofꢀ8ꢀefficientlyꢀyieldedꢀC5ꢀmono-coupledꢀ
pyroneꢀ26ꢀinꢀ70–75%ꢀyieldꢀonꢀaꢀ5ꢀgꢀscale.ꢀAlternatively,ꢀaꢀsite-
3
4
selectiveꢀStilleꢀcouplingꢀofꢀ8ꢀandꢀstannaneꢀester ꢀ24ꢀgaveꢀ26ꢀinꢀ
comparableꢀyield.ꢀStilleꢀcouplingꢀofꢀ26ꢀwithꢀknownꢀstannaneꢀ
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
4a
aldehyde ꢀ25ꢀthenꢀdeliveredꢀpseudosymmetricꢀpyroneꢀ27.ꢀꢀ
Withꢀbis-coupledꢀpyroneꢀ27ꢀinꢀhand,ꢀweꢀinitiallyꢀsoughtꢀtoꢀopenꢀ
theꢀlactoneꢀmoietyꢀwithꢀanꢀalkoxideꢀinꢀorderꢀtoꢀinduceꢀtheꢀde-
siredꢀcascadeꢀsequenceꢀ(cf.ꢀ7ꢀ®ꢀ5,ꢀSchemeꢀ1b).ꢀHowever,ꢀun-
derꢀaꢀvarietyꢀofꢀreactionꢀconditions,ꢀtheꢀpyroneꢀopeningꢀwasꢀ
notꢀ successfulꢀ andꢀ resultedꢀ merelyꢀ inꢀ decompositionꢀ ofꢀ 27.ꢀ
Eventuallyꢀ weꢀ discoveredꢀ thatꢀ pyroneꢀ 27ꢀ couldꢀ beꢀ cleanlyꢀ
3
6
3
0ꢀinꢀ25–35%ꢀoverallꢀyield. ꢀTricycleꢀ30ꢀwasꢀthenꢀreducedꢀus-
ingꢀlithiumꢀaluminumꢀhydride,ꢀandꢀtheꢀcorrespondingꢀtriolꢀwasꢀ
subjectedꢀtoꢀglobalꢀSwernꢀoxidationꢀtoꢀprovideꢀtheꢀproposedꢀ
biosyntheticꢀintermediateꢀ4.ꢀFinally,ꢀtreatmentꢀofꢀtrisaldehydeꢀ
3
5
,
openedꢀinꢀaꢀ1,6-fashionꢀusingꢀsodiumꢀcyanide ꢀandꢀtheꢀresult-
4
ꢀwithꢀammoniumꢀacetateꢀledꢀtoꢀformationꢀofꢀtheꢀisoquinolineꢀ
ingꢀcarboxylateꢀwasꢀalkylatedꢀtoꢀfurnishꢀmethylꢀesterꢀ28.ꢀIm-
pressively,ꢀsequentialꢀStilleꢀcouplingꢀofꢀ8,ꢀ24,ꢀandꢀ25,ꢀfollowedꢀ
byꢀpyroneꢀopeningꢀcouldꢀalsoꢀbeꢀachievedꢀtoꢀfurnishꢀmethylꢀ
moietyꢀtoꢀprovideꢀdelavatineꢀAꢀ(1),ꢀwhichꢀpossessedꢀanalyticalꢀ
1
13
dataꢀ( Hꢀandꢀ CꢀNMR,ꢀHRMS,ꢀIR,ꢀ[α]
D
)ꢀinꢀfullꢀagreementꢀwithꢀ
thoseꢀreportedꢀforꢀtheꢀnaturallyꢀoccurringꢀmaterial.ꢀ
Schemeꢀ4.ꢀTotalꢀsynthesisꢀofꢀdelavatineꢀAꢀꢀ
ꢀ
1
) 8, 24, Pd(PPh ) , CuTC
3 4
then 25
then NaCN
then K CO , MeI
32% from 25
2
3
O
Br
3
O
R
23, Pd(PPh3)4
CuI, DMF
70–75%
Me
Me
O
CHO
O
CHO
CO Me
Br
5
Br
O
25, Pd(PPh3)4,
2
8
5 g scale
O
CuTC
NaCN
then K CO , MeI
+
or
CN
NMP
72%
2
4, Pd(PPh3)4,
CO Et
2
2
3
X
CO Et 75–81%, dr 12:1
CO Et
CuTC, NMP
2
2
5
g scale
2 g scale
7
0%
O
Me
Me
Me
2
6
27
28
Me
2
2
2
2
2, X = OTf, R = OEt
3, X = Bpin, R = OEt
Pd(dppf)Cl , B pin
2 2 2
96%, 20 g scale
4, X = SnMe , R = OEt
3
5, X = SnMe , R = H
3
TBSO
Me
Me
Me
CHO
CHO
CO Me
Me
CHO
2) TBSOTf
2
CO Me
N
2
NH OAc
3) LiAlH4
DBU
4
CN
Et N
3
Δ
4) (COCl)2
DMSO, Et N
Δ
, PhMe
E
PhMe
CHO
CO Et
4
8% over
2
25–35%
from 28
dr 12:1
3
CO Et
2
CHO
2 steps
Me
Me
Me
delavatine A (1)
Me
4
30
29
ꢀ
ꢀ
ꢀ
ACS Paragon Plus Environment

Journal of the American Chemical Society
ACKNOWLEDGMENT
Page 8 of 11
Conclusionꢀ
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Inꢀsummary,ꢀweꢀhaveꢀemployedꢀcomputationalꢀanalysisꢀasꢀ
aꢀpowerfulꢀtoolꢀtoꢀgainꢀinsightꢀintoꢀtheꢀobservedꢀsite-se-
lectiveꢀcross-couplingꢀinꢀ3,5-dibromo-2-pyrone.ꢀTheꢀcalcu-
lationsꢀ showꢀ thatꢀ bis-phosphineꢀ ligatedꢀ palladiumꢀ com-
plexesꢀpromoteꢀoxidativeꢀadditionꢀatꢀC3ꢀofꢀ3,5-dibromopy-
roneꢀasꢀaꢀresultꢀofꢀmoreꢀfavorableꢀFMOꢀinteractionsꢀbe-
tweenꢀtheꢀHOMOꢀ(dxy)ꢀofꢀtheꢀPdꢀcomplexꢀandꢀtheꢀpyroneꢀ
LUMOꢀ (π*).ꢀ Additionally,ꢀ combinedꢀ experimentalꢀ andꢀ
computationalꢀ investigationsꢀ suggestꢀ thatꢀ theꢀ oxidativeꢀ
additionꢀinꢀtheꢀpresenceꢀofꢀCuIꢀproceedsꢀviaꢀaꢀpathwayꢀ
thatꢀ involvesꢀ aꢀ mono-phosphineꢀ ligatedꢀ Pdꢀ complex.ꢀ Inꢀ
thisꢀcase,ꢀtheꢀsite-selectivityꢀforꢀoxidativeꢀadditionꢀisꢀdi-
minishedꢀandꢀtheꢀC5ꢀcross-couplingꢀisꢀpreferredꢀdueꢀtoꢀaꢀ
moreꢀ facileꢀ transmetallationꢀ step.ꢀ Thisꢀ outcomeꢀ isꢀ at-
tributedꢀtoꢀmoreꢀfavorableꢀsolvationꢀeffectsꢀthatꢀstabilizeꢀ
theꢀmoreꢀpolarꢀtransitionꢀstateꢀinꢀtheꢀC5-selectiveꢀpath-
way.ꢀTheseꢀinsightsꢀmayꢀproveꢀvaluableꢀinꢀdevelopingꢀaꢀ
moreꢀgeneralꢀunderstandingꢀofꢀtheꢀeffectsꢀofꢀsolventsꢀandꢀ
CuIꢀadditivesꢀinꢀsite-selectiveꢀcrossꢀcouplingsꢀinꢀotherꢀpol-
yhalogentatedꢀheterocycles.ꢀTheꢀsite-selectiveꢀcross-cou-
plingꢀhasꢀenabledꢀaꢀshortꢀtotalꢀsynthesisꢀofꢀdelavatineꢀAꢀ
thatꢀtakesꢀadvantageꢀofꢀaꢀstrategyꢀinspiredꢀbyꢀtheꢀinherentꢀ
symmetryꢀofꢀthisꢀnaturalꢀproduct.ꢀTheꢀsynthesisꢀofꢀ1ꢀpro-
ceedsꢀinꢀonlyꢀfourꢀstepsꢀfromꢀknownꢀ3,5-dibromo-2-py-
roneꢀ8ꢀ(orꢀinꢀaꢀlongestꢀlinearꢀsequenceꢀofꢀtenꢀstepsꢀfromꢀ
commerciallyꢀavailableꢀ(R)-pulegone)ꢀandꢀfeaturesꢀaꢀcas-
cadeꢀsequenceꢀinvolvingꢀfiveꢀtransformationsꢀoccurringꢀinꢀ
aꢀsingleꢀpot.ꢀOurꢀconciseꢀandꢀmodularꢀrouteꢀtoꢀdelavatineꢀ
Aꢀsetsꢀtheꢀstageꢀforꢀtheꢀsynthesisꢀofꢀaꢀlibraryꢀofꢀstructurallyꢀ
relatedꢀanaloguesꢀtoꢀfacilitateꢀbiologicalꢀstudies.ꢀ
FinancialꢀsupportꢀforꢀthisꢀresearchꢀwasꢀprovidedꢀtoꢀR.S.ꢀbyꢀanꢀ
ACSꢀPRFꢀNewꢀDirectionsꢀGrantꢀ(ACSꢀPRFꢀNDꢀ56509)ꢀandꢀtoꢀP.L.ꢀ
byꢀtheꢀNSFꢀ(CHE-1654122).ꢀCalculationsꢀwereꢀperformedꢀatꢀtheꢀ
CenterꢀforꢀResearchꢀComputingꢀatꢀtheꢀUniversityꢀofꢀPittsburghꢀ
andꢀ theꢀ Extremeꢀ Scienceꢀ andꢀ Engineeringꢀ Discoveryꢀ Environ-
mentꢀ(XSEDE)ꢀsupportedꢀbyꢀtheꢀNSF.ꢀV.P.ꢀacknowledgesꢀTRDRPꢀ
forꢀaꢀpredoctoralꢀfellowship.ꢀC.L.Hꢀisꢀgratefulꢀforꢀaꢀpostdoctoralꢀ
scholarshipꢀ fromꢀ theꢀ Swissꢀ Nationalꢀ Scienceꢀ Foundation.ꢀ Weꢀ
thankꢀProf.ꢀC.-G.ꢀChoꢀ(HanyangꢀUniversity,ꢀKorea)ꢀforꢀinsightfulꢀ
discussionsꢀ regardingꢀ studiesꢀ ofꢀ theꢀ selectiveꢀ cross-couplingꢀ
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chemistry.ꢀꢀ
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ASSOCIATED CONTENT
Supporting Information
(4) (a)ꢀZhang,ꢀZ.;ꢀWang,ꢀJ.;ꢀLi,ꢀJ.;ꢀYang,ꢀF.;ꢀLiu,ꢀG.;ꢀTang,ꢀW.;ꢀHe,ꢀ
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ACSꢀPublicationsꢀwebsiteꢀatꢀhttp://pubs.acs.orgꢀ
ꢀ
Experimentalꢀdetailsꢀandꢀspectroscopicꢀdataꢀ(PDF)ꢀ
Crystallographicꢀdataꢀforꢀ12-transꢀ(CIF)ꢀꢀ
Crystallographicꢀdataꢀforꢀ13-transꢀ(CIF)ꢀ
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Corresponding Author
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433.ꢀ(c)ꢀMahapatra,ꢀS.;ꢀCarter,ꢀR.ꢀG.ꢀExploitingꢀhiddenꢀsym-
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*
rsarpong@berkeley.eduꢀ
*
pengliu@pitt.edu
Notes
Theꢀauthorsꢀdeclareꢀnoꢀcompetingꢀfinancialꢀinterests.ꢀ
ACS Paragon Plus Environment

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Journal of the American Chemical Society
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2
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(16) Inꢀourꢀhands,ꢀcross-couplingꢀdidꢀnotꢀproceedꢀatꢀroomꢀtem-
peratureꢀinꢀtheꢀabsenceꢀofꢀCuIꢀinꢀanyꢀofꢀtheꢀinvestigatedꢀsol-
vents.ꢀꢀ
(17) InterestinglyꢀandꢀinꢀcontrastꢀtoꢀRef.ꢀ10,ꢀwhenꢀtheꢀoxidativeꢀ
additionꢀwasꢀcarriedꢀoutꢀwithꢀaꢀstoichiometricꢀamountꢀofꢀ
(
8) Fairlamb,ꢀI.ꢀJ.ꢀS.ꢀRegioselectiveꢀ(site-selective)ꢀfunctionalisa-
tionꢀofꢀunsaturatedꢀhalogenatedꢀnitrogen,ꢀoxygenꢀandꢀsulfurꢀ
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rencesꢀtherein.ꢀꢀ
3 4
Pd(PPh ) ,ꢀformationꢀofꢀC5-Pdꢀcomplexꢀ13ꢀwasꢀnotꢀobservedꢀ
(9) Forꢀsite-selectiveꢀSonogashiraꢀcouplingꢀofꢀ3,5-dibromo-2-py-
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thesisꢀofꢀ3-alkynyl-5-bromo-2-pyronesꢀviaꢀPd-catalyzedꢀcou-
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andꢀonlyꢀC3-Pdꢀcomplexꢀ12ꢀcouldꢀbeꢀisolated.ꢀSeeꢀtheꢀSup-
portingꢀInformationꢀforꢀexperimentalꢀdetails.ꢀ
(18) a)ꢀVogel,ꢀA.ꢀI.;ꢀFurniss,ꢀB.ꢀS.;ꢀHannaford,ꢀA.ꢀJ.;ꢀSmith,ꢀP.ꢀW.ꢀG.;ꢀ
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https://www.organicdivision.org/orig/organic_sol-
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(
10) Forꢀ site-selectiveꢀ Stilleꢀ couplingꢀ ofꢀ 3,5-dibromo-2-pyroneꢀ
see,ꢀKim,ꢀW.-S.;ꢀKim,ꢀH.-J.;ꢀCho,ꢀC.-G.ꢀRegioselectivityꢀinꢀtheꢀ
Stilleꢀ couplingꢀ reactionsꢀ ofꢀ 3,5-dibromo-2-pyrone.ꢀ J.ꢀ Am.ꢀ
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(19) TheꢀX-rayꢀstructuresꢀofꢀ12ꢀandꢀ13ꢀwereꢀalsoꢀreportedꢀinꢀref.ꢀ
10.ꢀꢀ
(11) Forꢀsite-selectiveꢀSuzukiꢀcouplingꢀofꢀ3,5-dibromo-2-pyroneꢀ
see,ꢀRyu,ꢀK.-M.;ꢀGupta,ꢀA.ꢀK.;ꢀHan,ꢀJ.ꢀW.;ꢀOh,ꢀC.ꢀH.;ꢀCho,ꢀC.-G.ꢀ
Regiocontrolledꢀ Suzuki-Miyauraꢀcouplingsꢀ ofꢀ 3,5-dibromo-
(20) SeeꢀtheꢀSupportingꢀInformationꢀforꢀfurtherꢀdetails.ꢀ
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(
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ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 10 of 11
(
24) (a)ꢀFarina,ꢀV.;ꢀKapadia,ꢀS.;ꢀKrishnan,ꢀB.;ꢀWang,ꢀC.;ꢀLiebeskind,ꢀ
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1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
L.ꢀS.ꢀOnꢀtheꢀnatureꢀofꢀtheꢀ“copperꢀeffect“ꢀinꢀtheꢀStilleꢀcross-
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per(I)ꢀiodideꢀpolyphosphineꢀadductsꢀatꢀlowꢀloadingꢀforꢀSo-
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theꢀacceleratingꢀand/orꢀinhibitingꢀeffectsꢀofꢀcopperꢀandꢀsil-
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cross-couplingꢀ byꢀ theꢀ palladium-catalyzedꢀ reactionꢀ ofꢀ 1-
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L.ꢀC.;ꢀCosta,ꢀB.;ꢀGoldstein,ꢀR.ꢀChemoselectiveꢀ1,3-dipolarꢀcy-
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(36) Aꢀsummaryꢀofꢀtheꢀreactionꢀconditionsꢀinvestigatedꢀforꢀthisꢀ
cascadeꢀsequenceꢀisꢀincludedꢀinꢀtheꢀSI.ꢀ
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
7
226.ꢀ
(
25) (a)ꢀLi,ꢀZ.;ꢀFu,ꢀY.;ꢀGuo,ꢀQ.-X.;ꢀLiu,ꢀL.ꢀTheoreticalꢀstudyꢀonꢀmon-
oligatedꢀPd-catalyzedꢀcross-couplingꢀreactionsꢀofꢀarylꢀchlo-
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Lam,ꢀK.ꢀC.;ꢀMarder,ꢀT.ꢀB.;ꢀLin,ꢀZ.ꢀDFTꢀstudiesꢀonꢀtheꢀeffectꢀofꢀ
theꢀnatureꢀofꢀtheꢀarylꢀhalideꢀY–C H –Xꢀonꢀtheꢀmechanismꢀofꢀ
6 4
0
0
itsꢀoxidativeꢀadditionꢀtoꢀPd LꢀversusꢀPd L
2
.ꢀOrganometallicsꢀ
2
007,ꢀ26,ꢀ758.ꢀ(c)ꢀAhlquist,ꢀM.;ꢀNorrby,ꢀP.-O.ꢀOxidativeꢀaddi-
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2
complexꢀasꢀtheꢀenergyꢀzero.ꢀWeꢀcannotꢀruleꢀoutꢀtheꢀfor-
mationꢀofꢀCuIꢀoligomersꢀunderꢀtheꢀreactionꢀconditions.ꢀHow-
ever,ꢀtheꢀpolarꢀsolventꢀ(DMF)ꢀisꢀexpectedꢀtoꢀpromoteꢀtheꢀ
formationꢀofꢀtheꢀCuIꢀmonomer.ꢀ
(
27) (a)ꢀBickelhaupt,ꢀF.ꢀM.;ꢀHouk,ꢀK.ꢀN.ꢀAnalyzingꢀreactionꢀratesꢀ
withꢀtheꢀdistortion/interaction-activationꢀstrainꢀmodel.ꢀAn-
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portingꢀInformationꢀforꢀdetailedꢀdiscussions.ꢀ
(
(
(
29) Schoenebeck,ꢀF.;ꢀHouk,ꢀK.ꢀN.ꢀLigand-controlledꢀregioselectiv-
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tionallyꢀlocateꢀenergyꢀvaluesꢀthatꢀsupportꢀtheꢀexperimen-
tallyꢀobservedꢀCurtin-Hammettꢀscenario.ꢀTheꢀexactꢀmecha-
nismꢀforꢀtheꢀreversibleꢀoxidativeꢀadditionꢀremainsꢀunclear.ꢀ
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Theoreticalꢀinsightsꢀintoꢀtheꢀopenꢀpathway.ꢀOrganometallicsꢀ
(
2
008,ꢀ27,ꢀ3378.ꢀ(e)ꢀCarrizo,ꢀE.ꢀD.ꢀS.;ꢀFernández,ꢀI.;ꢀMartin,ꢀS.ꢀ
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3 2 3 2
Organometallicsꢀ2015,ꢀ34,ꢀ159.ꢀ(f)ꢀNova,ꢀA.;ꢀUjaque,ꢀG.;ꢀMa-
seras,ꢀF.;ꢀLledós,ꢀA.;ꢀEspinet,ꢀP.ꢀAꢀcriticalꢀanalysisꢀofꢀtheꢀcyclicꢀ
andꢀ openꢀ alternativesꢀ ofꢀ theꢀ transmetalationꢀ stepꢀ inꢀ theꢀ
Stilleꢀcross-couplingꢀreaction.ꢀJ.ꢀAm.ꢀChem.ꢀSoc.ꢀ2006,ꢀ128,ꢀ
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4571.ꢀ
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XL Pd
O
O
Me
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N symmetry
Me
O
inspired
Br
Br
R
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steps
O
O
SnMe3
CHO
!
!
site-selective cross coupling
Me
computational/experimental
mechanistic investigations
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delavatine A
XL Pd
2
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