review 1 - thieme · review 1 reviewrecent advances in phenol dearomatizat ion and its application...

REVIEW ▌1

reviewRecent Advances in Phenol Dearomatization and Its Application in Complex SynthesesRecent Advances in Phenol DearomatizationQiuping Ding,a Yang Ye,b Renhua Fan*b

a Key Laboratory of Functional Small Organic Molecules, Ministry of Education, Jiangxi Normal University, Nanchang 330022, P. R. of Chinab Department of Chemistry, Fudan University, 220 Handan Road, Shanghai 200433, P. R. of China

Fax +86(21)65642412; E-mail: [email protected]

Received: 15.09.2012; Accepted after revision: 22.10.2012

Abstract: As a powerful tool, the dearomatization of phenols hasbeen explored extensively and utilized by organic chemists duringthe course of complex syntheses. This review highlights recent ad-vances in phenol dearomatizations, especially those accomplishedin an enantioselective manner, and the application of dearomatiza-tion strategies in complex syntheses.

1 Introduction

2 New Developments in Phenol Dearomatization

3 Enantioselective Phenol Dearomatization

3.1 Controlled by Chiral Substrate

3.2 Controlled by Chiral Catalyst

3.3 Controlled by Chiral Hypervalent Iodine

4 Enantioselective Phenol Dearomatization Strategies inComplex Syntheses

4.1 With the Formation of a Carbon–Oxygen Bond

4.2 With the Formation of a Carbon–Carbon Bond

4.3 With the Formation of a Carbon–Nitrogen Bond

5 Conclusion

Key words: dearomatization, enantioselectivity, oxidation, phe-nols, tandem reaction

1 Introduction

Organic synthesis has reached a considerable level of ma-turity. Nowadays, almost any complex molecule can besynthesized, and selective functionalizations achieved.However, with ever-tighter resources, efficiency in organ-ic synthesis is becoming more and more important. Anideal synthesis demands simplicity, safety, brevity, envi-ronmental friendliness, as well as high selectivity, yieldand diversity.1

Phenols are the most frequently utilized substrates fordearomatization to access complex molecules. A numberof dearomatization strategies have been used by organicchemists to construct fused, bridged and spiro structures.Owing to the high efficiency of these tactics, more andmore investigations have focused on this field.2

The oxidation of o- and p-hydroquinones generally pro-ceeds in methanol solution at room temperature, and the

yield of benzoquinones is almost quantitative.3 Dearoma-tization of 4- or 2-substituted phenols in the presence of anappropriate nucleophile (Nu) leading to the respective4,4- or 2,2-disubstituted cyclohexadienones is especiallyinteresting and synthetically useful (Scheme 1). Variousnucleophiles, such as water,4 alcohols,3,5 fluoride ion,6

carboxylic acids,5d,7 amides,8 oximes,9 and electron-richaromatic rings10,11 have been used successfully in dearo-matization in either an inter- or an intramolecular mode.Besides, the resulting cyclohexadienones are good elec-trophilic substrates for various reactions, such as theDiels–Alder reaction, 1,4-addition, reduction and [3+2]cyclization. The following section of this report highlightssome recent investigations on phenol dearomatizations,especially those accomplished in an enantioselectivemanner, and their application in complex syntheses.

Scheme 1 Dearomatization of 4- or 2-substituted phenols

2 New Developments in Phenol Dearomatiza-tion

Besides electron-rich aromatic rings, other carbon re-sources can be introduced into the cyclohexa-2,5-dienonestructure through an oxidative dearomatization process.Canesi and co-workers developed an iodine(III)-mediatedoxidative Wagner–Meerwein transposition involving dif-ferent functionalities (Scheme 2).12 The reaction occurredrapidly in hexafluoroisopropanol (HFIP) using iodoben-zene diacetate as oxidant. This transformation providesnew strategic opportunities to prepare highly functional-ized compounds containing a prochiral dienone and a qua-ternary carbon center connected to several sp2 carbons.

OH

R

[O]

Nu

O

R Nu

OH

[O]

Nu

O

RNu

R

Diels–Alder reaction

1,4-addition

[3+2] cyclization

reduction

SYNTHESIS 2013, 45, 0001–0016Advanced online publication: 07.11.20120 0 3 9 - 7 8 8 1 1 4 3 7 - 2 1 0 XDOI: 10.1055/s-0032-1317575; Art ID: SS-2012-E0721-R© Georg Thieme Verlag Stuttgart · New York

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2 Q. Ding et al. REVIEW

Synthesis 2013, 45, 1–16 © Georg Thieme Verlag Stuttgart · New York

One year later, the same research group reported a bimo-lecular oxidative process occurring with carbon–carbonbond formation that has been extended to allylsilanes(Scheme 3).13 In this reaction, different 4-alkyl-2-6-disub-stituted phenols 19 were successfully oxidized leading toan oxidative variant of the famous Hosomi–Sakurai al-lylation.11 It is noteworthy that the first approach to thisreaction was developed by Quideau and co-workers inaprotic solvents with phenyliodine(III) bis(trifluoroace-tate) (PIFA), which provided some examples of oxidativeallylation on substituted 1-naphthol.14

Canesi and co-workers also reported a dearomatization ofphenol derivatives that promotes the formation of bicyclicand tricyclic products via a cationic cyclization process.15

First, an oxidative vicinal-fused carbocycle formation wasperformed with a terminal alkyne on a lateral chain at themeta-position of phenol 21. The authors speculated that astrained half-chair intermediate 22 was generated, andthat this strongly favored nucleophile capture, leading to

the unsaturated decalin system 24 (Scheme 4). Vicinal-fused carbocycles were produced in good yields (43–91%). This new process could have application in asym-metric synthesis governed by the benzylic stereogeniccenter at the meta position (Scheme 5). Such scaffolds arepresent in numerous natural products such as anominine,16

andrographolide,17 or the decalin core of azadirachtin.18

The cyclization reaction occurred with total stereocontrolin agreement with the configuration of the starting olefin,since a 2:1 mixture of diastereomers was obtained. To ver-ify the high diastereoselectivity of this process, cis-25 wasprepared, and led exclusively to the tricyclic core 28 in a43% yield. Recently, Canesi’s research group also report-ed an oxidative ipso-rearrangement mediated by a hyper-valent iodine reagent. A functionalized dienone systemcontaining a quaternary carbon center connected to sever-al sp2 centers was constructed. This transformation wasused in the total synthesis of sceletenone, a small alka-loid.19

Biographical Sketches█

Qiuping Ding was born inJiangxi, China, in 1975. Hereceived his Ph.D. from Fu-dan University under the su-

pervision of Professor JieWu in 2009. He is currentlyan associate professor atJiangxi Normal University,

China. His research interestis focused on cascade reac-tions.

Yang Ye was born in Hu-nan, China, in 1985. In2012, he received his Ph.D.

from Fudan University un-der the supervision of Pro-fessor Renhua Fan. He is

currently a technician inPharmaron Beijing Co., Ltd.

Renhua Fan was born in Ji-angxi, China, in 1976. Hereceived his Ph.D. fromShanghai Institute of Organ-ic Chemistry, ChineseAcademy of Sciences underthe supervision of Professor

Xuelong Hou in 2003. Afterpostdoctoral studies (2003–2006) at Purdue University,USA with Professor Alex-ander Wei, he moved to Fu-dan University, China. He iscurrently a full professor of

organic chemistry at the De-partment of Chemistry ofFudan University. His re-search interest is focused onhypervalent iodine chemis-try.

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REVIEW Recent Advances in Phenol Dearomatization 3

© Georg Thieme Verlag Stuttgart · New York Synthesis 2013, 45, 1–16

Scheme 2 Wagner–Meerwein transposition by dearomatization ofphenols

OH

HOR2

R3

R1

PhI(OAc)2, HFIP

0 °C, 2 min

O

OR2

R3

R1

H

O

R1

R2

OR3

1 2 33a R1 = R3 = H, R2 = Me, 62%3b R1 = R3 = H, R2 = CH2CH=CH2, 67%3c R1 = R2 = Me, R3 = H, 63%3d R1 = H, R2 = R3 = Me, 37%3e R1 = R3 = H, R2 = CH2OTBS, 33%

OH

R2HOR1

PhI(OAc)2, HFIP

0 °C, 2 min

O

R2OR1

H

O

R2

R1

O

4 5 6

6a R1 = Me, R2 = CH=CH2, 34%6b R1 = Me, R2 = Ph, 51%6c R1 = Et, R2 = Ph, 35%6d R1 = Me, R2 = n-Bu, 35%6e R1 = n-Bu, R2 = n-Bu, 41%OH

HO

R

PhI(OAc)2, HFIP

0 °C, 2 min

O

R

O

7 8

OH

HO

PhI(OAc)2, HFIP

0 °C, 2 min

O

9 10

O

53%

OH

OH

R

PhI(OAc)2, HFIP, CH2Cl2

–17 °C, 2 min

11

O

R

O

H

O

R

O

12 13

OH

OTBS

PhI(OAc)2, HFIP, CH2Cl2

–17 °C, 2 min

O

OTBS

OAc

+

O

CHO

72%

14

15 16

Br Br

OH

OHPhI(OAc)2, HFIP, CH2Cl2

–17 °C, 2 min

52%

Br Br

O

O

17 18

Scheme 3 Bimolecular oxidative process between phenols and allyl-silanes

OH

R2 R3

R1

PhI(OAc)2, HFIP or TFE

SiMe3

O

R1

R2 R3

34–84%

R1 = Me, Et, n-Bu, CH2CH2OH, i-Pr, Ph, CH2OTBDMS, CH2CO2MeR2 = t-Bu, TMS, Cl, Br, IR3 = t-Bu, TMS

19 20

Scheme 4 Oxidative formation of fused carbocycles

HO

R1

R1 R2

R3

21

R2

O

R1 R1

R3

H

22

R2

O

R1 R1

23

H

R3

CF3

HO CF3

O

R1

R1

O CF3

CF3

R2

R3

PhI(OAc)2

CF3

HO CF3

2443–91%

Scheme 5 Asymmetric synthesis of a tricyclic scaffold

HO

Br

Br

PhI(OAc)2

HFIP, r.t., 2 min41%

OCH(CF3)2

O

Br

Br

OCH(CF3)2

O

Br

Br

H

H

H

H

+

25

27

28

27/28 = 1:2

O

Br

Br26

HOCH(CF3)2

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The substituted alkynyl group in 29, where R2 ≠ H, alsoperformed as a nucleophile in the carbon–carbon bondformation. Kita and colleagues developed a very effectivespirocyclization procedure for installing nucleophiles(Nu = N3, NO2, SCN, SO2Tol, and Br) induced by iodoni-um(III) salts (Scheme 6).20 The in situ generated cationiciodonium(III) species activates the alkynyl group and in-duces the ipso-cyclization of compound 29, thereby lead-ing to a spirocyclized iodonium(III) salt. The latterundergoes a reductive coupling21 with nucleophiles to af-ford the functionalized spirocyclic compounds 30.

Zhang and co-workers reported a condition-controlled ox-idative dearomatization of phenolic amides (Scheme 7).22

In the presence of copper(II) sulfate pentahydrate and 4-dimethylaminopyridine (DMAP), the oxidation of pheno-lic amides with iodobenzene diacetate as oxidant gave riseto highly functionalized spiro β-lactams. In the absence ofcopper salts and DMAP, the oxidation provided 4-meth-oxycyclohexadienones in nearly quantitative yields. Afterbase-catalyzed intramolecular Michael addition and acid-catalyzed rearomatization, oxindoles were formed.

In addition to oxidative dearomatization, a high-valent-palladium-mediated intramolecular cyclization cascadereaction developed by Stephenson and co-workers hasbeen used to prepare spirocyclic cyclohexadienone struc-tures from phenols (Scheme 8).23 The resulting spirocy-clic cyclohexadienone could be a precursor for a radical

conjugate addition to efficiently provide the bicyclic frag-ment of platensimycin.24 A plausible catalytic cycle isoutlined in Scheme 9. In path A, palladium(II) coordinatesto the olefin of the substrate and induces an oxypallada-tion to form a Wacker intermediate.25 Metallation of thecarbon–hydrogen bond and subsequent oxidation by iodo-benzene diacetate provides a palladacycle, which under-goes reductive elimination to produce the C–H insertionproduct 36. For phenols, the catalytic cycle proceedsthrough a dearomatization pathway (path B). The result-ing Wacker intermediate undergoes oxidation to form ahighly electrophilic alkylpalladium(IV) intermediate. Af-ter reductive nucleophilic substitution by the phenol ring,spirocyclohexadienone product 37 is formed.Scheme 6 Synthesis of spirocycles

OMe

XY

R2

R1

Ar

I L

ArI

MCPBA OMe

XY

R2

R1

I

Ar

L

H2O

– MeOH– L

X

Y

R2

I

Ar

R1

O

Nu

– ArI 60–99%

X

Y

R2

R1

O

Nu

R1 = H, OMe, Cl, t-BuR2 = Ph, 4-anisyl, BrXY = OC=O, CH2CH2, (CH2)3

Nu = N3, NO2, SCN, SO2Tol, BrArI:

I I

30

29

Scheme 7 Synthesis of spirolactams and oxindoles via oxidativedearomatization

N

OH

R1

O

R2

OEt

O

PhI(OAc)2CuSO4⋅5H2O

DMAP, MeOH

1) PhI(OAc)2, MeOH2) DBU, CH2Cl2

3) TsOH⋅H2O

N

R1

O

R2

COOEt

O

N

HO

O

R1

R2COOEt

R1 = arylR2 = H

R1 = PhR2 = alkyl

32

33

31

76–87%

81–89%

Scheme 8 Synthesis of spirocyclic cyclohexadienones and tricyclicscaffolds

OMe

MeO

COOH

COOH

HO

Pd(OAc)2 (10 mol%)

oxidant (2 equiv)MeCN, r.t., 12 h

OMe

MeO

O

O

O

O

OH

oxidant: PhI(OAc)2 or

N

N

Cl

F

34

35

36 92%

37 40%

H

2BF4

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3 Enantioselective Phenol Dearomatization

3.1 Controlled by Chiral Substrate

Quideau and co-workers reported a convenient and enan-tioselective route to access spiroketals through dearomati-zation of phenols (Scheme 10).5a,26 Phenolic alcohols39a,b,e,f,h, with a tert-butyl substituent on the carbonatom attached to the hydroxy group in the side chain, un-derwent a highly diastereoselective transformation, incontrast to 39c,d,g, which have an ethyl or n-decyl groupat this position. The stereoselectivity is controlled by thechiral alkyl branch, and a density–functional theory(DFT) calculation was done to explain the stereoselectiv-ity. The authors hypothesized that the spiroketals wereformed via a tandem ligand-exchange and ligand-coupling reaction (Scheme 11). The ability of these chiralspiroketals to promote asymmetric induction was demon-strated during the synthesis of (+)-biscarvacrol,27 a natu-rally occurring bridge-ring system (Scheme 12).

Pettus and co-workers developed a diastereoselectivedearomatization reaction and utilized it in the enantiose-lective synthesis of 4,6-dihydroxy-4-alkylcyclohexenone

core structure with anticancer properties (Scheme 13).28

This transformation was presumed to involve (1) in situgeneration of PhI(OTf)OTMS, (2) oxidation of the phenolring, (3) cyclization with the amide carbonyl, and finally(4) hydrolysis of the iminium species. The other diaste-reomer was not observed in the 1H NMR spectrum of thecrude product mixture. The modified conditions used herehave significantly improved the versatility of this dearo-matization process compared to their previous conditions,which used iodobenzene di(trifluoroacetate) as theoxidant.29 Compound (–)-45 is the precursor of syn-diol(–)-46, a structure with anticancer properties.

Scheme 11 Plausible mechanism of the iodobenzene diacetate me-diated spiroketalization of phenolic alcohols 39

Scheme 9 Mechanism of Pd-mediated cyclization reactions leading to spirocyclic cyclohexadienones and tricyclic scaffolds

RO

PdII

O

COOHR

Pd(OAc)2Pd(OAc)2

O

PdIV

O

R

OH

H

O

O

OH

O

PdIV

O

H

O

O

R

34 or 3536 37

path A path B

H

dearomatizationC–H fuctionalization

metallationoxidation

oxidation

reductivedisplacement reductive

elimination

nucleopalladation

38

Scheme 10 Dearomatization of phenolic alcohols 39 into orthoqui-none monoketals 40 and 41

OH

R1

OR2

OHPhI(OAc)2 (1.0 equiv)CF3CH2OH, –35 °C

powdered NaHCO3

O

R1

O

OO

R1

O

O

R2

R2

+

39 40 41

(R)-39a, R1 = R2 = t-Bu, (R,R)-40a/(R,S)-41a >95:5(S)-39b, R1 = R2 = t-Bu, (S,R)-40b/(S,S)-41b >5:95(R)-39c, R1 = t-Bu, R2 = Et, (R,R)-40c/(R,S)-41c = 60:40(S)-39d, R1 = t-Bu, R2 = Et, (S,R)-40d/(S,S)-41d = 40:60(R)-39e, R1 = OMe, R2 = t-Bu, (R,R)-40e/(R,S)-41e >95:5(S)-39f, R1 = OMe, R2 = t-Bu, (S,R)-40f/(S,S)-41f >5:95(R)-39g, R1 = OMe, R2 = (CH2)9Me, (R,R)-40g/(R,S)-41g = 60:40(R)-39h, R1 = Br, R2 = t-Bu, (R,R)-40h/(R,S)-41h >95:5

*

**

OH

R1

O

OH

R2R

I

OAc

OAc

Ph

ab

(R)-39

a b1st ligandexchange– AcOH

OI

OOH

R2

R1

OAcPh OH

R1

O

OI

OAc

Ph

R2

2nd ligandexchange– AcOH

IO

O R2

PhO

R1

OI O

O

R1

Ph

R2

+

pro-R ketal pro-S ketal

– PhIligand coupling

(R,R)-40 (major) + (R,S)-41 (minor)

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Scheme 13 Dearomatization and diastereoselective synthesis of res-orcinol-derived cyclohexadienone 45

3.2 Controlled by Chiral Catalyst

Gaunt and co-workers reported a process that directlyconverts para-substituted phenol 47 into the highly func-tionalized chiral molecule 48 via oxidative dearomatiza-tion and a desymmetrizing secondary-amine-catalyzedasymmetric intramolecular Michael addition (Scheme14).30 This one-step transformation constructs a complexstructure with exquisite control of three new stereogeniccenters. The corresponding decalin derivatives wereformed with superb control of stereochemistry (up to>20:1 dr and 99% ee)

You and Gu developed an intramolecular aza-Michael re-action catalyzed by a cinchonine-derived thiourea

(Scheme 15).31 With 5 mol% of the thiourea in dichloro-methane at room temperature, cyclohexadienones 50 re-acted smoothly to provide compounds 51 in excellentyields and enantiomeric excess. With this methodology,asymmetric total synthesis of (–)-mesembrine32 was ac-complished with high enantioselectivity (98% ee). Thesame catalyst was also used in the dearomatization of phe-nols 52 bearing a bis(phenylsulfonyl)methylene group(Scheme 16).33 Various highly enantioenriched polycycliccyclohexenones 54 were prepared.

Scheme 15 Synthesis of pyrrolidine derivatives via enantioselectiveintramolecular aza-Michael reaction

Scheme 12 Enantioselective synthesis of (+)-biscarvacrol

OH

Ot-Bu

OH

i-Pr

PhI(OAc)2

CF3CH2OH–35 °C

O

i-Pr

O

Ot-Bu MeMgBr

THF–78 °C

(S)-39i (S,S)-41ii-Pr

O

Ot-Bu

HO

(S,S,R)-42dr >95:5

54%

TsOH⋅H2Oacetone

O

i-Pr

HO

[4+2]O

i-Pr

i-Pr

OHO

HO

(+)-biscarvacroler 93:7

56%

(R)-43

OH

Br

O

O

N

OMe

Me

( )8 ( )5

PhIO, TMSOTf

CH2Cl255%

O

O

Br

O

O

44

(–)-45S

S

R

O

OH

HO( ) ( )

(–)-46

O

O

Br

O

O

S

R

not observed

8 5

( ) ( )8 5

( ) ( )8 5

Scheme 14 Catalytic enantioselective dearomatization

OH

X

O

H

( )n

47

NH Ar

OTMSAr

catalyst (10 mol%) (Ar = 2-naphthyl)

PhI(OAc)2 (1 equiv)MeOH, 0 °C

O

X

O

HMeO

H

( )n

48

O

O

HMeO

H

(–)-48c, 75%ee 99%, dr > 20:1

O

MeO

H O

H

O

O

HMeO

H

O

O

HMeO

H

Cl

O

MeO

H O

H

Me Me

O

O

O

HMeO

H

O

N

O

HMeO

H

Ts

O

MeO

H

O

H

O

(–)-48d, 70%ee 97%, dr 1:15

(–)-48e, 75%ee 99%, dr > 20:1

(–)-48f, 52%ee 99%, dr > 20:1

(–)-48g, 75%ee 40%, dr 2:1

(–)-48h, 84%ee 99%, dr > 20:1

(–)-48i, 68%ee 99%, dr > 20:1

(–)-48j, 74%ee 97%, dr 6.7:1

OH

NHPg

PhI(OAc)2

Nu-H

Nu

NHPg

O

catalyst (5 mol%)

CH2Cl2, r.t.NPgNu

O

4950 51

N

HN

NHN S

F3C CF3

catalyst:

Nu = OH, OMe, OEt, O(CH2)2OH, O(CH2)3OH, OAc, NHAc, 3,4-(MeO)2C6H3Pg = Ts, Ms, Ns

26–94%80–99% ee

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Scheme 16 Asymmetric intramolecular Michael reaction

In an alternative to oxidation, the enantioselective dearo-matization of phenols can also proceed in another way.Recently, Hamada and colleagues reported a palladium-catalyzed intramolecular ipso-Friedel–Crafts allylic al-kylation of phenols 55 to afford spiro[4.5]cyclohexadi-enones 56 (Scheme 17).34 The method was thus applied tothe catalytic enantioselective construction of an all-carbon quaternary spirocenter.

Scheme 17 Enantioselective construction of an all-carbon quaterna-ry spirocenter

3.3 Controlled by Chiral Hypervalent Iodine

Asymmetric dearomatization induced by chiral hyperva-lent iodine reagent is still a challenge in organic synthe-sis.35 In 2008, Kita and co-workers developed thesymmetric chiral iodine(III) reagent 60 and applied it inthe tandem enantioselective oxidative dearomatizationand spirolactonization reaction of naphthols (Scheme18).36 The enantiomeric excess values for the productsreached 86%. The reaction might proceed through an ‘as-sociative’14,37 or ‘dissociative’38 pathway. The higher lev-els of asymmetric induction were observed in thosereactions carried out in nonpolar and moderately polarsolvents such as carbon tetrachloride, dichloromethane,and chloroform, in contrast to the polar solvents such ashexafluoroisopropanol, and with substrates carrying elec-tron-withdrawing substituents, rather than those withelectron-donating substituents. These observations sup-port an associative mechanism. A catalytic version of thesame reaction afforded inferior enantioselectivity (up to69% ee; Scheme 19).

Scheme 18 Enantioselective spirolactonization and plausible reac-tion mechanisms

Scheme 19 Catalytic application of the chiral hypervalent iodine(III)reagent (R)-62

Ishihara and colleagues reported a similar spirolactoniza-tion reaction mediated by chiral iodoarenes 65 with m-chloroperoxybenzoic acid as co-oxidant (Scheme 20).39 Inthe presence of 10 mol% of 65, lactones 64 bearing anelectron-donating or an electron-withdrawing group wereformed in good to excellent yields (up to 92% ee). The ac-tive λ3-iodane catalyst may be stabilized by the electrondonation from the carbonyl groups of the lactic amides to

OH

X

PhI(OAc)2

Nu-H

Nu X

Ocatalyst

(10–20 mol%)

DCE, r.t.

XNu

O

52 53 54

N

HN

NHN O

F3C CF3

catalyst:

SO2Ph

SO2Ph

SO2Ph

SO2Ph SO2Ph

SO2Ph

Nu = OH, OMe, OEt, O(CH2)2OH, O(CH2)3OH, OAc

X = CH2,

82–97%84–91% ee

OH

t-BuOOC COOt-Bu

OCOOMe

Pd(dba)2 (5 mol%)(+)-ligand (6 mol%)

Li2CO3 (1 equiv)

MeCN10 °C, 40 h

t-BuOOCCOOt-Bu

O

55 5680% (dr 9.2:1)89% ee (major isomer)

HNNH

PPPh2

OO(+)-ligand:

Ph2

HO

X

R2

OCOOOMe

R1

Pd(0)ligand

HO

X

R2

R1

PdP P

CO2

–O

X

R1

H

R2

PdP P

X

R1

H

Pd

–HOP

P

O

XR1

R2

55

56

MeO–

OH

R

COOH

O

R

HO O

IAr

OAc

O

O

R

O

associative pathway

I

IO

OAc

OAc

57 58 59

60

O

R

OHO

61

dissociative pathway

*

OH

R

COOH O

O

R

O

I

57 59

I

(R)-62 (0.15 equiv)

MCPBA, AcOHCH2Cl2, 0 °C, 3 h

R = H, 65% eeR = Br, 69% ee

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the electron-deficient iodine(III) center, as in 66, or maybe activated by the hydrogen bonding between the mesi-tyl-protected NH groups and the oxygen ligands connect-ed to the iodine atom, as in 67.

In 2009, Quideau et al. developed an asymmetric iodo-arene-mediated hydroxylative dearomatization reaction(Scheme 21).40 In the presence of 10–200 mol% of thechiral iodoarene, the enantioselectivities of o-quinol 69 orepoxide 70 were up to 50% ee. Both λ3- and λ5-iodane-mediated mechanisms were proposed (Scheme 22).

Scheme 20 Catalytic oxidative spirolactonization

Scheme 21 Enantioselective iodoarene-mediated hydroxylativedearomatization

Scheme 22 Proposed mechanism of hydroxylative dearomatization

In the same year, Birman and Boppisetti developed a newclass of chiral iodine(V) derivatives such as 76 with a chi-ral oxazoline group at the ortho-position (Scheme 23).41

This kind of chiral polyvalent iodine reagent proved to beefficient in promoting the transformation of o-alkylphe-nols to o-quinol Diels–Alder dimers with significantasymmetric induction.

Scheme 23 Asymmetric oxidation of isomeric dimethylphenols with76

4 Enantioselective Phenol Dearomatization Strategies in Complex Syntheses

4.1 With the Formation of a Carbon–Oxygen Bond

In the total synthesis of (–)-acutumine (81), which wasoriginally isolated from the Asian vine Menispermumdauricum and possesses selective T-cell cytotoxicity andantiamnesic properties, the iodobenzene diacetate mediat-ed oxidative dearomatization was used as the key step toconstruct masked o-benzoquinone derivative 78 (Scheme24).42 This result highlighted the utility of iodine(III) re-agents for the dearomatization of complex substrates.

Scheme 24 Total synthesis of (–)-acutumine

OH

COOH

O

O

O

6364

MCPBA (1.3 equiv) 0 °CR R

I

O O

O

NHMesMesHN

O

65 (10 mol%)

ee up to 92%

I

O O

O OMesHN NHMesL

L

66

I

O ON

OMes

N

H

H

Mes

OL

L

67

OH

Ar*I

MCPBACH2Cl2, r.t.

O O

or OHOH

O68 69 70

COOH

R

I

R = Me, Et, n-Bu, i-Pr, i-Bu

COOH

I

I

OMeI

OMe

MeO

MeO

COOHCOOH

71

72a

72b 72c

Ar I

O

OH

O

Ar I

O

OH

O

Ar I

OH

O

[O] [O]

ligandexchanges

ArOH ArOH

Ar I

OH

OAr

COOH

O

Ar I

O

OAr

O

O

* * *

**

OH

R

X

(S)-76 (1.0 equiv) AcOH (1.0 equiv)

DME, r.t., 12 h

73

RHO

O

X

O

X

R

OH

OOHR

X

[2+4]

74

75

IO2

N

Ot-Bu

76

OHCl

TBSO

TBSO

HO

OMe

OMe

OHCl

TBSO

TBSO

O OMe

MeO OMe

OBnCl

TBSO

TBSO

O OMe

OMeOMeZn

N

N

O

O

Ph

Ph

OBn

Cl

TBSO

TBSO

OMe

MeO OMeHO

NMe

MeO

O

O

OMe

OMe

OHCl

PhI(OAc)2KHCO3

MeOH, –10 °C67%

1) NaH, BnBr2) THF, –78 °C

(S,S)-ligand (1 equiv) 70% (2 steps)

(S,S)-ligand

77 78

79 80dr 93:7 (–)-acutumine (81)

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A cascade process involving a hypervalent iodine inducedintramolecular oxidative dearomatization and an intramo-lecular dipolar cycloaddition43 was reported by Sorensenand co-workers44 for the construction of the pentacycliccore of cortistatin A (86; Scheme 25). The exposure ofcompound 82 to iodobenzene diacetate45 in trifluoroetha-nol directly produced compound 85 as a single diastereo-mer through two oxidations and two ring formations.

Scheme 25 Total synthesis of cortistatin A

As shown in Scheme 26, a concise asymmetric synthesisof (+)-rishirilide B (92) was reported by Pettus and co-workers.46 Resorcinol 87 was coupled with lactate deriva-tive 88 through a Mitsunobu reaction and a deprotection.Diastereoselective oxidative dearomatization of 89 pre-sumably proceeds via chair-like transition state 90 andleads to chirality transfer from the chiral auxiliary to af-

ford 1,4-dioxan-2-one 91 in high diastereoselectivity.Further transformations of 91 completed an efficientasymmetric total synthesis of (+)-rishirilide B (92) in 15steps and a 12.5% overall yield.

Recently, Pettus and colleagues also developed an oxida-tive dearomatization induced [5+2]-cascade reaction en-abling the synthesis of α-cedrene, α-pipitzol, and sec-cedrenol (Scheme 27).47 The benzylic stereocenter effec-tively guides the formation of the first two stereocentersduring the intramolecular [5+2] cycloaddition of the re-spective phenoxonium intermediate across the tetheredolefin.46

Scheme 27 Synthesis of α-cedrene, α-pipitzol, and sec-cedrenol

Baran and co-workers executed a sequential Barton aryla-tion, Wessely oxidation and Diels–Alder strategy to createthe core of the natural product, maoecrystal V (Scheme28).48 A similar process was reported by Mehta and Maityin the preparation of the complete carbon framework pres-ent in tashironin-type sesquiterpenoid natural products.49

Porco and co-workers described the synthesis of (–)-mito-rubrin (106) and related azaphilone natural products usingcopper-mediated enantioselective oxidative dearomatiza-tion of resorcinols (Scheme 29).50 Dearomatization of theresorcinol aldehyde 101 using complex 102 was achievedin a regioselective manner with high enantioselectivity toafford vinylogous acid 103. Enyne 103 was subjected tocopper(I) iodide catalyzed cycloisomerization to affordthe mitorubrin core structure 104 (58% yield and 97% eefor two steps). Further esterification with acid 105 and fi-nal deprotection afforded the desired azaphilone (–)-mito-

HON

HO

OTBSHO

H

ON

HO

OTBSHO

H

ON

O

OTBSO

H

ON

OTBSO

H

OH

H

I

Ph

AcO

O

H

OH

Me2N

HO

N

[3+2]cycloaddition

PhI(OAc)2, TFE

r.t., 1 h, then 50 °C80%

82

83

8485

cortistatin A (86)

Scheme 26 Total synthesis of (+)-rishirilide B

OBoc

OH

HON

O

Me

OMe

OH

ON

O

Me

OMe

OH

N

O

O

O

OO

OH

COOHHOOH

O

1) Ph3P, DEAD

2) ZnBr2, MeNO2 84% (2 steps)

PhIO, TMSOTfCH2Cl2

73%

87

88

89

9091dr 13:1

O

MeO

(+)-rishirilide B (92)

‡

HO

Pb(OAc)4, CHCl3

–40 °C

61%

O OAcα-cedreneα-pipitzolsec-cedrenol

93 94

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rubrin (106). This convergent synthesis features thehighly enantioselective oxidative dearomatization of res-orcinol aldehyde using a readily accessible chiral bis-μ-oxodicopper complex.

Scheme 29 Total synthesis of (–)-mitorubrin

This oxidation system was also used in the enantioselec-tive synthesis of (+)-chamaecypanone C, a novel microtu-bule inhibitor (Scheme 30).51 In the presence of copperbis(oxo) complex derived from (–)-sparteine, the che-moselective ortho-dearomatization of 2,4-disubstitutedlithium phenolate led to o-quinol 108 which equilibratedby means of a [1,2]-ketol shift to isomer 109. The latterunderwent a Diels–Alder dimerization to generate bicyc-

lo[2.2.2]octenone 110 (>99% ee). After a retro-Diels–Alder reaction and a subsequent Diels–Alder cycloaddi-tion with the in situ generated diarylcyclopentadienone,the desired enantiopure cycloadduct 113 was obtained in61% yield.

Scheme 30 Total synthesis of (+)-chamaecypanone C

Dimethylketal 116, generated from the corresponding ox-idative dearomatization of o-prenylphenol 115, under-went a transketalization with (2S,4S)-pentanediol to formchiral quinone monoketal 117. The latter is a key interme-diate in the total synthesis of 118, the epoxyquinoid natu-ral product (–)-jesterone (Scheme 31).52

Scheme 31 Total synthesis of (–)-jesterone

Scheme 28 Total synthesis of maoecrystal V

O

OMOMO

O

TBSOTFA

65%

O

HOTBSO

O

O

Pb(OAc)4

AcOH81%

dr 7:3

O

OMOMO

O

TBSO

O

OAc

165 °C

79%

O

OAcO

OTBS

H

O

HO

O

OH

OTBS

H

O

HO

O

OH

O

HO

O

95 96

97 98major diastereomer

99 maoecrystal V (100)

H

H H

(–)-mitorubrin (106)

HO

OH

CHO

102 [Cu(MeCN)4]PF6(–)-sparteine

DIPEA, DMAP, O2, –10 °C

O

O OHHO

O

OHO

O

CuIDIPEACH2Cl2

58%2 steps

BnO

OMe

COOH

1) 105, CO2Cl2, DMF; then DIPEA, DMAP, CH2Cl2

2) BBr3, CH2Cl2

101103

104

105

39% (2 steps)

O

OO

O

O

OHHO

N

NCu Cu

N

N

O

O

III III

2+

102

97% ee

2PF6–

OH

1) LiOH; then [Cu(MeCN)4]PF6,(–)-sparteine, O2, MS2) benzene, heat

O

O

OHOH

O

H

HOHO

HO

MeO

O

OMe

DDQ150 °C, 1 h

O

OH

O

OMeMeO

61%

O

OH

OR

O

OR

H

BBr386%

107 108 109

110

111

112

109

113, R = Me

114, R = H(+)-chamaecypanone C

MeO OMe

TBDPSO

O

Br

(2S,4S)-(+)-pentanediolPPTS

benzene, 80 °CTBDPSO

O

Br

OO

HO

O

O

OH

116

117

(–)-jesterone (118)

TBDPSO

OH

Br

115

PhI(OAc)2 MeOH, r.t.

83%

80%

OMe

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4.2 With the Formation of a Carbon–Carbon Bond

As highlighted in the previous section, many oxidativedearomatizations involve soft carbon nucleophiles. Thecarbon–carbon bond formation during the oxidativedearomatization is of significant interest in complex natu-ral product synthesis. Kita and co-workers reported thefirst versatile iodoarene-catalyzed carbon–carbon bond-forming reaction (Scheme 32).53 With the in situ generat-ed active catalytic iodine(III) species, the oxidative dearo-matization of compound 119 produced the discretecarbocation intermediate 120, which was selectivelytrapped by the pendant aromatic ring to afford the desiredspirocyclic amino ester 121. This reaction was used in thekey synthetic process of producing biologically importantamaryllidaceae alkaloids, such as (+)-maritidine (123).

An important example of the oxidative dearomatization ofa phenolic substrate with concomitant carbon–carbonbond formation in the context of complex total synthesiswas reported by Nicolaou and colleagues in their enantio-selective synthesis of (–)-platensimycin (Scheme 33).54

The authors employed oxidative dearomatization with anintramolecular para-spiroannulation of a pendantallylsilane13,14,37e,55 using hypervalent iodine activation toassemble the first two rings of the natural product. Activa-tion of the free phenol moiety by iodobenzene diacetate ina polar solvent (trifluoroethanol) afforded the activatedintermediate 125 bearing a delocalized carbocation whichreacted internally with the allylsilane to furnish the de-sired spirocyclic dienone. Subsequent removal of the eth-ylene acetal group led to the free aldehyde substrate 126,which was ready to undergo a radical-mediated cycliza-tion and an acid-mediated etherification to efficiently pro-duce the tetracyclic core of platensimycin (129).Danishefsky and Dai developed an alkylative para-dearo-matization of compound 130 to synthesize 131, the corematrix of the steroidal alkaloid cortistatin A (Scheme34).56

Porco and Wang made efforts toward the synthesis of thesoybean lipoxygenase inhibitors, tetrapetalones A to D(Scheme 35).57 Treatment of macrocyclic hydroquinone132 with iodobenzene diacetate led to a diastereoselectivetransannular [4+3] cyclization and formed the tetracycliccore of the targeted molecules. The attack of the electron-rich diene unit at the oxidatively activated hydroquinonemoiety generated an intermediate with an allylic cation,which could rotate to form a suitable conformation (134)for reaction with the amide nitrogen atom. The para-quinolic tetracycle 135 was obtained in 42% yield from132 via this one-pot process.

In the first total synthesis of the amaryllidaceae alkaloid(+)-plicamine (139), Ley and co-workers used a solid-supported iodobenzene diacetate (PS-DIB) to mediate thespirocyclization of 136 (Scheme 36).58 The resulting ad-vanced intermediate 138 was also exploited for the syn-thesis of both (–)-obliquine (141) and (+)-plicane (142)via the common secondary amine precursor 140.59

An iron(III)-mediated cascade oxidative dearomatizationand intramolecular Diels–Alder reaction was developed

Scheme 32 Total synthesis of (+)-maritidine

N

HO

COCF3

MeOOC

OMe

OMe

N

O

COCF3

MeOOC

OMe

OMe

N

O

COCF3

MeOOC

OMe

OMe

N

O

COOMe

MeO

MeO N

MeO

MeO

OH

F I, urea-H2O2

TFAA, TFE–40 to –10 °C

K2CO3MeOH

119120

121 122 (+)-maritidine (123)

73%

Scheme 33 Total synthesis of (–)-platensimycin

OTBS

TMSO

O

1) NaOH, MeOH2) PhI(OAc)2, TFE3) HCl

61% (3 steps)

O

O

OTMS

H

O

O

HO

O

O

O

O

O

O

NH

OH

OH

HOOC

SmI2, HFIP–78 °C, 1 min 46%

TFA, CH2Cl2

87%

124 125

126

127128129

d.r. 2:1

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by Mulzer and Heckrodt in their total synthesis of (+)-elis-abethin A (Scheme 37).60 Tricyclic compound 146 wasformed via endo transition state 145. This cascade processrelied on the Z-configuration of the terminal olefin to in-duce the desired stereochemistry. The facial selectivity ofthe diene–quinone cycloaddition is presumably dictatedby the minimization of allylic strain between the substitu-ents at C9 and the quinone carbonyl moiety in endo tran-sition state 145 such that cycloadduct 146 is produced asa single diastereoisomer. The required chemoselective re-

moval of the endocyclic alkene, epimerization at C2, anddeprotection afforded (+)-elisabethin A (147).

Scheme 34 Total synthesis of cortistatin

O

SiMe

Me

OO

O

OMs

TBAF, 130 °C20 min

88%

O

SiMe

Me

OO

O

OMs

F

O

O

O

O O

H

OH

Me2N

HO

N

130

131 cortistatin A (86)

Scheme 35 Synthesis of tetrapetalones A to D

O

N

OH

O

OO

OH

HR

OH

R = H, tetrapentalone AR = OAc, tetrapentalone B

O

N

O

O

OO

OH

HR

OHOH

R = H, tetrapentalone CR = OAc, tetrapentalone D

HN

OH

OH

Et

O

OMOM

TBSO42%

O

N

O

TBSO

H

OH

EtOMOM

HN

OH

O

Et

O

OMOM

TBSO

PhI(OAc)2

I

Ph

OAc O

HN

O

TBSO

H

OHOMOM

Et

132

133134

135

PhI(OAc)2CH2Cl2, 0 °C

Scheme 36 Polymer-supported approach to the total synthesis of am-aryllidaceae alkaloids

OH

N

NHMe

O

CF3O

O

O

PS-DIBCF3CH2OH

–5 °C

82%

O

ON CF3

O

O

NHMe

O

N

N

O

O

Me

OCF3

O

HO

H

H

N

N

O

O

Me

O

MeO

H

H

O

OH

N

N

O

O

Me

O

MeO

H

H

H

N

N

O

O

Me

O

MeO

H

H

OH

N

N

O

O

Me

O

MeO

H

H

99% (2 steps)

96% (2 steps)

57%(7 steps)

92%(2 steps)

96%

136

137

138

139

140

(–)-obliquine (141)

(+)-plicane (142) Thi

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Scheme 37 Total synthesis of (+)-elisabethin A

In the total synthesis of the antimitotic natural product(–)-diazonamide A (154), Harran and co-workers subject-ed the advanced phenolic–indolic amide intermediate 148to reaction with iodobenzene diacetate in the presence oflithium acetate in trifluoroethanol at –20 °C (Scheme38).61 This treatment led to the formation of an undesireddearomatized and spiroannulated cyclohexa-2,5-dienoneproduct 150 in 15% yield (path a). Nevertheless, the twodiastereomeric macrolactams 152 and 153 were fortunate-ly also obtained in a 1:3 ratio (ca. 30% yield) according tothe proposed path b, through which the transient interme-diate 149 is trapped intramolecularly by the nucleophilicindolic moiety, followed by rearomatization of the result-ing cyclohexa-2,4-dienone intermediate 151 with a con-certed oxocyclization onto its iminium unit leading to theobserved benzofurans. Finally, the major benzofuranproduct 153 was further transformed to afford (–)-diazon-amide A (154) after 14 additional steps.

4.3 With the Formation of a Carbon–Nitrogen Bond

Matsumoto and co-workers62 relied on 6,6-dimethoxycy-clohexa-2,4-dienone derivatives as key intermediates inthe synthesis of the erythrinan skeleton, an indolo[7a,1-α]isoquinoline core common to alkaloids isolated frommany plant species of the Erythrina family. These uniquetetracyclic amino structures were shown to exhibit curare-like, sedative, hypotensive and central-nervous-system-depressant activities. The atropisomerically pure biphe-nylic phenol 155 was successfully dearomatized into thedesired o-quinone monoketal 156 upon treatment with io-dobenzene diacetate in methanol at room temperature(Scheme 39).62 Subsequent Lewis acid promoted aza-spi-rocyclization converted compound 156 into 157. Both cy-clohexa-2,4-dienone and the spiro-isoquinoline productproved to be enantiomerically pure, thus demonstratingthe efficacious transmission of the axial chirality of the bi-phenyl 155 to the sp3-center chirality of the spirocycle 157during this focal SN2′-type reaction of the synthesis.62a

The total synthesis of (+)-O-methylerysodienone (158)

was next completed through three additional steps.62b

More recently, this strategy was followed by the same re-search group to achieve the total synthesis of (+)-11-hy-droxyerythratidine (162), a C-11 oxygenated erythrinanalkaloid (Scheme 40).63

Ciufolini and co-workers reported a synthesis of the cy-clohexa-2,5-dienone spirolactam 164 by treating the L-ty-rosine-derived oxazoline 163 with iodobenzene diacetatein trifluoroethanol, following immediately with an acety-lation (Scheme 41).64 This spirolactam then served as acommon intermediate for the synthesis of (+)-FR901483(165)8a,65 and (+)-TAN1251C (166).61 Further investiga-tions led them to work with phenolic sulfonamides thatturned out to be much better substrates than oxazolines foraza-spirocyclization.66 For example, sulfonamide 167 wasconverted into the cyclohexa-2,5-dienone spirocycle 168,which is the key synthetic intermediate for the total syn-thesis of the ascidian Clavelina cylindrica metabolite (–)-cylindricine C (169) (Scheme 42).67

OTBS

OTBS

OMeTBAF

FeCl3, H2O, r.t.91%

O

O

OMe

O O

H

OMe

O

OH

OMeH

O

OH

OHH

143 144

145 146 (+)-elisabethin A (147)

H

HH

H

Scheme 38 Total synthesis of (–)-diazonamide A

HO

ArO2SHN

O

NH

O

NCO2Me

NH

BrPhI(OAc)2, LiOAc

CF3CH2OH–20 °C

O

ArO2SHN

O

NH

O

NCO2Me

NH

BrI

OAc

Ph

a

b

N

O

NCO2Me

NH

Br

O

O

ArO2SHN 1:1

15%

path a

path b

HN

O

NCO2Me

O

O

H

NH

ArO2SHN

Br

HN

O

NCO2Me

O

O NH

ArO2SHN

BrH

HN

O

NCO2Me

O

O NH

ArO2SHN

Br

+

HN

O

N

O

O NH

HN

O

HOO

N

NH

Cl

148

149

150

151

152 7–8%

153 20–25%

(–)-diazonamide A (154)

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Scheme 41 Synthesis of (+)-FR901483 (165) and (+)-TAN1251C(166)

Scheme 42 Synthesis of (–)-cylindricine C (169)

Sorensen and co-workers also accomplished an enantio-specific synthesis of the potent immunosuppressant (+)-FR901483 (165) by relying on a λ3-iodane-mediated oxi-dative phenol dearomatization reaction to cast the azaspi-rane system (Scheme 43).68 In this case, phenolicsecondary amine 170 was used as substrate to afford aza-spiro[4.5]decadienone 171. Eight additional transforma-tions completed the synthesis of the targeted (+)-FR901483 (165).

Scheme 43 Synthesis of (+)-FR901483 (165)

A similar strategy was used by Honda and colleagues asthe key step in the synthesis of (–)-TAN1251A (175), iso-lated from a culture of Penicillium thomii RA-89 (Scheme44).69

Scheme 44 Synthesis of (–)-TAN1251A (175)

5 Conclusions

A large number of papers have been published since thebeginning of the century on the investigation of phenoldearomatizations, both in natural product synthesis andmethodology development. This review highlights somerecent advances in the phenol dearomatization reactions,especially those carried out in an enantioselective manner,and the application of dearomatization strategies in com-

Scheme 39 Total synthesis of (+)-O-methylerysodienone

(+)-O-methylerysodienone (158)

MeO

OMe

NHBoc

TMS

MeO

OH

OTIPSPhI(OAc)2, MeOH, r.t.

99%> 99% ee

MeO

OMe

NHBoc

TMS

MeO

O

OTIPS

MeO

BF3⋅OEt2CH2Cl2

4 Å MS, –20 °C

90%> 98% ee

TMS

O

OTIPS

MeO

NBoc

MeO

MeO

O

MeO

N

MeO

MeO

155 156

157

Scheme 40 Total synthesis of (+)-11-hydroxyerythratidine

MeO

OMe

MeO

OH

OBz

1) H2, Pd/C, MeOH, r.t.2) DIB, MeOH, 0 °C

99%

MeO

OMe

MeO

OMeO

Cu(OTf)2, toluene –20 °C to r.t.

95%dr 14:1

O

OBz

MeO

NBoc

MeO

MeO

MeO

N

MeO

MeO

159 160

161 162

NHBoc

OTIPS

OBzNHBoc

OTIPS

OTIPSOH

OH

O

NNHTs

PAN

HO

PhI(OAc)2

CF3CH2OH;then Ac2OPy, DMAP

41%O

NNHTs

OAcO

PAN

PAN = p-anysyl

NHO

OMe

NHTs

OP(O)(OH)2

N

N

O

O

Me

163

164

165

166

HO

MsHN

HO

PhI(OAc)2(CF3)2CHOH;

then TBDPSClimidazole, DMF

82–87%

MsN

TBDPSO

O

N

OH

n-C5H13

OH167 168 169

NH

MeOOC

OH

NPG

MePAN

PAN = p-anysylPG = p-NO2C6H4SO2

PhI(OAc)2

(CF3)2CHOH51%

NMeOOC

PAN

NMe

PGO

165

170171

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NMe

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174

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plex syntheses. Future research in this area should lead toadditional strategies and methods for the use of new andefficient chiral reagents and catalysts which should be ofgreat value to the field of natural products total synthesis.

Acknowledgment

Financial supports from National Natural Science Foundation ofChina (21072033), and the Open Project Program of Key Laborato-ry of Functional Small Organic Molecules, Ministry of Education,Jiangxi Normal University (No. KLFS-KF-201201) is gratefullyacknowledged.

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