polyprenylated phloroglucinols and xanthonestheodorakisgroup.ucsd.edu/publications...

433

12Polyprenylated Phloroglucinols and XanthonesMarianna Dakanali and Emmanuel A. Theodorakis

12.1Introduction

Guttiferae (Clusiaceae) is a family of plants that includes more than 37 generaand 1600 species [1]. Characteristic to this family is its large variation in plantmorphology, which makes it an important group of plants for the study of floraldiversification and evolutionary plasticity. Although mainly confined to the tropicalareas, this family also includes the genus Hypericum, a plant that is found widelyaround the Mediterranean area. Several plants of the Guttiferae family have arich history in ethnomedicine for their broad-spectrum antibacterial and healingproperties. For instance, the antibacterial and antidepressant activities of Hypericumperforatum (St. John’s wort) have been noted in traditional European medicine. Infact, Hypericum extracts have been tested in various clinical trials and are currentlyused in certain countries for the treatment of depressive, anxiety, and sleepdisorders [2–11]. On the other hand, members of the Garcinia genus of tropicaltrees have considerable value as sources of medicines, pigments, foodstuffs, andlumber [12, 13].

Chemically, the Clusiaceae family of plants constitutes a rich source of polypreny-lated acylphloroglucinols and xanthones. Both chemical classes have generatedsubstantial interest due to their fascinating chemical structures and potent bioac-tivities [10]. This chapter summarizes the chemical classification, biosynthesis, andsynthetic approaches toward these compounds.

12.2Polycyclic Polyprenylated Phloroglucinols

12.2.1Introduction and Chemical Classification

The chemical structures of all known polycyclic polyprenylated acylphloroglucinols(PPAPs) can be classified into three types that are related to the biosynthesis

Biomimetic Organic Synthesis, First Edition. Edited by Erwan Poupon and Bastien Nay. 2011 Wiley-VCH Verlag GmbH & Co. KGaA. Published 2011 by Wiley-VCH Verlag GmbH & Co. KGaA.

434 12 Polyprenylated Phloroglucinols and Xanthones

Type A

R1 = Me, C5H9, or C10H17R2 = H or prenylR3 = i -Pr, i -Bu, s-Bu,

Ph, 3-(OH)C6H4, or 3,4-(OH)2C6H3R4 = Me, R5 = OH or R4, R5 = CH2CHR6R6 = H, C(CH3) = CH2, or C(CH3)2OH

Type B Type C

OO15

3

7

8

9

OHO

R2R1

R1

R1

O

R3OHO

R3O

R1 R1

R2

R1

15

3

7

915

3

O

OHO

R3O

R4R1

R5

8

O

OHO

R1

R1

3

7

6

9

A

BR1

O

R3

15

R2

Figure 12.1 Classification of polycyclic polyprenylated acylphloroglucinols (PPAPs).

proposal (Scheme 12.2 below). Types A, B(I), and C PPAPs are distinguished bythe presence of a highly oxygenated bicyclo[3.3.1]nonane-2,4,9-trione motif, whiletype B(II) PPAPs contain a bicyclo[3.2.1]octane-2,4,8-trione carbon framework(Figure 12.1). In all types, the bicyclic motif is further decorated with prenyl,geranyl, and related side chains. Certain family members contain additionalrings, formed by cyclizations between the β-diketone and an alkene, leading toadamantanes, pyrano-fused, or other cyclic substructures. Type A PPAPs havean acyl-substituent at C1 adjacent to a quaternary C8 carbon, while the type Bcompounds have the acyl-substituent at C3. The more rare type C PPAPs have theacyl group at C1 but the quaternary carbon is located at the distant C6 (Figure 12.1)[14]. For the purpose of this chapter, the carbon numbering of these molecules isbased on the nemorosone numbering [14].

Figure 12.2 shows representative members of the PPAPs. Hyperforin (1), oneof the bioactive ingredients of Hypericum perforatum [15, 16], belongs to the typeA PPAPs and is also known for its antibacterial [17] and anticancer properties [9,18]. Another type A phloroglucinol is garsubellin A (2), a natural product notedfor its activities against neurodegenerative diseases. In fact, recent studies haveshown that garsubellin A induces biosynthesis of acetylcholine, a neurotransmitterthat at low concentrations can lead to Alzheimer’s disease [19]. Nemorosone (3)exhibits antimicrobial [20, 21], cytotoxic, and antioxidant activities [20], while,clusianone (4), a type B(I) PPAP, is known for its anti-HIV activity [22]. The typeB(II) enaimeone A (5) was isolated from Hypericum papuanum, the leaves of whichare used in the traditional medicine of Papua New Guinea for treating sores [23].Garcinielliptone M (6), a type C PPAP, isolated from Garcinia subelliptica, showspotential anti-inflammatory activity [24].

12.2.2Biosynthesis of PPAPs

PPAPs derive biosynthetically from the less complex monocyclic polyprenylatedacylphloroglucinols (MPAPs), a class of natural products isolated from plants of the

12.2 Polycyclic Polyprenylated Phloroglucinols 435

O

OHO

O

O

OHO

O

OHO

O

O

O O

O

O

HO

clusianone7-epi-clusianone (4)

nemorosone (3)hyperforin (1) garsubellin A (2)

7

Type A

Type B(I)

O

OHO

O

OH

Type B(II)enaimeone A (5)

O

OO

O

OH

garcinielliptone M (6)Type C

Type A Type A

Figure 12.2 Representative members of the PPAP family.

R

OOH

HO OHO

R

OOH

HO O

a-acids (7) b-acids (8)

R = iPr or CH2iPr ornBu or, CH2iBuetc

Figure 12.3 Monocyclic polyprenylated acylphloroglucinols (MPAPs) from Humulus lupulus.

Myrtaceae and Cannabinaceae families [10]. There are two main classes of MPAPs:the diprenylated α-acids (7) and triprenylated β-acids (8) (Figure 12.3). α-Acids areresponsible for the flavor and bitter taste of beer [25] while β-acids show, amongother properties, free radical scavenger activity [7, 26].

Labeling and enzymological experiments have provided evidence that bitteracids are biosynthesized via condensation of three malonyl-CoA and one acyl-CoA,such as isobutyryl-CoA (9) (Scheme 12.1) [27–30]. The intermediate polyketide10 can then cyclize via an intramolecular Dieckmann condensation to pro-duce acylphloroglucinol 11 [31, 32]. Subsequent prenylations (or geranylations)occur via an enzymatic process that involves prenyltransferase-catalyzed reactions


HO OH

OH O

CoAS

O

3 x malonyl-CoA

CoAS

O

O

O

isobutyryl-CoA (9)

O SACoO

O O

phlorisobutyrophenone (11)10

OPP

PT = prenyltransferase

HO OH

OH O

DMAPP

PT

HO OH

OH O

HO OH

O O

HO

HO OH

O O

deoxycohumulone (13)cohumulone (14)colupulone (15)

PT

DMAPP

DMAPP =

12

malonyl-CoA

proposed

proposeddimethylallyl diphosphate

Scheme 12.1 Biosynthesis of acylphloroglucinol 11 and bitter acids 14 and 15.

of the appropriate diphosphates with phloroglucinol [25, 33–37]. This stepwiseprenylation process is illustrated in Scheme 12.1 for the construction of 12 and 13(deoxycohumulone) from 11. It has been shown that chemical and/or enzymaticoxidation of 13 can lead to cohumulone (14), a representative α-acid. It has alsobeen proposed that additional prenylation of 13 can form colupulone (15), a typicalβ-acid [25].

Type A and type B PPAPs are proposed to arise via reaction of acylphloroglucinol16 with prenyl diphosphate. The resulting carbocation 17 can be attacked by the C1′

or C5′ enol to produce compounds 18 or 19, respectively, that represent type A andtype B PPAPs (Scheme 12.2) [14]. Acylphloroglucinol 20, containing a prenylatedC1′ center, is the proposed intermediate of type C PPAPs. Specifically, reaction of20 with prenyl diphosphate can form carbocation 21 and, after cyclization, bicyclic22, a type C PPAP [10].

12.2.3Biomimetic Synthesis of PPAPs

A 2006 review summarizes the synthetic efforts toward PPAPs [10]. These stud-ies set the stage for the first total synthesis of garsubellin A, reported by theShibasaki group [38], and were followed a few months later by a synthesis fromthe Danishefsky group [39]. Since then, additional total syntheses have been pub-lished of either type A [hyperforin (1), garsubellin A (2), nemorosone (3)] [40–42],or type B [clusianone (4)] [41, 43–45] PPAPs. Among all published approachesthere are only two strategies built upon biomimetic considerations that involve:(i) formation of a fully prenylated B ring and (ii) construction of the A ringvia a cation-based alkylative dearomatization. Both strategies departed from the


HO

HO

O

R

O

OPP

HO

HO

O

R

O1 ′5 ′

C5attack

C1attack

HO

O

O

R

O

Type A

O

HO

O

R

O

1 ′5 ′

1 ′5 ′16 17

18

19

HO

OH

O

OPP

RHO

OH

O

O RO

HO

O

OR

OType C20 21 22

O

O15

3

7

8

9

OHO

O

R

OHO

RO

15

3

7

9

O

OHO

R1

3

7

6

9

O

R

15

1 ′

path toward type A, B PAPPs

path toward type C PAPPs

Type B

Scheme 12.2 Biosynthesis of type A, type B, and type C PPAPs from MPAPs.

O

OHO

O

clusianone (4)

OH

OHHO

RO

OHCOAc

Michaeladdition-Elimination

IntramolecularMichael addition

R = Ph

Alkylation

Annulationbased oncationcyclization

R1X

HO

R = i-PrR1 = H or CH2OTBSR2 = H or prenylX = Cl or Br

R2

O

OHO

R2

R1

24

23

25

26

R

O

Scheme 12.3 Biomimetic approaches toward type A and type B PPAPs.

bis-prenylated acylphloroglucinol 23, a key intermediate in the biosynthesis ofthese natural products (Scheme 12.3). The first one, reported by the Porco group,resulted in the total synthesis of clusianone (type B PPAP) [45] using a doubleMichael reaction as a key step. More recently, the Couladouros group producedcompound 26, representing the fully functionalized bicyclic core of the type APPAPs, by a double alkylation of 23 with allyl electrophile 25 [46].


12.2.3.1 Biomimetic Total Synthesis of (±)-ClusianoneThe Porco synthesis of clusianone (4) is summarized in Scheme 12.4 and featuresa double Michael addition of clusianophenone B (27) with α-acetoxy enal 24. Thebicyclic product 28 was methylated to form 29 as a mixture of regioisomers [45].The employment of enal 24 proved to be a useful handle for the ensuing installationof the prenyl group at C7 (Scheme 12.4). Addition of vinyl magnesium bromideto aldehyde 29 and acetylation of the resulting alcohol gave access to acetate 30.Palladium-mediated formate reduction followed by cross metathesis using Grubbssecond-generation catalyst (31) yielded methylated clusianone 32 (81% over twosteps). Finally, demethylation of 32 afforded (±)-clusianone (4) as a mixture of enoltautomers.

OH

OHHO

O

KHMDS, 24,65 °C

TMSCHN2,iPr2EtN

54% (2 steps)

O

CHO

ORO

O

1. MgBr

2. Ac2O, i Pr2EtN, DMAP

74%

O

OMeO

O

AcO

1. Pd(PPh3)4, HCO2NH4, 90%2. Grubbs 2nd generation cat (31)

2-methyl-2-butene,89%

O

OMeO

O

LiOH, ∆, 77%

orLiCl, ∆, 69%

clusianone (4)

clusianophenone B (27)

28: R = H 30

32

7

OHCOAc24

N N

RuPh

P(Cy)3

Cl

Cl

Grubbs 2ndgeneration catalyst (31)

O

OHO

O

29: R = Me

Scheme 12.4 Biomimetic synthesis of clusianone by Porco, Jr. et al.

The double Michael reaction, used for the conversion of 27 into 28, deserves anadditional comment. The authors reported that heating of this reaction at 65 ◦C ledto desired compound 28 via epimerization of the C7 aldehyde stereocenter. Inter-estingly, performing this reaction at 0 ◦C formed the adamantane-like compound34 via an intramolecular aldol reaction. When 34 was treated with potassium hex-amethyldisilazane (KHMDS) at 65 ◦C compound 28 was synthesized, presumablyvia a retro-aldol epimerization process (Scheme 12.5). This observation allows thesynthesis of adamantane-like compounds that are structurally related to hyperiboneK (36).


27KHMDS, 24, 0 °C

O

H

OOO

OH

O

OOO

CH

O

33 34

1 eq. KHMDS, 65 °Cretro-aldolepimerization

O

OOO

H

35

H

HC

O

H3O+

O

CHO

OHO

O

28

O

H

OOO

hyperibone K (36)

Scheme 12.5 Observations related to the double Michael reaction 27 → 28.

12.2.3.2 Biomimetic Approach to the Bicyclic Framework of Type A PPAPsThe Couladouros approach towards the bicyclic core of type A PPAPs is highlightedin Scheme 12.6 [46]. C-alkylation of deoxycohumulone (13) with chloride 37, undera two-phase solvent system at pH 14, produced compound 38 as a mixture of twodiastereoisomers. Acetylation of the C4 hydroxyl group of 38 followed by mesylation

OH

OHHO

O

Cl

HO

OTBS

KOH (3 N), 37,PhCl/H2O

aliquat 336,pH=14

99%

O

OHHO

O

OTBS

OH

*1. Ac2O,

2. MsCl,

65–73%

O

OHAcO

O

OTBS

1a

b

b

b

O

AcO

O

OTBS

O

O O

OAcO

+

via path avia path b

TBSO

deoxycohumulone (13)

37

38 39

4041

4

9

8

8

pyridine

Et3N

Scheme 12.6 Biomimetic formation of the type A carbon framework.


of the C8 alcohol produced bicyclic motifs 40 and 41 in 1.5 : 1 ratio, presumablyvia common intermediate 39. Compound 41 is generated via O-alkylation of theC9 enol to the intermediate C8 carbocation formed during the reaction (pathβ). Notably, the presence of the double bond, allylic to the tertiary alcohol, is ofimportance for the stabilization of the cation 39.

The authors have also evaluated a Michael addition for construction of the typeA skeleton, in a similar manner as that presented above, in the synthesis ofclusianone [45]. This approach was only successful for the synthesis of compoundsnon-substituted at C8 (Scheme 12.7). These results illustrate the difficulty insynthesizing the fully functionalized carbon framework of type A PPAPs, wherethe quaternary bridgehead C1 is located next to the fully substituted C8.

TBSO Br

H H

KOH (3 N),PhCl/H2O

O

OHHO

O

OTBS

13

1. Ac2O, pyridine, 89%2. HF⋅pyr

3. IBX 69% (2 steps)

O

OHAcO

O

O

NaHCO3

O

AcO

O

O

8

O

42 43 44

aliquat 336,pH=14, 38%

71%

1

Scheme 12.7 Construction of a type A PPAP motif via an intramolecular Michael addition.

12.2.3.3 Biomimetic Synthesis of (±)-Ialibinone A and B and (±)-Hyperguinone BVery recently a biomimetic synthesis of PPAPs isolated from Hypericum papuanumwas reported. Scheme 12.8 depicts the total synthesis of racemic ialibinones A and

NaOMe, MeI13

45

78%

PhI(OAc)2

O

O

OH

O

I

O

O

OH

O

IIH

O

O

OH

O

IIIH

O

O

OH

+

O

IVH

O

O

OH

O

HO

O

OH

O

ialibinone A

H

ialibinone B

58%

−H+

O

OHHO

O

O

OHO

O

V

73%

O

OHO

O

hyperguinone B

PhI(OAc)2

TEMPO

Scheme 12.8 Biomimetic synthesis of PPAPs via oxidative cyclization reactions.


B and hyperguinone B [47]. The synthesis of all three natural products started withcompound 13, which is the same starting material used in Couladouros’ approachand similar to that used in Porco’s synthesis of clusianone. The C-methylationof 13 was carried out by treatment with NaOMe–MeI to give 45 in very goodyield. Reaction of 45 with PhI(OAc)2 gave a 1 : 1 mixture of (±)-ialibinones Aand B in 58% combined yield. The reaction most likely proceeds via an initialsingle-electron oxidation of 45 to give intermediate I. A stereoselective 5-exo-trigcyclization of this radical onto the pendant prenyl group would then give tertiaryradical II, which can undergo a second cyclization onto the other prenyl groupto give the tertiary radical III. Finally, an additional single-electron oxidation ofIII would lead to the tertiary carbocation IV and then to the final racemic naturalproducts. In contrast, treatment of 45 with PhI(OAc)2 in the presence of TEMPO(2,2,6,6-tetramethylpiperidine-1-oxyl) gave (±)-hyperguinone B in 73% yield. Thereaction presumably proceeds via hydride abstraction by the in situ generatedTEMPO cation to give intermediate V, which undergoes a 6π -electrocyclizationleading to the pyran ring of hyperguinone B.

12.2.4Non-biomimetic Synthesis of PPAPs

In addition to the biomimetic approaches toward PPAPs, presented above, thereare also a few non-biomimetic total syntheses that have been reported in theliterature in the past few years. In this section we present briefly the total synthesisof garsubellin A, nemorosone, and hyperforin – representative members of type APPAPs – and the synthesis of clusianone, a type B PPAP.

12.2.4.1 Total Synthesis of Garsubellin AThe Shibasaki synthesis of garsubellin A (2) is summarized in Scheme 12.9 [38]. Aninteresting structural feature of this natural product is the additional ring (C-ring)that is formed by oxidative cyclization of a prenyl group. Key to the synthesiswas the conversion of compound 47 into 51 via two steps: (i) a stereoselectiveClaisen rearrangement of 47 → 49 via intermediate 48, which installs the alkenesubstituents at C1 and C5 syn to each other, and (ii) a ring-closing metathesis usingthe Hoveyda–Grubbs catalyst 50. The fused tetrahydrofuran ring was constructedafter allylic oxidation, hydrolysis of the carbonate, and Wacker oxidative cyclization.Finally, Stille coupling of 53 with tributyl(prenyl)tin completed the total synthesisof (±)-garsubellin A.

The Danishefsky synthesis of garsubellin A (2) is highlighted in Schemes 12.10and 12.11 [39]. Compound 54, representing the B ring of the target molecule,was converted into acetonide 55 in five steps in 43% overall yield (Scheme 12.10).Treatment of 55 with HClO4 at 80 ◦C led to a mixture of bicyclic adducts 57 and58 that, upon further heating, produced initially 59 and ultimately adduct 60 (71%isolated yield).

Iodocarbocyclization of 61 provided 62 using standard iodolactonization condi-tions (Scheme 12.11). Conceptually, this reaction is similar to the Se-mediated


OEt

O

O O

OO

O

NaOAc, ∆96%

OO

O

OO

92%

MOMO MOMO

1. (PhSe)2, PhIO2, pyr2. CSA, 70% (2 steps)

3. LiOH4. Na2PdCl4, TBHP 71% (2 steps)

1. I2, CAN

2. pTsOH⋅H2O80% (2 steps)

PdCl2⋅dppf

SnBu320%

garsubellin A (2)

OCOiPr

MOMO

46 47 48 49

50

515253

A

BC

N N MesMes

Ru

O

ClCl

50

14 steps

6% combinedyield

A

O O

O O

O

MOMO

O O

HO

OO

HOO O

OO

HO

I

A

BC

A

B

AA 15

Scheme 12.9 Total synthesis of garsubellin A by the Shibasaki group.

OTIPS

MeO OMe

O

MeO OMe

O

O

HClO4

O

MeO OMe

HO

HO

O O

OMe

HO

OMeHO O

OMe

HO

OMeHO O

OMe

HO

HO O

O

HO

H

60 (71%)

54 55 56

575859

5 steps

43% combinedyield

C B C B C B C B

BBB

H2O/dioxane80 °C

Scheme 12.10 Formation of the B-C ring system of garsubellin A by Danishefsky et al.

cyclization approach reported by Nicolaou during his efforts towards the synthesisof garsubellin [48, 49]. Compound 62 underwent additional iodination to formtriiodide 63. Treatment of 63 with excess isopropylmagnesium chloride led tocompound 64 via an intramolecular Wurtz cyclopropanation and subsequent al-lylation. Reaction of 64 with TMSI (trimethylsilyl iodide) formed 65, containingthe tricyclic framework of garsubellin A. Finally, the synthesis of garsubellin A(2) was completed after decoration of 65 with the appropriate prenyl and acylsubstituents.


2. Grubbs 2ndgeneration cat.2-methyl-2-butene

68% O O

O

HO

H

I2, KI, KHCO3

85%

O

O O

HO

H

I

I I2, CAN

O

O O

HO

H

I

I

77%

iPrMgCl thenLi2CuCl4

Br67%

O

O O

HO

H

TMSI then1 N HCl

98%

O

O O

HO

H

I

H

1. AIBN,

SnBu3

Grubbs 2ndgeneration cat. (31)2-methyl-2-butene

73%

82%

O

O O

HO

H

H

LDA, TMSCl,

then I2

O

O O

TMSO

H

I

−iPrMgCl then

O

72%

O

O O

TMSO

H

1. Dess-Martin

2. Et3N(HF)388% (2 steps)

garsubellin A (2)

60

61 62 63

646566

67 68

OH

I

I

25–36%

Scheme 12.11 Total synthesis of garsubellin A by the Danishefsky group.

12.2.4.2 Total Synthesis of Nemorosone and Clusianone through Differentiation of‘‘Carbanions’’More recently, the Danishefsky group has extended the above strategy to thesynthesis of nemorosone (3) and clusianone (4) [41]. These natural products provedto be more demanding targets than garsubellin A, due to the lack of the furano-fusedring that provides further stability to the molecule. A significant complication aroseduring the iodonium-induced carbocyclization of compound 70 (Scheme 12.12).In addition to the desired product 73, the authors obtained substantial quantitiesof 71 and 72 (53% combined yield). Most likely, these side products were formedvia O-alkylation of an iodonium intermediate. Gratifyingly, treatment of 71 and 72with zinc in aqueous THF could regenerate 70 in high yield, allowing recycling ofthe starting material. Reaction of 73 with isopropylmagnesium chloride producedcyclopropane adduct 74 that, in turn, upon treatment with TMSI gave rise to bicyclicmotif 75. Radical allylation then produced compound 76, a common intermediatein the synthesis of nemorosone and clusianone.

Completion of the synthesis of 3 and 4 required differentiation of carbons C1and C3 of common intermediate 76. To this end, treatment of 76 with an excess


OM

e

MeO

OH

OM

eO

OO

OM

eO

I

I

+

OI

I

MeO

O

O

I

MeO

I O

+

I 2, K

I,K

HC

O3

73 (

32%

)71

(29

%)

72 (

24%

)70

7070

iPrM

gCl

93%

Zn

78%

Zn

87%

O

OM

eO98

%

OI

OM

eO

AIB

N

84%

O

OM

eO

1

376

69

7475

I

TM

SI

SnB

u 3

13

step

s

32%

Sche

me

12.1

2Fo

rmat

ion

ofth

eco

mm

onin

term

edia

te70

tow

ards

the

synt

hesi

sof

nem

oros

one

and

clus

iano

ne.


of LDA (lithium diisopropylamide) and TMSCl (trimethylsilyl chloride) followedby oxidative quenching with iodine provided 77 in moderate yield along with 78,which can in turn be converted into 77 by applying the same reaction conditions(Scheme 12.13). The total synthesis of 3 was completed after, first, acylation of C1and then lithium-mediated allylation at C3.

O

OMeO

TMS

LDA, TMSCl,

then I2

R1

77: R1 = I

51% for 7712% for 78

78: R1 = H

LDA, TMSClthen I2, 41%

O

OHO

O

nemorosone (3)

5 steps

15% combinedyield

O

OMeO

1

3

76

Scheme 12.13 Total synthesis of nemorosone.

On the other hand, treatment of 76 with LDA without the presence of TMSCl andquenching with benzaldehyde gave rise to 79, after acylation at C3 (Scheme 12.14).Conversion of 79 into its C1 iodo derivative and transformation of the iodo groupinto an allyl functionality concluded the synthesis of clusianone (4).

1. LDA, thenPhCHO

2. Dess-Martin

57%

O

OMeO

O

79

O

OHO

O

clusianone (4)

4 steps

20% combinedyield

O

OMeO

1

3

76

Scheme 12.14 Total synthesis of clusianone by the Danishefsky group.

12.2.4.3 Total Synthesis of (−)-Hyperforin(+)-Hyperforin (1), a type A PPAP, contains an additional chiral quaternary centercompared to the other herein mentioned acylphloroglucinols, thus presentinggreater difficulties towards its total synthesis. In early 2010 a catalytic asymmetrictotal synthesis of (−)-hyperforin was published by Shibasaki and coworkers [42].Notably, this is the first catalytic asymmetric synthesis of any PPAP, since thepreviously reported asymmetric synthesis of clusianone involved a late-stage kineticresolution (Section 12.2.4.4) [50].

Compound 83, having the desired stereochemistry at C7 and C8 carbons, wasconstructed via a catalytic asymmetric Diels–Alder reaction between 80 and 81(Scheme 12.15). Compound 83 was then converted into allyl ether 84, whichunderwent a stereoselective Claisen rearrangement to form ketone 86. This rear-rangement proceeded with high selectivity from the β face, most likely due to the


ON

OO

OTIPS

OTIPS+

FeBr3, AgSbF6, 82

80 81

OTIPS

OTIPS

N O

O O 83

NN

OO

N

Ar Ar

Ar = 4-EtOC6H4

82

93%, 96% ee

O

MOMO

O

∆

MeiPrCO

H H

R

MOMO

O

O

MOMO

O

O O

O

84

858687

88 89

8

17 steps

33%

6 steps

53% combined yield

1. NaOEt2. Dess-Martin

86% (2 steps)

1. (Sia)2BH,H2O2, NaOH

2. Dess-Martin

74% (2 steps)

O

MOMO

OO

>99%(d.r. = 12:1)

A A

AA

MOMO

O O

O

OMe

A A

B B

7

8

Scheme 12.15 Catalytic asymmetric synthesis of the bicyclic framework of hyperforin.

pseudo-axial orientation of the methyl group at C8, which blocks the α face, asshown in intermediate 85. Initial attempts to form the B ring of hyperforin viaan olefin metathesis approach proved unsuccessful, prompting the developmentof an alternative strategy using an intramolecular aldol reaction [51]. With this inmind, hydroxylation and oxidation of the terminal alkene of 86 produced aldehyde87 that after intramolecular aldol reaction and oxidation gave rise to bicyclic adduct88. Peripheral decoration of 88 afforded ketone 89 in six steps (53% combinedyield).

Scheme 12.16 shows the completion of the (−)-hyperforin synthesis from 89.Oxidation of C2 proved to be more difficult than anticipated since any attempt atnucleophilic addition in 90 failed. Furthermore, efforts to induce a [3.3] sigmatropicrearrangement of xanthate 91 led to dithionate 92 after a [1.3] rearrangement. Thisfinding, however, allowed the use of a vinylogous Pummerer rearrangement for theoxidation of C2. To this end, dithionate 92 was converted into methylsulfoxide 93and, after Pummerer rearrangement, to the desired allylic alcohol 94 (three steps,61% combined yield). Finally, the prenyl group at C3 was installed by intramolecularallyl transfer via a π -allyl-palladium intermediate and cross metathesis to give(−)-(1).


89

1. T

MS

Cl,

Et 3N

DM

AP

, 84%

2. P

d(O

Ac)

2, O

2

>99

%

1. N

aBH

4, 9

5%(d

.r.>

33:1

)

2. C

S2,

NaH

,M

eI, >

99%

∆

1. E

tSLi

, MeI

, Et 3N

98%

(2

step

s)2.

NaB

O3· 4

H2O

95%

(d.

r. =

1.3

:1)

TF

A, 2

,6-d

i-ter

t-bu

tylp

yrid

ine,

65%

(d.r

.>33

:1)

O

OH

O

O

9091

92 9394

(−)-

hyp

erfo

rin (

1)

7 st

eps

4% c

ombi

ned

yiel

d

OO

O

OM

e

A

B

OO

O

OM

e

A

B

SM

eS

OO

MeS

OM

e

A

B

OO

S

OM

e

A

B

SM

eO

OO

MeS

OM

e

A

B

OO

H

A

B

2

3

Sche

me

12.1

6To

tal

synt

hesi

sof

ent-

hype

rfor

in.


12.2.4.4 Total Synthesis of ClusianoneIn 2006 the Simpkins laboratory reported the first total synthesis of (±)-clusianoneusing as a key step a regioselective lithiation of enol ether derivatives [43]. Theconstruction of the bicyclic core was inspired by the approach described by Spessardand Stoltz (Scheme 12.17) [52]. These authors accomplished a diastereoselectiveconversion of enol ether 95 into bicyclic trione 96, using dichloromalonate as theelectrophile. Notably, construction of the bicyclo[3.3.1]nonane by the use of malonyldichloride was reported initially by Effenburger [53].

OTBS

1.

Cl Cl

OO

2. KOH, BnEt3NCl36%

87% brsm

O

OHO95 96

15

7 7

Scheme 12.17 Model studiestoward the synthesis ofbicyclo[3.3.1]nonane-2,4,9-triones.

Scheme 12.18 summarizes Simpkins’ synthesis of clusianone [43]. Notably, enolether 98 was pre-functionalized with a prenyl group at the C1 center to overcomeproblems deriving from the steric hindrance of this center after the formation ofthe bicycle. In fact, Danishefsky had already reported similar problems during theinstallation of such a substituent in the synthesis of garsubellin A (Section 12.2.4.1).Interestingly, prenylation of 100 at the bridgehead position afforded compound 101in high yield. The same efficiency was observed for the acylation of C3 by the actionof lithium tetramethyl piperidine (LTMP), leading, after hydrolysis, to racemicclusianone. Importantly, prenylation of racemic 100 using a chiral base, such as103, led to selective alkylation of the (−) isomer via a kinetic resolution process.This reaction allowed assignment of the absolute configuration of clusianone,isolated from Clusia torresii, as the (+) isomer. Interestingly, the (−) isomer of 4matches the data of a compound reported by a Brazilian group [54]. Based on this,it is possible that clusianone exists in Nature in either enantiomeric form [50].

The above strategy was then extended to a formal synthesis of garsubellin A[40]. Specifically, application of the Effenburger-type cyclization to 105 afforded110, a compound isolated by the Danishefsky group en route to the synthesis ofgarsubellin A (Scheme 12.19) [39].

Marazano and coworkers have also published their synthesis of (±)-clusianoneincorporating a similar approach [44]. In their synthesis the starting enol ether 114contains all three prenyl groups, yielding, after reaction with dichloromalonate,compound 115, which has both quaternary bridgehead centers (Scheme 12.20).Notably, formation of the desired product 115 was accompanied with side product116 and desilylated compounds 112/113. Under different Lewis acid catalysis,this reaction produced significant amounts of bicyclic adduct 117. In principlethe double alkylation of 114 to 115 has some biosynthetic relevance. However,the sequence of ring construction (formation of the B ring at the end) is not inaccordance with the biosynthesis scenario in which the B ring is formed at the


O

OH

O

Ocl

usia

none

(4)

1. Cl

Cl

OO

2. K

OH

, BnE

t 3N

Cl

O

OH

O

HC

(CH

3)3

pTsO

H24

% fr

om 9

8

O

OM

eO

LDA

then

O

OM

eO

91%

O

OM

eO

LTM

P

91%

O

9899

100

101

102

11

Br

PhC

OC

l

LiO

H

5 st

eps

67%

97

5

3

OM

e

77

OM

e

O

N

Ph

NLi

LiP

hP

h

Ph

103

Sche

me

12.1

8To

tal

synt

hesi

sof

clus

iano

neby

the

Sim

pkin

sgr

oup.


OT

BS

1.

Cl

Cl

OO

2. K

OH

, BnE

t 3N

Cl

O

OH

O

LTM

P, L

i(2-T

h)C

uCN

then

50%

105

106

107:

X=O

H

mC

PB

A

22%

from

105

O

OO

X

H

H*

TM

SC

l, D

MA

Pim

idaz

ole,

90%

108:

X=O

TM

S

Br

O

OO

HO

H

H

O

OO

TM

SO

H

HE

t 3N

-HF

93%

109

110

O

3 st

eps

47%

104

gars

ubel

lin A

(2)

see

Sch

eme

12.1

0

Sche

me

12.1

9Fo

rmal

synt

hesi

sof

gars

ubel

linA

byth

eSi

mpk

ins

grou

p.


O

TMSOTf, Et3N

OTMS

+

O

7 : 3

1.

Cl Cl

OO

TMSOTf2. DMAP

O

OH

O

38%

1.

Cl Cl

OO

BF3·Et2O2. DMAP

O

OHO

+ O

OO

+ 112/113

35%25% 22%

clusianone (4)

benzoyl cyanideEt3N

65%

112 113 114

115 116 117

OH

O

111

6 steps

B

A

AAAA

Scheme 12.20 Total synthesis of clusianone by Marazano and coworkers.

beginning. Based on this, such an approach cannot be considered as a biomimeticstrategy.

12.2.5Concluding Remarks

In short, biomimetic approaches toward PPAPs are based on double alkylation on afunctionalized B ring with an electrophile. These strategies require fewer steps in alinear sense and can potentially produce the natural product target in higher yield.The total synthesis of racemic clusianone, by the Porco group [45], was completedin seven synthetic steps, starting from the biosynthetic intermediate 27, with atotal yield of 25%. The approach is based on biosynthetic hypotheses that involvealkylative dearomatization of phloroglucinols and carbocation-mediated cyclization.This method can be applied with minor changes for the synthesis of other typeB PPAPs and can also be implemented to the synthesis of adamantane-likePPAPs. The strategy presented by Couladouros et al. [46] can give access infew steps and satisfactory yields to several compounds possessing the bicyclicframework of natural products for SAR (structure–activity relationship) studies.In contrast to other reported methods, the two quaternary centers (C1 and C8)are connected during the cyclization step, thereby eliminating steric hindranceproblems encountered in other reported approaches. A similar approach, and themost recently published biomimetic synthesis of PPAPs [47], starts with alkylationof a functionalized B ring, yet formation of the second ring occurs after oxidativecyclization. On the other hand, the non-biomimetic strategies require many steps,


as shown by the Danishefsky group syntheses of garsubellin A, nemorosone, andclusianone that were completed in 17, 14, and 12 steps respectively, or by thesynthesis of (−)-hyperforin by the Shibasaki group, which required 44 steps. Theadvantage of the non-biomimetic approaches is that they are more flexible interms of the synthetic route followed to the target and can lead to asymmetricfinal products. In such a way the asymmetric total synthesis of (−)-hyperforin wasachieved.

In addition to the synthetic strategies described herein, there is still ongoinginterest towards the synthesis of PPAPs and their analogs. New approaches haveappeared in the literature, aimed at a facile method for the construction of thebicyclic core of PPAPs that will allow easier access to those compounds for theirbiological evaluation and SAR studies [55–61].

12.3Polyprenylated Xanthones

12.3.1Introduction and Chemical Classification

Polyprenylated xanthones constitute a subclass of a larger class of compoundsknown as xanthones, all bearing a dibenzo-γ -pyrone scaffold [62]. Polyprenylatedxanthones can further be divided, according to their oxidation degree, into mono-,di-, tri-, and so on, oxygenated compounds. Recently, the classification, synthesis,and biological evaluation of simple xanthones have been reviewed extensively[62–71]. In this chapter we focus on the so-called caged Garcinia xanthones(CGXs), owing to their similarities (isolation, biosynthesis) to the aforementionedpolyprenylated phloroglucinols.

Caged xanthones are natural products isolated from plants of the genus Garcinia(Guttiferae family) that are found in lowland rainforests of India, Indochina,Indonesia, West and Central Africa, and Brazil [1, 72]. The most studied memberof this family is gambogic acid (118), a compound isolated from gamboge, the resinof Garcinia hanburyi (Figure 12.4). Common to the chemical structure of all CGXsis a xanthone backbone in which the C ring has been converted into an unusual4-oxa-tricyclo[4.3.1.03,7]dec-8-en-2-one ring (caged) scaffold (see structure 120) [73,74]. This general motif can be further decorated with different substituents onthe aromatic ring A and/or can be oxidized to yield a wide range of compounds,representative members of which are shown in Figure 12.4. This concept isexemplified by the structure of forbesione (125), a natural product isolated fromGarcinia forbesii [75] and Garcinia hanburyi [76]. Specifically, prenylation at the C5center of forbesione (gambogic acid numbering) gives access to the gaudichaudionescaffold [77], represented here by deoxygaudichaudione A (126) [78]. Alternatively,prenylation of 125 at C5 followed by cyclization with the pendant phenol givesaccess to the morellin scaffold, represented here by desoxymorellin (123) [79].Progressive oxidations at the C29 center of 123 produce morellinol (122), morellin

12.3 Polyprenylated Xanthones 453

O

O

O

O

120: general motif ofcaged xanthones

O

O

O

OO

OH R

118: R = CO2H: gambogic acid119: R = CH3: gambogin

O

O

O

OA

B

C

O

OH R

121: R = CHO: morellin122: R = CH2OH: morellinol123: R = CH3: desoxymorellin124: R = CO2H: morellic acid

O

O

O

O

OH

HO

125: forbesione

O

O

O

O

OH

HO

126: deoxygaudichaudione A 127: 6-O-methylbractatin

O

O

O

O

OMe

HO

O

OOMe

HO

O

O

128: 6-O-methylneobractatin

O

O

O

A16

O

OO

O

O

11

B

129: lateriflorone

6

29

AB

C

29

28

27

5

5

17 17

C

Figure 12.4 Representative members of the caged Garcinia xanthone family.

(121), and morellic acid (124) [80]. Geranylation at the C5 center of forbesioneaffords, after formation of the pyran ring, gambogin (119) [81]. Further oxidationat C29 leads to the structure of gambogic acid (118) [76]. Compounds arising fromisomerization around the C27=C28 double bond have also been isolated. Thus,morellin (121), having the cis configuration about the C27=C28 double bond, isknown to isomerize to the trans isomer, isomorellin [82]. Similar observations havebeen reported for gambogic acid [83]. In contrast, the bractatin subfamily (127,128) [84, 85] provides examples of forbesione-type natural products that contain areverse prenyl group at the C17 center.

Although the vast majority of the CGXs contain the general motif 120, there are afew examples of natural products with alternative cage structures or with additionaloxidations of the xanthone motif. For instance, 6-O-methylneobractatin (128) is theonly natural product known to contain a modified caged scaffold, referred to as theneo-motif [84, 85]. In addition, in the structure of lateriflorone (129) [86], the cagedmotif is attached to a spiroxalactone core, which is likely a product of oxidation ofthe xanthone B ring.

Biologically, CGXs are known for their antimicrobial and anticancer activities andare widely used as herbal medicines in traditional Eastern medicine [83, 87–89].Initial biological studies with semi-purified gamboge extracts documented itsantiprotozoal activities, thus lending support for its indigenous use in the treatmentof enteric diseases [90–94]. It has also been shown that morellin (121) and gambogicacid (118) exhibit a high specific growth inhibitory effect on Gram-positive bacteriain vitro and a protective action against experimental staphylococcal infections inmice [95–98]. In addition to their antimicrobial activity, most CGXs have received agreat deal of attention for their anticancer activity [99, 100]. An ever increasing bodyof evidence indicates that these compounds are cytotoxic against various cancercell lines at low micromolar concentrations [79].


12.3.2Biosynthesis of Polyprenylated Xanthones

Biosynthetically, the xanthone backbone of the caged compounds is assumedto derive from common benzophenone intermediates that are synthesized in asimilar manner to that described for PPAPs. Their oxygenation patterns indicatea mixed shikimate (formation of C ring)–acetate (formation of A ring) pathway[101–106]. The proposed biosynthesis is exemplified with the synthesis of maclurin(134) and 1,3,5,6-tetrahydroxyxanthone (135) in Scheme 12.21 [107–110]. Shikimicacid, derived from the shikimic pathway, can be converted into protocatechuicacid (131) after oxidation, dehydration, and enolization. Reaction of 131 withcoenzyme A (HSCoA) can produce activated ester 132 that can further reactwith three units of malonyl-coenzyme A to yield intermediate 133. A Dieckmanncondensation gives rise to benzophenones, such as maclurin (134). Dependingupon the benzophenone produced, this is a branch point in the biogenesis of otherbenzophenone-type natural products. It is generally accepted that xanthones suchas 1,3,5,6-tetrahydroxyxanthone (135) are formed by means of phenolic coupling ofthe benzophenone precursors [109, 110].

HO

O

OH

OHOH

shikimic acid (130)

NADP+ [O]dehydrationenolization HO

O

OH

OH

protocatechuic acid (131)

HSCoA CoAS

O

OHOH

132

3 x malonyl-CoA

O

OH

OH

O

O

SCoAO133

Dieckmanncondensation

O

OH

OH

OH

HO OHA

maclurin (134)

C

O

OH

OH

OH

HO O

A C

tetrahydroxyxanthone (135)

−

Scheme 12.21 Biosynthesis of the backbone of xanthones in higher plants.

Different hypotheses have been proposed for the biosynthetic conversion ofsimpler xanthones such as 135 into the more complex caged structures. The firstproposal, illustrated in Scheme 12.22, requires at an early stage the prenylationof a xanthone, as 136, at C11 and C13 positions to produce 137 [111]. Anoxidation–reduction–oxidation sequence of reactions is then required to form thefinal caged structure 141. Essential to this hypothesis is a presumed nucleophilicattack by the C13 tertiary alcohol of 138 on the pendant prenyl group that couldinitiate a cyclization cascade leading to the caged structure 140. Nonetheless,as shown with structure 139, neither the molecular geometry nor the reactivityrequired for this cascade is optimal, making this proposal unlikely.


O

O

11

O

O

O

O13

13OH

O

O

1113

OH

oxidationreduction

O

O

13

OOH

O

O

HO

O13O

O

O

O13

136 137 138

139140141

Scheme 12.22 Proposed biosynthesis of the CGX motif viaa cascade of nucleophilic attacks.

A more plausible biosynthetic scenario stems from the pioneering work ofQuillinan and Scheinmann [112]. In their work, they proposed that the caged motifcan be formed via a Claisen rearrangement followed by a Diels–Alder reaction onthe intermediate dienone (Scheme 12.23). The authors also provided experimentalevidence in support of the Claisen/Diels–Alder reaction cascade: upon heating ofcompound 143, prepared by allylation of mesuaxanthone B (142), at 190 ◦C for14 h they observed products showing NMR signals characteristic of cage structure145. At present, there have been no labeling experiments testing the biosyntheticfeasibility of the Claisen/Diels–Alder reaction cascade. Nonetheless, additionalsupport for the validity of this proposal was obtained by recent studies in whichretro-Diels–Alder fragments have been detected in mass spectroscopy studies ofseveral CGXs [113, 114].

O

OH O

OH

OHmesuaxanthone (142)

O

OH O

OO

143

O

O

OO

Claisenrearrangement

144

Diels–Alderreaction

O

O

O

O

145

190 °C, 14 h

Scheme 12.23 Proposed biosynthesis of the CGX motif viaa Claisen/Diels–Alder reaction cascade.

12.3.3Biomimetic Synthesis of Caged Garcinia Xanthones

Inspired by Quillinan and Scheinmann’s proposed biosynthesis, both the Nicolaou[115] and Theodorakis [116] groups evaluated the tandem Claisen/Diels–Aldersequence for the synthesis of representative members of the CGX family. Theirwork provided further support for the proposed biosynthetic hypothesis.


Starting from the tris-allylated xanthone 146 both groups investigated the pos-sibility of synthesizing forbesione (125) in one pot. In principle, exposure of suchmotif to heat could produce four products arising from a combination of twocompeting C-ring Claisen/Diels–Alder reactions, leading to regular and neo-cagedmotifs, and two A-ring Claisen migrations, producing C17 and C5 prenylations.Working with methoxy xanthone 146c, the Nicolaou group was the first to describeits conversion into methyl forbesione 147c and methyl neoforbesione (148c) in a2.4 : 1 ratio and 89% combined yield (Scheme 12.24) [115]. On the other hand,studies by the Theodorakis group showed that heating of xanthone 146a led only tothe isolation of forbesione 147a and isoforbesione (149a). The neo-C-ring isomers

O

O

O

O12

13

O

OOH

HO

HO OH

AB

C O

O

1213

OR

O

O O

5 6

17

146a: R = H146b: R = Ac146c: R = Me

135

1. C-ring Claisen/Diels–AlderClaisen migration (C26–C28 unit)then Diels–Alder using C21–C22alkene as the dienophile

2. A-ring Claisen reactionmigration at C17 or C5

1. C-ring Claisen/Diels–AlderClaisen migration (C21–C23 unit)then Diels–Alder using C26–C27alkene as the dienophile

21

2223 2627

28

OR

HO

5

17

2123

26

28

O

OOR

HO

O

O

1213

5

17

26

147a: R = H forbesione (125) (49%)147b: R = Ac (79%)147c: R = Me methyl forbesione (63%)

148a: R = H neoforbesione (ND)148b: R = Ac (ND)148c: R = Me methyl neoforbesione (26%)

O

O

O

O12

13

OR

HO

5

17

2123

26

28

O

OOR

HO

O

O12

13

5

17

26

149a: R = H isoforbesione (35%)149b: R = Ac (ND)149c: R = Me (ND)

150a: R = H isoneoforbesione (ND)150b: R = Ac (ND)150c: R = Me (ND)

2. A-ring Claisen reaction

8

migration at C17 or C5

Scheme 12.24 Biomimetic synthesis of forbesione (125) and related structures via aClaisen/Diels–Alder/Claisen reaction cascade.


148a and 150a were not detected in this case. More impressively, the O6-acetylatedxanthone 146b afforded, upon heating, solely acetyl forbesione (147b) [116]. Sim-ilar observations have been reported more recently by other groups [117]. Theabove-described results towards the synthesis of forbesione along with the resultsfrom several model studies [118] can be summarized as follows:

• The C-ring Claisen/Diels–Alder rearrangement proceeds first and is followed byan A-ring Claisen reaction.

• The site-selectivity of the A-ring Claisen rearrangement (C17 versus C5 preny-lation) is controlled by the steric and electronic effects of the C6 phenolicsubstituent.

• The site-selectivity of the C-ring Claisen/Diels–Alder reaction is attributed toand governed by the electronic density of the C8 carbonyl-group. Being parato the C12 allyloxy unit, the electron-deficient C8 carbonyl carbon polarizesselectively the O–C28 bond and facilitates its rupture. In turn, this leads to asite-selective Claisen rearrangement of the C12 allyloxy unit onto the C13 center,thereby producing exclusively the regular caged motif found in the structure offorbesione (147a).

• Substitution of the C6 phenol can regulate the electronic density of the C8 car-bonyl group, thus affecting the site selectivity of the C-ring Claisen/Diels–Alderreaction.

The experimental findings on the tandem Claisen/Diels–Alder/Claisenreaction cascade provide useful insights regarding the biosynthesis of all knownCGXs [118]. All these natural products (representative examples shown inFigure 12.4) share a common caged motif, exemplified by structure 120, exceptfor 6-O-methylneobractatin (128), which contains the neo-caged motif. Theremote electronic effects of the seemingly innocuous 6-O-methyl group mayexplain the concomitant biosynthesis of both 6-O-methylbractatin (127) and6-O-methylneobractatin (128).

Studies by the Nicolaou group have shown that the Claisen/Diels–Alder reactioncan be accelerated in the presence of polar solvents [119]. For instance, as depictedfor the synthesis of gambogin (Scheme 12.25), the conversion of allyl ether 159into caged structure 160a and the neo-isomer 160b was dramatically acceleratedupon changing the solvent from benzene to DMF to a MeOH–water (1 : 2)mixture. It has been proposed that polar aprotic solvents, such as DMF, andmore impressively protic solvents, such as water, can accelerate the Claisenrearrangement by stabilizing its polar transition state [120–124]. The concurrentacceleration of the Diels–Alder component of this cascade may be due to thehydrophobic effect of water [125] rather than to a polarity or hydrogen-bondingphenomena [126–128]. Computational studies on the above-mentioned reactionhave also concluded that the Claisen rearrangement is reversible and the energeticsof the irreversible Diels–Alder cyclization can determine the product formation[129].


1. NaHMDS, 1542. TBAF

O

O

O

O

OH

O

1. HCl

2. DBU, 161CuI (cat)

3. H2, Lindlar

162

48%

1. Ac2O, pyr2. DMF, ∆3. DBU, CuI (cat), 1634. DMF, ∆

12%

gambogin (119)

OCOCF3

161

OCOCF3

163

O

O

O

O

O

OOMOM

MOMO

HO OH

AB

C

6

8

18

O

OOMOM

MOMO

R2O OR1

6

18

157

MOMO

MOMO

O

OOMOM

MOMO

O

O

MOMO

OMOM

Br

OMOM

H

O

TBSOOBn

OBn

1. nBuLi2. TBAF3. MnO2

4. KOH5. H2, Pd/C

44%

156

152

A

C

H

O

Br154

3. Ph3P=CH2

158a: R1 = H, R2 = CMe2CH=CH2

158b: R1 = CMe2CH=CH2, R2 = H

57%

1. t BuOK, 1542. Ph3P=CH2

74%

O

OOMOM

MOMO

O O

618

159

MeOH/H2O, ∆

100%+

160a (75%)160b (25%)

66

17O

O

O

OO

OH

17

Scheme 12.25 Biomimetic synthesis of gambogin by the Nicolaou group.

12.3.3.1 Nicolaou Approach to Forbesione and GamboginScheme 12.26 depicts the synthetic strategy developed by Nicolaou and Li [115]for the synthesis of 6-O-methylforbesione (147c). Xanthone 153 was generated infive steps and in 78% combined yield starting from the aryl bromide 151 and thebenzaldehyde 152. Treatment of 153 with α-bromoisobutyraldehyde (154) underbasic conditions followed by Wittig olefination produced a mixture of the diallylatedcompounds 155a and 155b that, after reiteration of the alkylation/olefinationreactions, yielded the triallylated xanthone 146c. Heating of 146c in DMF at 120 ◦Cinduced the Claisen/Diels–Alder/Claisen reaction cascade to produce compound147c along with its neo-isomer 148c in 89% combined yield.

In a similar manner, the total synthesis of gambogin was achieved startingfrom the partially protected xanthone 157 (Scheme 12.25) [119]. This time theClaisen/Diels–Alder reaction proceeded quantitatively in refluxing MeOH–H2O(1 : 2) to produce the regular caged motif 160a along with its neo-isomer 160b in a3 : 1 ratio. Methoxymethyl (MOM) deprotection of 160a followed by propargylationwith alkyne 161 at C18 and partial reduction with Lindlar catalyst gave rise tocompound 162. Gambogin was then synthesized after a sequence of four reactions


O

O

O

O

O

O

1213

OMe

HO

HO OH

AB

C

818

O

OOMe

O

R2O OR1

18

153

OMe

HO

O

OOMe

HO

O

O

BnO

OMe

Br

OMe

H

O

TBSO

OBn

OBn

1. nBuLi2. TBAF3. MnO2

4. KOH5. H2, Pd/C

78%

151

152

A

C

1. t BuOK, 154

H

O

Br154

2. Ph3P=CH2

155a: R1 = H, R2 = CMe2CH=CH2

155b: R1 = CMe2CH=CH2, R2 = H

64%

1. t BuOK, 1542. Ph3P=CH2

86%

O

OOMe

O

O O

18

146c

DMF, ∆89%

+

147c: 6-O-methylforbesione(63%)

148c: 6-O-methylneoforbesione(26%)

66

Scheme 12.26 Biomimetic synthesis of 6-O-methylforbesione (147c).

that included: (i) acetylation of C6 phenol; (ii) Claisen rearrangement to install theprenyl group at C17; (iii) propargylation of the resulting phenol with alkyne 163; and(iv) Claisen rearrangement to form the dihydropyran ring of the natural product.

12.3.3.2 Theodorakis’ Unified Approach to Caged Garcinia XanthonesThe common structural motif of most CGXs suggests that they can be synthesizedby functionalizing the A ring of forbesione. Along these lines, the Theodorakisgroup developed a strategy that uses forbesione (125) to gain access to representativemembers of the gaudichaudiones, morellins, and gambogins [118].

As illustrated in Scheme 12.27, ZnCl2-mediated condensation of phloroglucinol(164) with benzoic acid 165 produced xanthone 135. Propargylation of 135 withthe propargyl chloride 166 followed by partial reduction using Lindlar catalyst andacetylation of phenol at C6 gave rise to compound 146b. Heating of 146b (DMF,1 h, 120 ◦C) set the stage for a site-selective Claisen/Diels–Alder/Claisen reactioncascade that produced, after deprotection of the C6 acetate, forbesione (125) in72% combined yield. Further decoration of the A ring of forbesione gave access tomore functionalized CGX family members. Specifically, propargylation of the C18phenol of forbesione with chloride 166 afforded, after Lindlar reduction and Claisenrearrangement, deoxygaudichaudione A (126). On the other hand, propargylationof 125 and immediate Claisen rearrangement formed desoxymorellin (123). Finally,condensation of forbesione (125) with citral (168) in Et3N produced gambogin (119).

12.3.3.3 Synthesis of MethyllaterifloroneIt has been proposed that the unprecedented spiroxalactone motif of lateriflorone(129) could be formed by condensation of two fully functionalized fragments,169 and 170 (Scheme 12.28) [86]. An alternative and likely more biosynthetically


O

O

O

O

O

OOH

HO

HO OH

AB

C

6

18

O

OOAc

O

O O

618

135

OH

HO

HO

OH

OH

HO

O

HOOH

OH

46%

164

165

A

C

1. K2CO3, CuI (cat),166

2. H2, Lindlar

Cl166

3. Ac2O, pyr16%

DMF, ∆ 79%

desoxymorellin (123)

ZnCl2,

POCl3

146b

O

OOAc

O

OO

K2CO3,MeOH

91%

forbesione (125) 167

O

O

O

O

OH

HO

deoxygaudichaudione A (126)

1. K2CO3, 1662. H2, Lindlar3. DMF, ∆

34%

O

O

O

O

OH

O

1. K2CO3, 1662. DMF, ∆ 61%

gambogin (119) (C2 epimers)

O

O

O

O

OH

O

Et3N, 16875%O

H168

6

1818

Scheme 12.27 Unified biomimetic synthesis of CGXs by the Theodorakis group.

relevant hypothesis could involve conversion of xanthone (172) into dioxepanone(171) that, upon hydrolysis and spirocyclization at the C16 center, could form thespiroxalactone ring system of lateriflorone.

Quite recently, the Nicolaou group has reported a synthesis of C11-methyllateriflorone (178) (Scheme 12.29) [130]. Key to the strategy was the couplingof orthogonally protected hydroquinone 173 with acid 174 that after selectivedeprotection of the C7 MOM ether produced compound 175 (61% combinedyield). Oxidation of 175 in the presence of iodosobenzene bis(trifluoroacetate) inmethanol, followed by heating under acidic conditions formed spiroxalactone 177.Acid-catalyzed hydrolysis of 177 gave rise to C11-methyllateriflorone (178) in 66%yield.

12.3.3.4 Non-biomimetic Synthesis of the Caged Garcinia XanthonesAn alternative non-biomimetic synthesis of CGXs relies on a tandem Wesselyoxidation/Diels–Alder reaction cascade. Yates and coworkers applied this strategyto the synthesis of caged structures reminiscent of the CGX motif. Thus, treatment


O

O

O

O

O

O

OHAOH

HO+

HO

16

O

O

O

A16O

OO

O

O

OH

B

O

O

O

OH

O

OO

OOH

HO

HO OH

AB

C

O

HO 1616 OH

169 170 129: lateriflorone

171172

B-ring hydrolysisand reorganization

prenylationB-ring oxidation

Scheme 12.28 Proposed biosynthesis of lateriflorone (129).

of phenol 179 with Pb(OAc)4 in acetic acid produced 2,4-cyclohexadienone 180that, upon heating at 140 ◦C, formed compound 181 (gambogic acid numbering)(Scheme 12.30) [131]. In a previous study, xanthene 182 was treated with leadtetraacrylate [formed in situ by Pb(OAc)4 and acrylic acid] to produce dienone183 and, after an intramolecular Diels–Alder reaction, caged compound 184[132].

Theodorakis and coworkers [133] investigated the application of theWessely/Diels–Alder strategy for the synthesis of a more hydroxylated caged motifrelated to the structure of lateriflorone (129) (Figure 12.4). Treatment of 185 withPb(OAc)4 in acrylic acid–dichloromethane produced, after heating in refluxingbenzene (80 ◦C), tricyclic lactone 187 in 82% combined yield (Scheme 12.31).Crystallographic studies established that 187 is a constitutional isomer of thedesired structure 190 and is reminiscent of the so-called neo-caged structure.The connectivity of compound 187 suggested that during the Wessely oxidationthe acrylate unit was attached exclusively at the more electronically rich C11center of 185, instead of the desired C13 carbon. In turn, this produced dienone186 that subsequently underwent an efficient Diels–Alder cycloaddition withthe pendant acrylate dienophile. To alter the connectivity of the caged structure,one could have the acetoxy group preinstalled at the C13 center and promotethe migration of the prenyl group. Along these lines, heating of allyl ether188 in m-xylene (140 ◦C) gave rise exclusively to caged motif 190 via a Claisenrearrangement and Diels–Alder cycloaddition. The selectivity of the Claisenrearrangement at the C13 center can be explained by considering that intermediate189 has the necessary geometry that allows it to be trapped as the Diels–Alderadduct.


O

O

O

O

MeO

OM

OM

OH

AO

Me

HO

+H

O

11

OO

O

AOO

O

O

O

OM

e11

B

7

1. E

DC

, DM

AP

2. H

Cl,

MeO

H

61%

O

MeO

OH

OA

O

O OM

eH

O

9

11

OP

hI(T

FA

) 2,

MeO

H

60%

OO

OA

O

O OM

eH

O11

OO

Me

MeO

PP

TS

, PhH

, ∆

69%

O

MeO

O

AOO

O

O

O

OM

e11

B

1. H

2O, H

+

2. P

PT

S, ∆

66%

173

174

175

176

177

178

Sche

me

12.2

9To

tal

synt

hesi

sof

C11

-met

hylla

teri

floro

ne(1

78).


OH

Pd(OAc)4

ACOH

Wesselyoxidation

OOO

C6H4Me2

140 °C

Diels–Alderreaction

OO

O

179 180 181

O

O

OH

Pd(OAc)4

OH

O O

O

OHOO

80 °C

O

O

O

O

183182 184

1213

1213

12

13

1213

1213

12

13

Scheme 12.30 Representative examples of caged structures,181 and 184, formed via a Wessely oxidation/Diels–Alderreaction cascade.

OH

Pd(OAc)4

O

80 °C

185 186 187

O

O

188 190

1213

1213

1213

1213

MeO OMe O

OH

11MeO

OMeO

11

O MeO O OMe11

11

O

O

82%

OO12

13

MeO OMe11

O

14 140 °C92%

189

O12

13MeO OMe

1114

OO

OMeMeO14

Scheme 12.31 Synthesis of caged structures 187 and 190.

12.3.3.5 Concluding RemarksCGXs are a family of polyprenylated xanthones that have a remarkable chemicalstructure, inspiring biosynthesis, and significant medicinal potential. Their chem-ical structure is represented by an unusual xanthone backbone in which the C ringhas been converted into a 4-oxa-tricyclo[4.3.1.03,7]dec-8-en-2-one (caged) scaffold.Their biosynthesis is proposed to involve a cascade of Claisen and Diels–Alderreactions and has provided the inspiration for the development of efficient labo-ratory syntheses of the parent molecules and designed analogs. Their medicinalvalue stems from their use in ethnomedicine and remains still largely unexplored[134]. The recent advances in the synthesis of these compounds have paved theway for the generation of analogs with the desired pharmacological and biologicalprofile. In particular, the biosynthetically inspired Claisen/Diels–Alder reaction


cascade can reliably produce the caged motif of CGXs in excellent yields. On theother hand, the non-biomimetic Wessely/Diels–Alder strategy can form analogsof the caged motif that cannot be made by fragmentation of the natural products.It is very likely that these strategies will be used for the development of morepotent CGX analogs. One limitation of both strategies is that, at present, theyboth deliver racemic mixtures of the caged structures. Thus, the development ofan enantioselective variant of the Claisen/Diels–Alder and Wessely/Diels–Alderreaction cascades still needs to be addressed.

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