review01-natural product reports (2010), 27(8), 1186-1203

REVIEW www.rsc.org/npr | Natural Product Reports

Dow

nloa

ded

by D

UK

E U

NIV

ER

SIT

Y o

n 01

Oct

ober

201

0Pu

blis

hed

on 2

2 Ju

ne 2

010

on h

ttp://

pubs

.rsc

.org

| do

i:10.

1039

/B91

9366

AView Online

Marine natural products: synthetic aspects†

Jonathan C. Morris*a and Andrew J. Phillipsb

Received 3rd March 2010, Accepted 7th June 2010

DOI: 10.1039/b919366a

Covering: January to December 2008. Previous review: Nat. Prod. Rep., 2009, 26, 245

An overview of marine natural products synthesis during 2008 is provided. As with earlier installments

in this series, the emphasis is on total syntheses of molecules of contemporary interest, new total

syntheses, and syntheses that have resulted in structure confirmation or stereochemical assignments.

1 Introduction

2 Review articles

3 Pinnatoxin

4 Theopederin D

5 Polyketides: callystatin, aburatubolactam, 15G256 (and

related compounds) and bryostatin 16

6 Terpenoids: vannusal B and cortistatin A

7 Largazole and the trichodermamides

8 Acknowledgements

9 References

1 Introduction

This review is designed to provide an overview of key features of

the 2008 literature covering the synthesis of marine natural

products, and should act as a companion to the Marine Natural

Products review published in this journal.1 The emphasis is on

total syntheses of molecules of contemporary interest. Tabulated

data for other syntheses are also provided. While every effort has

been made to be comprehensive within these boundary condi-

tions, we apologize in advance for any oversights.2

2 Review articles

A number of reviews that cover various aspects of marine natural

products synthesis have appeared: ‘‘Synthesis of marine alkaloids

from the oroidin family’’,3 ‘‘Analogues of marine pyrroloimino-

quinone alkaloids: synthesis and antitumor properties’’,4

‘‘Synthetic studies of heterocyclic natural products’’,5 ‘‘Amphi-

dinolides and its related macrolides from marine dinoflagel-

lates’’,6 ‘‘The synthetic challenge of diazonamide A,

a macrocyclic indole bis-oxazole marine natural product’’,7

‘‘Synthesis of marine natural products with antimalarial

activity’’,8 ‘‘The continuing saga of the marine polyether bio-

toxins’’,9 ‘‘Convergent strategies for the total synthesis of poly-

cyclic ether marine metabolites’’,10 ‘‘Natural marine antiviral

aSchool of Chemistry, University of New South Wales, Sydney, Australia2052. E-mail: [email protected]; Fax: +61 2 93856141; Tel:+61 2 93854733bDepartment of Chemistry, Yale University, New Haven, Connecticut,06520, USA.

† Footnote: This paper is part of an NPR themed issue on Synthesis,guest-edited by Andreas Kirschning and Andy Phillips.

1186 | Nat. Prod. Rep., 2010, 27, 1186–1203

products’’,11 ‘‘The biology and chemistry of the zoanthamine

alkaloids’’,12 ‘‘A potential source of anticancer agents: natural

products and their analogs. Extraction, characterization, bio-

logical activity and synthesis’’,13 ‘‘Synthetic efforts toward, and

biological activity of, thyrsiferol and structrurally-related

analogues’’,14 ‘‘Review of cytotoxic cephalostatins and ritter-

azines: isolation and synthesis’’,15 ‘‘The chemistry of marine

furanocembranoids, pseudopteranes, gersolanes, and related

natural products’’,16 and ‘‘The structure activity relationship of

discodermolide analogues’’.17 Other reviews of relevance are

cited in the text.

3 Pinnatoxin

Zakarian’s synthesis of pinnatoxin A 118,19 was based around the

dissection of the target into two key domains, 2 and 3, and

highlighted the power of the Ireland–Claisen rearrangement for

the establishment of quaternary stereocenters (Scheme 1).20 In

this context, when ester 7 (readily prepared by EDCI-mediated

coupling of 4 and 5) was subjected to deprotonation with chiral

amide base 6, the desired (Z)-enolate was formed. Trapping as

the silylketene acetal, followed by warming to room temperature,

resulted in the desired [3,3]-rearrangment to give 9 in an excellent

94% yield. A sequence of 14 steps installed the cyclohexene ring,

and advanced material to 3. Addition of the organolithium

derived from 2 (with t-BuLi) to aldehyde 3 occurred in 75% yield,

and three further steps (desilylation with TBAF, Dess–Martin

oxidation, and vinylmagnesium bromide addition) gave 10.

Ring-closing metathesis with the Hoveyda–Grubbs 2nd-genera-

tion catalyst (25 mol% loading) followed by oxidation gave 11 in

57% yield for the two steps. Diastereoselective conjugate addi-

tion of MeCu(CN)Li installed the final remaining methyl group

(11 / 12, 81%) and spiroketalization with LiBF4 in wet iPrOH

led to 13 in 60% yield. This material was advanced to 14 by

a sequence of 7 steps, and after Staudinger reduction of the azide

with Me3P, the imine was installed using Kishi’s conditions

(triethylammonium 2,4,6-triisopropylbenzoate in xylenes at

85 �C) to yield 15 (70% over two steps). The synthesis was

completed by ester hydrolysis to give (+)-pinnatoxin A.

Nakamura and Hashimoto have also reported a synthesis of

pinnatoxin A (Scheme 2).21 Taking a page from Trost’s recent

successes in complex molecule synthesis [see also the bryostatin

16 synthesis later in this review], the key step was

This journal is ª The Royal Society of Chemistry 2010

http://dx.doi.org/10.1039/B919366A

Scheme 1 Zakarian’s synthesis of pinnatoxin A. Reagents and conditions: (1) EDCI, DMAP, DMF, 94%; (2) (a) 6, THF, then TMSCl, �78 �C; (b)

25 �C, 6 h, 94%; (3) 2, tBuLi, Et2O,�78 �C, 75%; (4) TBAF, THF; (5) Dess–Martin periodinane, CH2Cl2; (6) H2C]CHMgBr, THF, 75% (over 3 steps);

(7) (a) 25 mol% Hoveyda–Grubbs II, CH2Cl2, 40 �C; (b) Dess–Martin periodinane, pyr, CH2Cl2, 57% (over 2 steps); (8) MeCu(CN)Li, BF3$OEt2, THF,

�78 �C, 81%; (9) LiBF4, 4% aq. iPrOH, 90 �C, 6h, 60%; (10) Me3P, aq. THF; (11) triethylammonium 2,4,6-triisopropylbenzoate, xylenes, 85 �C, 70%

(over 2 steps); (12) LiOH, THF–H2O, 80%.

Dow

nloa

ded

by D

UK

E U

NIV

ER

SIT

Y o

n 01

Oct

ober

201

0Pu

blis

hed

on 2

2 Ju

ne 2

010

on h

ttp://

pubs

.rsc

.org

| do

i:10.

1039

/B91

9366

AView Online

a macrocyclization by Ru-catalyzed enyne isomerization.22

Advanced intermediate 16 was subjected to a five-step sequence

that reorganized protecting groups, and freed the primary

alcohol, which was oxidized with Dess–Martin periodinane to

Jonathan C: Morris

Jonathan C. Morris obtained

his B.Sc. (Hons) degree from

the University of Western

Australia and his Ph.D. degree

from The Australian National

University in Canberra,

Australia. After a postdoctoral

appointment with Phil Magnus

at the University of Texas at

Austin, he joined the faculty at

the University of Canterbury,

New Zealand. In 2004, he

moved to the University of

Adelaide. In late 2009, he was

appointed at the University

of New South Wales. His

research interests focus around the synthesis of biologically

active natural products.


give the aldehyde 17. Horner–Wadsworth–Emmons reaction

with phosphonate 18 gave the expected enone 19 in 86% yield

(two steps). Wittig methylenation (Ph3P]CH2, 92%) provided

a diene, 20, that was exposed to lactone 21 (10 equivalents) in

Andrew J: Phillips

Andrew J. Phillips obtained his

B.Sc. (Hons) and Ph.D. degrees

from the University of Canter-

bury in Christchurch, New

Zealand. After a postdoctoral

appointment with Peter Wipf at

the University of Pittsburgh, he

joined the faculty at the

University of Colorado. In mid-

2010 he joined the faculty at

Yale University. His research

interests are broadly defined by

the chemistry and biology

of small molecules, including

natural products.

Nat. Prod. Rep., 2010, 27, 1186–1203 | 1187


Scheme 2 The synthesis of pinnatoxin A by Nakamura & Hashimoto. Reagents and conditions: (1) TBAF, THF, reflux, 72 h; (2) TBSCl, imid., DMF,

95% (2 steps); (3) TESOTf, 2,6-lut., CH2Cl2, 94%; (4) TBAF, THF, 0 �C, 91%; (5) Dess–Martin periodinane, pyr, CH2Cl2, (6) 18, LiCl, DIPEA, MeCN,

86% (2 steps); (7) MePPh3Br, nBuLi, THF, 92%; (8) 21 (10 equiv), 4 �A MS, p-xylene, 160 �C, 12 h, 35% of desired (+ 46% of other cycloadducts); (9)

[CpRu(MeCN)3]PF6 (10 mol%), acetone, 50 �C, 15 min, 79%.

Dow

nloa

ded

by D

UK

E U

NIV

ER

SIT

Y o

n 01

Oct

ober

201

0Pu

blis

hed

on 2

2 Ju

ne 2

010

on h

ttp://

pubs

.rsc

.org

| do

i:10.

1039

/B91

9366

AView Online

p-xylenes at 160 �C. Under these conditions the desired endo

product was obtained in 35% yield [3 other diastereomers were

formed, with a total yield in the cycloaddition of 83%]. A seven-

step sequence advanced material to enyne 23, and when treated

with 10 mol% of [CpRu(MeCN)3]PF6, macrocyclization to the

desired product 24 occurred in an impressive 79% yield. This

result underlines the value of this catalyst in complex molecule

synthesis. The synthesis was completed by a further nine

steps that paralleled the general strategy used by Kishi and

Zakarian.23–25

4 Theopederin D

Floreancig’s plan for the synthesis of theopederin D 2526 was

based around connection of known acid chloride 26 with aminal

27 (Scheme 3).27,28 One of the key bond formations en route to 27

was an electron-transfer-initiated cyclization29,30 whereby an

N-acyliminium ion was generated and intercepted by a proximal

acetal. The synthesis of 27 commenced with known homoallylic

alcohol 28, which was converted in six steps and 33% overall

yield to dihydropyran 29. DMDO epoxidation of 29, followed by

addition of trivinylalane to the intermediate alkoxy epoxide and

protection of the alcohol as the 4-(benzyloxy)butyl ether,

produced an intermediate (77% for the three steps) that was

readily ozonized and converted to sulfinylimine 30 by reaction

with (R)-tert-butylsulfonamide in 50% yield. Addition of ben-

zylmagnesium chloride, followed by (i) sulfonamide hydrolysis,

(ii) hydrogenolysis of the benzyl ether and (iii) Cbz group

installation gave alcohol 31. When subjected to iodobenzene

diacetate and I2 under irradiation, Su�arez oxidative ether-

ification31 occurred to give 32 in 80% yield, and set the stage for

the key electron-transfer initiated cyclization. Irradiation of 32

(medium-pressure Hg lamp with Pyrex filtration) in the presence

of 6 mol% of N-methylquinolinium hexafluorophosphate

(NMQPF6) and O2 provided 33 in 76% yield as a 2 : 1 mixture of

diastereomers at C10. The reaction presumably proceeds via

N-acyliminium ion 34, followed by oxononium ion 35. The

1188 | Nat. Prod. Rep., 2010, 27, 1186–1203

ability to generate N-acyliminium ions under such mild condi-

tions is especially noteworthy given the delicate substrate, and

this example should underscore the value of this approach for

complex molecule synthesis. The synthesis was completed by

a four-step sequence that involved oxidation of the lactol-derived

acetal to the lactone with Jones reagent, removal of the Cbz

group, acylation of the aminal with acid chloride 26 and, finally,

removal of the benzoyl group. The overall synthesis provided

theopederin D 25 in 16 steps (longest linear sequence).

5 Polyketides: callystatin, aburatubolactam,15G256 (and related compounds) and bryostatin 16

The Micalizio group has reported a synthesis of callystatin A 36

that features a novel direct reductive coupling of two alkynes

with Ti(II) reagents (Scheme 4).32 The subunit coupling

commenced with a palladium-catalyzed coupling between the

vinylzinc reagent derived from vinyl iodide 37, and (E)-vinyl

iodide 38 and was followed by removal of the terminal TMS

group to give 39. The direct titanium-mediated cross-coupling

between alkyne 40 and diene 39 was accomplished with

ClTi(OiPr)3 and cyclopentylmagnesium chloride in 75% yield

(>5 : 1 regioselectivity) to give 41 (presumably via 42), which

contains the complete callystatin A carbon backbone. TMS

deprotection followed by oxidation and TBS removal concluded

a total synthesis that proceeds in a remarkable 11-step longest

linear sequence.

In a follow-up to their earlier synthesis of the macrolactam

tetramic acid cylindramide A,33 the Phillips group has described

a total synthesis of aburatubolactam A 43 (Scheme 5).34 In the

same vein as cylindramide A, the bicyclo[3.3.0]octane domain

was formed by tandem metathesis of a readily accessible Diels–

Alder adduct. In the case at hand, treatment of 44 with 2.5 mol%

of the Grubbs 1st-generation catalyst under an atmosphere of

ethylene led to fused bicyclic compound 45 in 90% yield. A

15-step sequence advanced this compound to stannyldioxenone

46 in 9% overall and set the stage for an endgame that



Scheme 4 Micalizio’s Ti-based route to callystatin A. Reagents and

conditions: (1) 37, ZnCl2, tBuLi, Et2O then 38, cat. Pd(PPh3)4; (2) TBAF,

THF 60% (2 steps); (3) nBuLi, ClTi(OiPr)3, c-C5H9MgCl, PhMe, �78 �C

then NH4Cl, �30 �C, 75%; (4) PPTS, H2O, acetone; (5) PCC, AcOH; (6)

HF$pyr, pyr, THF, 24% (3 steps).

Scheme 5 Phillips’ synthesis of aburatubolactam A 43. Reagents and

conditions: (1) 2.5% Grubbs I, CH2]CH2 (1 atm), CH2Cl2, 90%; (2)

PhMe, 110 �C; (3) tert-butyl-b-iodoacrylate, 10 mol% Pd2(dba)3, Ph3As,

NMP; (4) NaOMe, MeOH, 50% (3 steps); (5) TFA, CH2Cl2; (6) DEPC,

Et3N, DMF, rt; (7) HF, MeCN, 46% (3 steps). DEPC ¼ diethy-

lphosphoryl cyanide.

Scheme 3 Floreancig’s synthesis of theopederin D. Reagents and

conditions: (1) DMDO, acetone, then (H2C]CH)3Al, CH2Cl2, 100%; (2)

BBMCl, DIPEA, CH2Cl2, 77%; (3) O3, CH2Cl2, �78 �C; then (R)-tBu-

S(O)NH2, Ti(OiPr)4, CH2Cl2, 50%; (4) BnMgCl, THF, 65%; (5) HCl,

MeOH, 80%; (6) H2, Pd/C, MeOH; then CbzCl, Et3N, CH2Cl2, 70%; (7)

PhI(OAc)2, hn, cyclohexane, 80%; (8) hn, NMQPF6, O2, NaOAc,

Na2S2O3, PhMe, DCE, 76%. BBMCl ¼ 4-(benzyloxy)chlorobutane,

NMQPF6 ¼ N-methylquinolinium hexafluorophosphate.

Dow

nloa

ded

by D

UK

E U

NIV

ER

SIT

Y o

n 01

Oct

ober

201

0Pu

blis

hed

on 2

2 Ju

ne 2

010

on h

ttp://

pubs

.rsc

.org

| do

i:10.

1039

/B91

9366

AView Online

commenced with thermolysis of 46 in the presence of amine 47 to

give b-ketoamide 48. Stille coupling with tert-butyl-b-iodoacry-

late produced the dienoate, and Lacey–Dieckmann cyclization

gave 49 in 50% yield (over three steps). Despite the potential for

subversion of the macrolactamization by stereochemical ques-

tions with respect to the exocyclic olefin of the tetramic acid,

treatment of 49 with TFA to remove the Boc carbamate and tert-

butyl ester, followed by DEPC, smoothly produced the desired

macrocycle. Removal of the TBS group with HF completed the

total synthesis (46% yield over 3 steps).

Barrett and coworkers have developed total syntheses of the

marine antifungal agents 15G256p (50), 15G256i (51), and

15G256b (52), using a biomimetic late-stage aromatization

strategy (Scheme 6).35 This strategy involves the thermolysis of


dioxinones such as 55 and trapping of the resulting triketoke-

tenes with an alcohol to afford 54. Treatment of 54 with base

generates the aromatic system 55.

To prepare these natural products, an efficient synthesis to the

15G26 monomer unit 60 is required. Using acid chlorides 64 and

65, the readily available dioxinone 56 could be sequentially

C-acylated to provide access to dioxinone 57 in 66% overall yield

Nat. Prod. Rep., 2010, 27, 1186–1203 | 1189


Scheme 6 Resorcylate lactones and a late-stage aromatization strategy.

Scheme 7 Barrett’s synthesis of key monomers 62 and 63. Reagents and

conditions: (1) 64, Bi(OTf)3, �15 / 20 �C, 80%; (2) 65, MgCl2, pyr,

CH2Cl2, 0 to 20 �C, 83%; (3) Pd(PPh3)4 4 mol%, morpholine, CH2Cl2,

0 to 20 �C, 89%; (4) 66, PhMe, 110 �C; (5) K2CO3, iPrOH, CH2Cl2, HCl,

MeOH, 70% (2 steps); (6) Cs2CO3, BnBr, DMF, 0 / 20 �C, 92%; (7) HF,

THF, pyr, 85%; (8) Pd(PPh3)4, morpholine, THF, 93%.

Scheme 8 Completion of Barrett’s synthesis of 15G256p (50), 15G256i

(51), and 15G256b (52). Reagents and conditions: (1) 63, 2,4,6-tri-

chlorobenzoyl chloride, iPr2NEt, then 62, DMAP, PhMe, 86%. (2)

Pd(PPh3)4, morpholine, THF, 87%; (3) H2, Pd/C, EtOAc; (4) HF, THF,

pyr, 86% (2 steps); (5) HF, THF, pyr; (6) 2,4,6-trichlorobenzoyl chloride,

DIPEA, DMAP, PhMe, 76% (2 steps); (7) H2, Pd/C, EtOAc, 75%; (8) 68,

2,4,6-trichlorobenzoyl chloride, iPr2NEt, then 66, DMAP, PhMe, 71%;

(9) Pd(PPh3)4, morpholine, THF; (10) HF, THF, pyr; (11) 2,4,6-tri-

chlorobenzoyl chloride, DIPEA, DMAP, PhMe, 65% (3 steps); (12) H2,

Pd/C, EtOAc, 85%.

Scheme 9 An overview of Trost’s synthesis plan for bryostatin 16.

Dow

nloa

ded

by D

UK

E U

NIV

ER

SIT

Y o

n 01

Oct

ober

201

0Pu

blis

hed

on 2

2 Ju

ne 2

010

on h

ttp://

pubs

.rsc

.org

| do

i:10.

1039

/B91

9366

AView Online

(Scheme 7). The tri-keto ester 58 was obtained in 89% yield after

application of a palladium-catalyzed deallylation–decarboxyl-

ation procedure (4 mol% Pd(PPh3)4, morpholine). Thermolysis

of the dioxinone in the presence of the chiral alcohol 66, followed

by sequential reaction with potassium carbonate and methanolic

hydrogen chloride gave the 15G256 monomer unit 60 in 70%

yield for the two steps. Benzylation (BnBr, Cs2CO3, DMF, 92%)

gave 61, which could then be converted into either alcohol 62 or

acid 63 by the use of selective deprotection protocols.

A Yamaguchi esterification of 62 and 63 gave the tetraester 67

in 86% yield (Scheme 8). Selective deallylation (4 mol%

Pd(PPh3)4, morpholine, 87%) gave the acid 68, which is the key

material for preparing the natural products. 15G256p (50) was

prepared in 86% yield by removal of the benzyl ethers (H2, Pd/C),

then desilylation (HF$pyr).

1190 | Nat. Prod. Rep., 2010, 27, 1186–1203

Conversion of 68 to the symmetrical natural product 15G256i

(51) required a three-step procedure, with the silyl group being

removed first, then a Yamaguchi lactonization, followed by

debenzylation. A 57% yield for the three steps was achieved. The

more complex macrolactone 15G256b (52) was accessed by

firstly converting 68 to macrolactone 69, using a four-step

procedure. Debenzylation of 14 provided the natural product 52

in 85% yield.

The bryostatins are an exciting class of macrolactone natural

products that exhibit exceptional biological activity.36,37 In

particular, it has been found that they have great potential as

anticancer agents when used in combination with other thera-

peutic agents. Due to the scarcity of the natural material and the

need for analogues, there has been much interest in the devel-

opment of efficient syntheses.38

Trost and Dong have reported a highly convergent total

synthesis of bryostatin 16 70 which is a key parent structure that



Dow

nloa

ded

by D

UK

E U

NIV

ER

SIT

Y o

n 01

Oct

ober

201

0Pu

blis

hed

on 2

2 Ju

ne 2

010

on h

ttp://

pubs

.rsc

.org

| do

i:10.

1039

/B91

9366

AView Online

could allow access to many other bryostatins.39 Starting from the

readily available aldehyde 75, the synthesis requires 39 steps in

total, with the longest linear sequence being 26 steps. As detailed

in Scheme 9, it was envisaged that the macrocycle could be

formed from 71 using a palladium-catalyzed alkyne–alkyne

coupling, followed by a metal-catalyzed 6-endo-dig cyclization.

The key substrate 3 would be assembled from the fragments 72,

73, and 74.

Lactone 73 was prepared in 11 steps from the readily available

aldehyde 75 (see Scheme 2) (Scheme 10). The same aldehyde was

also used to produce the alkyne coupling partner 72 by firstly

forming the enal, followed by an indium-mediated prop-

argylation. To obtain the enantio-enriched material, the racemic

72 was firstly oxidized (Dess–Martin periodinane) to the ketone,

then a Corey–Bakshi–Shibata reduction gave (R)-72 in 90% ee

and 90% overall yield. A chemoselective ruthenium-catalyzed

tandem alkene–alkyne coupling – Michael addition (13 mol%

CpRu(MeCN)3PF6, DCM) was used to form the cis-tetrahy-

dropyran 76 in 34% yield (80% based on recovered starting

material). Bromination of the vinyl silane (NBS, DMF), followed

by an acid-catalyzed process (10 mol% CSA, MeOH) afforded

the alcohol 77 in 94% overall yield for the two steps. With the

A-ring and B-ring substructures in place, 77 was transformed

into the desired acid 79 in six steps. Esterification of 79 with the

Scheme 10 Trost & Dong’s synthesis of acid 79. Reagents and conditions:

(1) (Z)-1-bromo-2-ethoxyethene, tBuLi, Me2Zn, then 75, Et2O, �78 �C,

97%; (2) (3-bromo-1-propynyl)trimethylsilane, In powder, InF3

(10 mol%), THF, 65 �C, 68%; (3) (i) Dess–Martin periodinane, NaHCO3,

CH2Cl2; (ii) (S)-2-methyl-CBS-oxazaborolidine (5 mol%), catecholbor-

ane, CH2Cl2, �78 �C, 90%, 90% e.e. (2 steps); (4) 1.2 equiv 73,

CpRu(MeCN)3PF6 (13 mol%), CH2Cl2, 34% (80% b.r.s.m.); (5) NBS,

DMF, 98%; (6) CSA (10 mol%), MeOH, 0 �C, 93–96%; (7)

PdCl2(MeCN)2 (10 mol%), dppf, CO, MeOH, NEt3, DMF, 80 �C, 83%

(90% b.r.s.m.); (8) Dess–Martin periodinane, NaHCO3, CH2Cl2, 88%; (9)

Ohira–Bestmann reagent, K2CO3, MeOH, 97%; (10) TBAF, HOAc,

THF, 90% (96% b.r.s.m.); (11) Me3SnOH, 1,2-DCE, 80 �C, 84%; (12)

TESOTf, 2,6-lutidine, CH2Cl2, �10 �C / 0 �C, 76–79%.


readily available 74 was achieved using Yamaguchi’s conditions

(2,4,6-Cl3C6H2COCl, DMAP, NEt3, PhMe), affording 80 in 92%

yield. Removal of the PMB protecting groups, using oxidative

conditions (DDQ, pH 7 buffer, 2 cycles), gave the macrocycle

precursor 81.

The macrocycle 82 was generated in 56% yield by reaction of

81 with 12 mol% of palladium acetate and 15 mol% tris(2,6-

dimethoxyphenyl)phosphine in PhMe at room temperature

(Scheme 11). It was found that the reaction had to be run at low

concentration (0.002 M) and that the choice of solvent and the

ligand/palladium ratio were critical to the success of the reaction.

Treatment of the resulting alcohol 82 with a cationic gold cata-

lyst (Au(PPh3)SbF6, NaHCO3) initiated a 6-endo-dig cyclization

and afforded the desired ring system 83 in 73% yield. After piv-

alation of the secondary alcohol (Piv2O, DMAP, 62%), efforts

focused on the global deprotection to afford bryostatin 16. After

some experimentation, it was found that treatment of 84 with 5

equivalents of tetrabutylammonium fluoride gave bryostatin 16

70 in 52% yield, after purification using reverse-phase HPLC.

Keck and his group40 have developed a convergent strategy to

highly potent bryostatin analogues, while Wender and coworkers

have reported41 on the development of new highly potent

analogues of the bryostatins, using a Prins-driven macro-

cylization strategy to allow efficient access to the target

molecules.

The isolation of (+)-neopeltolide 85a was reported42 in early

2007, and has attracted a great deal of attention due to the

reported potent biological activity and structural complexity of

the natural product. Indeed, there have been seven total

Scheme 11 Completion of Trost & Dong’s synthesis of bryostatin 16

(70). Reagents and conditions: (1) 79, 2,4,6-trichlorobenzoyl chloride,

NEt3, PhMe, then 74, DMAP, 92%; (2) DDQ, pH 7.0 buffer, DCM, 2

cycles, 75%; (3) Pd(OAc)2 (12 mol%), TDMPP (15 mol%), PhMe, 56%;

(4) AuCl(PPh3) (20 mol%), AgSbF6 (20 mol%), NaHCO3, DCM–MeCN,

0 �C to rt, 73%; (5) Piv2O, DMAP, DCM, 50 �C, 62%; (6) TBAF,

THF, 52%.

Nat. Prod. Rep., 2010, 27, 1186–1203 | 1191


Scheme 12 The original and revised structures of neopeltolide.

Scheme 14 Panek’s synthesis of (+)-neopeltolide (85b). Reagents and

conditions: (1) BH3$SMe2, THF, 0 �C to rt; (2) TBDPSCl, imid., DMF,

0 �C to rt, 80% (over 2 steps); (3) DIBAL-H, diethyl ether, �78 �C; (4)

1,3-propanedithiol, I2, CHCl3, rt, 85% (over 2 steps); (5) t-BuLi, HMPA,

THF, 90, �78 �C, 68%; (6) CaCO3, MeI, MeCN–H2O, rt, 73%; (7)

Zr(OtBu)4, iPrCHO, PhMe, �78 �C; (8) Me3OBF4, Proton Sponge, 4 �A

molecular sieves, CH2Cl2, rt, 90% (over 2 steps); (9) 49% HF in H2O,

MeCN, rt, 91%; (10) (COCl)2, DMSO, CH2Cl2, Et3N,�78 �C to rt, 89%.

(11) 86, TfOH, CH2Cl2–benzene (3 : 1), �78 �C, 75% (d.r. 10 : 1); (12)

NaCN, DMF, 60 �C, 84%; (13) DIBAL-H, Et2O, �78 �C, 96%; (14)

DIBAL-H, CH2Cl2, �78 �C, 60%; (15) NaClO2, 2-methyl-2-butene,

NaH2PO4$H2O, tBuOH, H2O, 85%; (16) 2,4,6-trichlorobenzoyl chloride,

PhMe, DMAP, Et3N, 44%; (17) Hg(O2CCF3)2 then NaBH4, THF–H2O

(1 : 1), 63% (d.r. >20 : 1); (18) (CF3CH2O)2P(O)CH2CO2H, EDCI$HCl,

HOBt$H2O, CH2Cl2, 99%; (19) 94, 18-crown-6, KHMDS, �78 �C, then

95, �85 �C, 62%.

Dow

nloa

ded

by D

UK

E U

NIV

ER

SIT

Y o

n 01

Oct

ober

201

0Pu

blis

hed

on 2

2 Ju

ne 2

010

on h

ttp://

pubs

.rsc

.org

| do

i:10.

1039

/B91

9366

AView Online

syntheses and one formal synthesis of the compound since its

isolation. Importantly, the first total syntheses of the proposed

structure 85a, by the groups of Panek43 and Scheidt44 respec-

tively, lead to the realization that the original stereochemical

assignment was incorrect. Both groups independently assigned

the configuration to structure 85b, and confirmed this by

synthesis (Scheme 12). Their syntheses of the revised structure

are discussed below.

The synthetic plan pursued by the Panek group revolved

around a Yamaguchi macrocyclization and Still–Gennari olefi-

nation (Scheme 13). Key building blocks were allyl silane 86 and

aldehyde 87.

Synthesis of the C7–C16 fragment 87 of neopeltolide was

achieved in 10 steps, starting from commercially available

(R)-(+)-3-methylglutarate (88) (Scheme 14). The dihydropyran

91 was prepared in 75% yield (10 : 1 diasteromeric ratio) by

reacting 87 with the readily available allylsilane 86, using a triflic

acid promoted [4 + 2] annulation. A four-step sequence was then

utilized to prepare the seco acid 92 required for the macro-

cyclization.

After macrocyclization (2,4,6-Cl3C6H2COCl, DMAP, PhMe,

44%), the axial C5 alcohol 93 was obtained by carrying out

a selective oxymercuration (Hg(O2CCF3)2; NaBH4, 63%, >20 : 1

ratio) of the pyran alkene 92. To attach the side-chain, Panek and

coworkers employed a Still–Gennari olefination. Acylation of

alcohol 93 with bis(2,2,2-trifluoroethyl)phosphonoacetic acid

(EDCI$HCl, HOBt$H2O, 99%) afforded phosphonate 94.

Deprotonation (KHMDS, 18-crown-6, �78 �C) of the phos-

phonate 94, followed by addition of the readily available alde-

hyde 95 at �85 �C provide a 7 : 1 mixture of neopeltolide (85b)

and the corresponding (E)-olefin. The longest linear sequence

was 19 steps, with an overall yield of 1.3%.

Scheme 13 Panek’s retrosynthetic analysis of (+)-neopeltolide (85b).

1192 | Nat. Prod. Rep., 2010, 27, 1186–1203

The Scheidt synthesis also focuses on the preparation of the

macrolactone moiety, but the endgame differs in that it was

proposed to attach the side-chain 96 via a Mitsunobu inversion

(Scheme 15). To prepare the macrolactone 97, they planned to

Scheme 15 Scheidt’s retrosynthesis of (+)-neopeltolide (85b)



Scheme 16 Scheidt’s synthesis of (+)-neopeltolide (85b). Reagents and

conditions: (1) H2N(Me)OMe$Cl, iPrMgBr, THF; (2) PMB-

OC(NH)CCl3, PPTS, cyclohexane–CH2Cl2 68% (2 steps); (3) 102, t-BuLi,

pentane–Et2O, �78 �C; (4); MeOTf, DTBMP, CH2Cl2, 30% (2 steps);

(5) DDQ, pH 7 buffer, CH2Cl2, 83%; (6) 4-NO2C6H4CO2H, DEAD,

PPh3, C6H6, 0 �C, 73%; (7) K2CO3, MeOH, 70%; (8) Ti(iPrO)4,

(R)-BINOL, 4 �A sieves, CH2Cl2, 63%; (9) TBSOTf, 2,6-lutidine, CH2Cl2;

(10) PPTS, EtOH; (11) PDC, DMF, 73% (3 steps); (12) 2,4,6-tri-

chlorobenzoyl chloride, DMAP, THF; (13) HF$pyr, THF; (14) TEMPO,

PhI(OAc)2, CH2Cl2, 76% (3 steps); (15) Sc(OTf)3, CaSO4, MeCN;

(16) DMSO, H2O, 130 �C, 21% (2 steps); (17) NaBH4, MeOH, 0 �C;

(18) DIAD, Ph3P, 96, benzene, 76% (2 steps).

Scheme 17 Summary of all of the other total and formal syntheses of

(+)-neopeltolide (85b).


Dow

nloa

ded

by D

UK

E U

NIV

ER

SIT

Y o

n 01

Oct

ober

201

0Pu

blis

hed

on 2

2 Ju

ne 2

010

on h

ttp://

pubs

.rsc

.org

| do

i:10.

1039

/B91

9366

AView Online

construct the tetrahydropyran and macrolactone simulta-

neously, using methodology they had developed previously. The

macrocyclization precursor 98 should be readily available from

acid 99 and alcohol 100.

Scheidt prepared the C7–C16 fragment 100 of neopeltolide in

seven steps and 19% overall yield, starting from the ester 101

(Scheme 16). Dienoxy silane 103 was converted to the required

dioxinone acid 104 in four steps (46% yield, 88% ee). Conversion

to the macrocyclization precursor 98 was achieved by Yamaguchi

coupling of 100 and 104, silyl deprotection (HF$pyr) and selective

oxidation of the primary alcohol (TEMPO, PhI(OAc)2). This

three-step procedure proceeded in 76% overall yield. Treatment of

98 with scandium(III) triflate initiated the Prins-type macro-

cyclization, and after heating of the resulting dioxinone 105 in

DMSO the macrolactone 106 was afforded in 21% yield. To

complete the synthesis, the carbonyl group of 106 was reduced

(NaBH4) and the resulting alcohol underwent a Misunobu reac-

tion with acid 96 to yield (+)-neopeltolide, 85b in 76% yield. The

longest linear sequence was 14 steps, with an overall yield of 1.0%.

Scheme 18 Nicolau’s synthesis of the proposed structure of vannusal

(107). Reagents and conditions: (1) 109 (1.3 equiv), tBuLi (2.6 equiv), THF,

�78 / �40 �C, then 108 (1 equiv). �40 / 0 �C, 80%; (2) TBAF, THF,

98%; (3) TESCl, imid., CH2Cl2, 25 �C, 99%; (4) KHMDS, ClCO2Me,

NEt3, THF; (5) HF$pyr/pyr (1 : 4), 0 / 25 �C, 88% (2 steps); (6) TEMPO,

PhI(OAc)2, CH2Cl2, 25 �C, 98%; (7) SmI2, HMPA (15 equiv), THF,

�10 / 25 �C, 80% (113a: 28%, 113b: 52%); (8) POCl3, pyr, 60 �C, 81%; (9)

(i) CS2, NaH, THF, 0 / 25 �C, then MeI, then 185 �C (microwave),

1,2-DCE, 92%; (10) ThexBH2, THF,�10 / 25 �C, then BH3$THF, 0 /

25 �C, then 30% H2O2–3 N NaOH, 65%; (11) o-NO2C6H4SeCN, nBu3P,

pyr, THF, then 30% H2O2, 67%; (12) KHMDS, TESCl, NEt3, THF,�78

/ 25 �C, 84%; (14) LiDBB (excess), THF, �78 / �50 �C, 84%; (15)

Ac2O, NEt3, DMAP, CH2Cl2, 25 �C, 100%; (16) HF$pyr–THF (1 : 4),

25 �C, then 3 N aq. HCl–THF (1 : 3), 25 �C, 80%.

Nat. Prod. Rep., 2010, 27, 1186–1203 | 1193


Dow

nloa

ded

by D

UK

E U

NIV

ER

SIT

Y o

n 01

Oct

ober

201

0Pu

blis

hed

on 2

2 Ju

ne 2

010

on h

ttp://

pubs

.rsc

.org

| do

i:10.

1039

/B91

9366

AView Online

The syntheses and subsequent structural revisions of Panek

and Scheidt have triggered a great deal of work, with a further six

new syntheses (Kozmin,45 Maier,46 Lee,47 Fuwa-Sasaki,48 Pater-

son,49 and Taylor50) reported in 2008. Due to space constraints,

these syntheses are not discussed, but a summary of the number

of steps and the overall yield for the sequence is provided in

Scheme 17. It should be noted that all but one (Taylor) have

utilized the Scheidt endgame, whereby they attach the oxazole

sidechain using a Mitsunobu inversion.

Kozmin and coworkers have carried out an investigation of

the mode of action of neopeltolide, 85b and have identified the

cytochrome bc1 complex of the mitochondrial respiratory chain

as the primary cellular target.45

6 Terpenoids: vannusal B and cortistatin A

Vannusal B 107 represents a significant synthetic challenge, with

seven rings and 13 stereogenic centers.51 However, Nicolaou and

Scheme 19 Highlights of the first three total syntheses of cortistatin A by B

conditions: (1) Co(acac)2 (0.2 equiv), PhSiH3 O2, THF, HC(OMe)3, 23 �C, 12

(5 equiv), Br2 (5 equiv), CH2Cl2, �30 �C, 10 h; then TMSCl, imid., 57%; (3

(1.1 equiv), 23 �C, 5 h; (5) LiBr, Li2CO3, DMF, 80 �C, (65% over 2 steps); (6) A

DMAP, CH2Cl2, 89%; (7) MgBr2$Et2O, 2,6-tBu2Py, PhH; then PPTS, butan

50 �C, 6 h, then I2 (2 equiv), Et3N (3 equiv), THF, 23 �C, 5 min; (b) 7-(trim

DMSO, 23 �C, 10 min, 53% (over 2 steps); (9) RANEY� Ni, iPrOH, H2O, 5

Reagents and conditions: (1) 3-oxocyclohex-1-enyl trifluoromethanesulfonat

Pd/BaSO4 (5% wt/wt, 0.24 equiv), H2, MeOH–THF, 64%; (4) K2CO3, dioxane

(dr � 1 : 1); (7) Me2NH, THF, Ti(OiPr)4, 80 �C, 5 h, 45%. (C) Shair’s synthes

70 �C, 1 h (49%, 2 steps); (3) SOCl2, pyr, CH2Cl2; (4) NaHMDS, THF, the

(3 steps); (6) CHBr3, KOtBu, hexane, 0 �C; (7) TASF (1.2 equiv), DMF, 80 �C

50 �C, 40 min, 65% (3 steps).

1194 | Nat. Prod. Rep., 2010, 27, 1186–1203

coworkers have synthesised the proposed structure of vannusal B

using a convergent strategy, starting from aldehyde 108 and

iodide 109 (Scheme 18).52 Unfortunately, the spectroscopic data

for the synthesized material does not match the reported data of

the natural product.

A six-step sequence, starting from 108 and 109, generates the

aldehyde carbonate 112. Formation of the carbon skeleton 113

(as a 1.9 : 1 mixture of alcohols) was achieved in 80% yield by

treatment of 112 with samarium iodide. Each of the diastereo-

mers of 113 could be independently deoxygenated to afford diene

114. This material was transformed to the proposed structure 107

using a seven-step sequence. At the time of writing, the Nicolaou

group has revised the structure on the basis of further synthetic

studies.53,54

The cortistatin family of steroidal alkaloids have generated

significant interest from the synthesis community55 since their

discovery in 2006–2007.56–58 Aside from their interesting

9-(10,19)-abeo-androstane type skeleton, attention has no doubt

aran, Nicolaou & Chen, and Shair. (A) Baran’s synthesis. Reagents and

h; then TsOH$H2O, rt, 2 h; then K2CO3 MeOH, 6 h, 65%; (2) PhI(OAc)2

) DBU, LiCl, THF, 85%; (4) SmI2, DMPU–THF, 23 �C; then TBCHD

lH3, THF, 23 �C, 1 h; then K2CO3, MeOH, 23 �C, 12 h; then Ac2O, Et3N,

one: H2O, 90 �C; then K2CO3, MeOH, 82%; (8) (a) N2H4, Et3N, EtOH,

ethylstannyl)isoquinoline (4 equiv), Pd(PPh3)4 (0.5 equiv), CuCl, LiCl,

0 �C, 1 h, 50% (at �50% conversion). (B) Nicolaou & Chen’s synthesis.

e, 10% Pd(PPh3)4, CuI, Et3N, DMF, 85%; (2) IBX, DMSO, 81%; (3)

, 52%; (5) tBuOOH, DBU, CH2Cl2, 70%; (6) NaBH4, CeCl3, MeOH, 80%

is. Reagents and conditions: (1) PPTS, Me2CO–H2O; (2) NaOMe, MeOH,

n PhNTf2; (5) Me(OiPr)2SiCH2MgCl, 5 mol% Pd(PPh3)4, THF, rt, 62%

, 30 min, 66% (2 steps); (8) Me2NH (3 equiv), ZnBr2 (1.5 equiv), CH3CN,



Dow

nloa

ded

by D

UK

E U

NIV

ER

SIT

Y o

n 01

Oct

ober

201

0Pu

blis

hed

on 2

2 Ju

ne 2

010

on h

ttp://

pubs

.rsc

.org

| do

i:10.

1039

/B91

9366

AView Online

been honed by their impressive biological activities, most notably

cortistatin A (115), which has highly selective and potent activity

against HUVEC cells (IC50 ¼ 1.8 nM).

The Baran synthesis of cortistatin A 115 commenced with

readily availabile prednisone (116), which was converted in five

steps and 26% overall yield to 117 (Scheme 19).59 Mukaiyama

hydration of the olefin with Co(acac)2 and PhSiH3, followed by

orthoamide formation and acetate cleavage (65% for the three

operations) gave an intermediate that was subjected to a newly

developed procedure that used in situ-formed acetylhypobromite

for the functionalization of hydrocarbons. Under direction of the

proximal alcohol, the C19 methyl group was dibrominated to

give 118 in 57% yield (with the alcohol being protected as the

TMS ether to prevent intramolecular etherification). Treatment

of 118 with DBU at elevated temperature resulted in enolization

and intramolecular alkylation with the germinal dibromide to

provide bromocyclopropane 119 as a single diastereomer. Ring

expansion mediated by SmI2, followed by treatment with 2,4,4,6-

tetrabromo-2,5-cyclohexadienone (TBCHD), gave 120. Elimi-

nation with LiBr/Li2CO3, removal of the orthoester, and finally

acetylation produced diene 121. Lewis acid-mediated SN20 reac-

tion installed the oxabicylo[3.2.1]octane motif, and removal of

the protecting groups led to 122.

Barton iodination of the ketone 122 produced an intermediate

iodide that was readily coupled with 7-(trimethyl-

stannyl)isoquinoline, leading to 123 in 53% yield (over the two

steps). The synthesis was completed by hydrogenation of the

styryl olefin using RANEY� nickel to give cortistatin A, 115 in

50% yield (at �50% conversion).

The Nicolaou synthesis, which was executed in conjunction

with David Chen at A-Star in Singapore, began with hydrindane

124, a derivative of the Hajos–Parrish ketone (Scheme 19).60

Nine steps converted 124 to alkyne 125, and set the stage for

a key four-step sequence that assembled the polycyclic

Scheme 20 (a) The synthesis of the pentacyclic cortistatin core by

Yamashita & Hirama. Reagents and conditions: (1) cyclohexane-1,3-

dione, piperidine, EtOAc, 87%, d.r. ¼ 5 : 1; (2) HF$pyr, THF, rt; (3) I2,

Ph3P, imid., THF, 87% (2 steps); (4) Et3B, (Me3Si)3SiH, THF, �78 �C.

(b) The key step of the Danishefsky synthesis of the cortistatin core.

Reagents and conditions: (1) TBAF, THF, 88%.


framework of cortistatin. After Sonagashira coupling of

the alkyne with 3-(triflyloxy)cyclohexenone (125 / 126), the

dithiane was removed under oxidative conditions with IBX, and

reduction of the alkyne with H2 and Pd/BaSO4 gave 127. An

elegant sequence of tandem heteroconjugate addition and aldol

condensation gave 128. After conversion of 128 to 129 (9 steps,

6% overall), functionalization of the cyclohexenone ring

commenced with conjugate epoxidation from the b-face to give

epoxyketone 130. Subsequent reduction with NaBH4/CeCl3 gave

the desired alcohol as a 1 : 1 mixture of separable diastereomers

(the minor could be recycled by quantitative oxidation with

Dess–Martin periodinane), and the synthesis was completed by

Ti(OiPr)4-mediated epoxide opening with Me2NH to yield cor-

tistatin A, 115 in 45% yield (unoptimized).

The departure point for the Shair synthesis was the Hajos–

Parrish ketone 131, which was advanced to 132 by a five-step

sequence of standard transformations (Scheme 19).61 Removal of

Scheme 21 (a) Sarpong’s synthesis of the pentacyclic cortistatin core.

Reagents and conditions: (1) 10–20 mol% PtCl2, PhH, rt / 40 �C; (2)

TsNHNH2, Et3N, 1,2-DCE, 65 �C, 95% (after one recycle); (3)

MgBr2$OEt2, Me2S (20 equiv), CH2Cl2, �78 �C / rt; (4) TESCl, imid.,

DMF; (5) MCPBA, NaHCO3, CH2Cl2, 0 �C, 46% (3 steps); (6) nBuLi,

THF, 0 �C, 1 h; (7) PhI(OAc)2, CH2Cl2–iPrOH–TFE (5 : 3 : 2), 0 �C, 30

min, 60% (2 steps). (b) Corey’s benzylic cyanation and Demjanov rear-

rangement approach to the cortistatin core. Reagents and conditions: (1)

DDQ, TMSCN, LiClO4, CH2Cl2, �10 �C, 95%; (2) LiAlH4, THF, 98%;

(3) NaNO2, AcOH, H2O–THF, 61%.

Nat. Prod. Rep., 2010, 27, 1186–1203 | 1195


Scheme 22 An overview of macrocyclization strategies for largazole, and the syntheses by Luesch and Williams. (a) Solution structure of largazole [as

determined by Phillips and co-workers]. (b) Sites of macrocyclization. (c) Luesch & Hong’s synthesis. Reagents and conditions: (1) Et3N, EtOH, 51%; (2)

TFA, CH2Cl2; (3) 158, DMAP, 94% (2 steps); (4) Boc-L-valine, 2,4,6-trichlorobenzoyl chloride, Et3N, DMAP, CH2Cl2, 99%; (5) LiOH, THF–H2O; (6)

TFA, CH2Cl2; (7) HATU, HOAt, DIPEA, CH2Cl2, 64% (3 steps); (8) Grubbs II (30 mol%), PhMe, 41%. (d) Williams’ synthesis. Reagents and conditions:

(1) Fmoc-L-valine, EDCI, DMAP, CH2Cl2; (2) Et2NH, CH3CN; (3) PyBOP, DIPEA, CH2Cl2, 78% (3 steps); (4) TFA, CH2Cl2; (5) HATU, HOBt,

DIPEA, CH2Cl2, 77% (2 steps); (6) iPr3SiH, TFA, CH2Cl2; (7) H3C(CH2)6COCl, Et3N, CH2Cl2, 89% (2 steps).

Scheme 23 (a) The syntheses of largazole by Phillips and Cramer.

Reagents and conditions: (1) Fmoc-L-valine, EDCI, DMAP (Phillips) or

Fmoc-L-valine, DIC, DMAP (Cramer); (2) Et2NH, 62% (2 steps, Phillips)

or piperidine, 93% (2 steps, Cramer); (3) DCC, PFP, 52% (Phillips) or

DCC, DMAP, 97%, (Cramer); (4) TFA, CH2Cl2 (Phillips) or TFA,

Et3SiH, CH2Cl2; (5) PyAOP, MeCN, DMAP, 50% (2 steps, Phillips) or

HATU, DIPEA, THF, 68–78% (2 steps, Cramer); (6) 157, 20% Grubbs

II, 34% (Phillips) or 157, 20% Grela catalyst, 54%. (b) The Ghosh mac-

rolactamization leading directly to largazole. Reagents and conditions: (1)

TFA, CH2Cl2; (2) HATU, HOAt, DIPEA, CH2Cl2, 40% (2 steps).

Dow

nloa

ded

by D

UK

E U

NIV

ER

SIT

Y o

n 01

Oct

ober

201

0Pu

blis

hed

on 2

2 Ju

ne 2

010

on h

ttp://

pubs

.rsc

.org

| do

i:10.

1039

/B91

9366

AView Online

the cyclic ketal with PPTS, followed by intramolecular aldol

reaction, produced 133 in 49% yield. A three-step process of

SOCl2-mediated elimination to the a,b-unsaturated ketone, vinyl

triflate formation and Pd(0)-catalyzed coupling with

Me(OiPr)2SiCH2MgCl provided 134 in 62% overall for the three

steps. Cyclopropanation with dibromocarbene (generated from

CHBr3 with tBuOK as base) gave 135. Warming this compound

in the presence of TASF at 80 �C in DMF produced the desired

ring-expanded compound 136 in 66% yield (over 2 steps). Five

further steps were employed to convert 136 to the precursor 137,

which is required for the key tandem Mannich-etherification

process. In this sequence, treatment of the aldehyde 137 with

Me2NH and ZnBr2 in CH3CN at 50 �C resulted in iminium ion

formation, cyclization of the olefin onto the iminium ion, and

trapping of the carbenium ion with the MEM ether. Termination

of this cascade occurred by scission of the MEM ether to give 138

in an excellent 65% yield (over the proceeding three steps). A

further six steps converted 138 into cortistatin A, 115.

Cortistatin also stimulated a number of studies that resulted

in novel and/or concise approaches to the framework of the

cortistatins. Yamashita and Hirama employed a Knoevenagel

reaction of 139 with cyclohexane-1,3-dione in the presence of

piperidine at room temperature (Scheme 20).62 The intermediate

product, 140, underwent electrocyclization to produce tetracycle

141 in 87% yield and with 5 : 1 diastereoselectivity. Removal of

the TBS ether and conversion of the alcohol to the iodide

(141 / 142, 87%) was followed by radical cyclization with Et3B

and (Me3Si)3SiH to give 143 in 78% yield. A similar strategy

1196 | Nat. Prod. Rep., 2010, 27, 1186–1203 This journal is ª The Royal Society of Chemistry 2010


Dow

nloa

ded

by D

UK

E U

NIV

ER

SIT

Y o

n 01

Oct

ober

201

0Pu

blis

hed

on 2

2 Ju

ne 2

010

on h

ttp://

pubs

.rsc

.org

| do

i:10.

1039

/B91

9366

AView Online

involving formation of the pentacyclic core by an alkylative

dearomatization was published by Danishefsky. In this case, the

key step was the reaction of 144 with TBAF, which proceeded

to give 145 in an excellent 88% yield.63 Danishefsky has also

published a synthesis of the cortistatin core that employs

a novel a,b-unsaturated nitrone–aryne [3 + 2] cycloaddition

followed by N–O bond reduction, elimination and electro-

cyclization.64

Sarpong and co-workers decribed a concise synthesis of the

pentacyclic cortistatin core that employed enyne cyclization

chemistry developed in their group (Scheme 21).65 When the key

substrate 148 (obtained from 146 and 147 in a four-step

sequence) was subjected to PtCl2, the desired product 149 was

obtained in 95% yield. A three-step sequence of (i) selective

reduction of the least hindered double bond with diiimide, (ii)

exchange of the PMB group for a TES group, and (iii)

Scheme 24 The syntheses of trichodermamide by Zakarian and Joulli�e. (a) Z

(2) LiOH, aq. THF, 90%; (3) TBSCl, imid., DMAP, DMF, 90 �C, 96%; (4) Sm

9-BBN, THF then NaOH, H2O2, 92%; (6) Swern oxidation, 99%; (7) (i) N

CH2Cl2–MeOH, 94%; (8) LDA, Me3SiCl, THF; (9) iC5H11ONO, TiCl4, D

Zn(OTf)2, EtSH, NaHCO3, CH2Cl2, 88%; (12) MsCl, pyr, CH2Cl2, 90%; (1

conditions: (1) TFAA, 90% H2O2, Na2HPO4, CH2Cl2, 95%; (2) TsOH, 2,2-D

EtOH, 95%; (5) Dess–Martin reagent, CH2Cl2, 95%; (6) NH2OH$HCl, NaOA

FeCl3$H2O, CH2Cl2, 85%; (9) 1,10-thiocarbonyldiimidazole, PhMe, reflux, 95

(11) K2CO3, MeOH, 72%; (12) TBAF, THF, 85%; (13) MsCl, NEt3, LiCl, C


epoxidation led to 150. Eliminative opening of the epoxide 150

gave the allylic alcohol, which upon exposure to PhI(OAc)2 was

oxidized to the dienone and resulted in the formation of the

oxabicylo[3.2.1]octene ring, yielding 151 in 60% yield (over two

steps).

Corey has also described preliminary ring-expansion studies

directed toward the cortistatins (Scheme 21).66 Readily avail-

able estrone derivative 152 was treated with DDQ and

TMSCN (at levels great enough to ensure that [TMSCN] >

3.0 M) to yield the benzylic cyanide 153. Reduction to the

primary amine (LAH, 98%, 153 / 154) was followed by

a Demjanov ring expansion using NaNO2 and AcOH to give

155 in 61% yield. Other reports on the cortistatins include

a CD-ring synthesis by intramolecular Michael-aldol reaction

and an intramolecular [4 + 3] cycloaddition approach to

a tetracyclic model system.67,68

akarian: Reagents and conditions: (1) vinylidene carbonate, 165 �C, 64%;

I2, MeOH, THF, 99%; (5) (i) MePPh3Br, KHMDS, THF, 99%, then (ii)

aClO2, NaH2PO4, 2-methyl-2-butene, tBuOH, H2O, then TMSCHN2,

BMP, CH2Cl2, 82% (2 steps); (10) EDCI, DMAP, CH2Cl2, 62%; (11)

3) LiCl, DMF, 74%; (14) aq. HF, THF, 90%. (b) Joulli�e: Reagents and

MP, acetone, 99%; (3) NaBH4, CeCl3, EtOH, �15 �C, 80%; (4) NaBH4,

c, EtOH–H2O then NaOH, 65%; (7) TBDPSCl, imid., CH2Cl2, quant.; (8)

%; then P(OMe)3, MW, 150 �C, 84%; (10) EDCI, 30% pyr, CH2Cl2, 83%;

H2Cl2, 60%.

Nat. Prod. Rep., 2010, 27, 1186–1203 | 1197


Table 1 First total syntheses of marine natural products reported in 2008

Compound Reference Notes

Gung and Omollo81 � 5 steps from known compound� Resolution� Absolute configuration determined

Giddens et al.82 � Pseudopyrinone A: 3 steps from known compound� Pseudopyrinone B: 5 steps from known compound� Biological activity: good potency and selectivity

against parasitic protozoa

Greshock et al.83 � 18 steps from commercially available 6-hydroxyindole

� Biomimetic synthesis� Racemic synthesis

Kumar and Shaw84 � 16 steps from commercially available materials� Non-racemic synthesis� Biological activity: potent cytotoxicity

Ghosh, Kumar and Shashidhar85 � 21 steps from known compound� Non-racemic synthesis� Determined absolute configuration� Biological activity: cytotoxic against 3YI rat normal

fibroblast cells

Skepper et al.86 � 5 steps from pentadecyne� Non-racemic synthesis� Biological activity: significant antifungal

Cordes et al.87 � 7 steps from 2,6-dimethoxybenzaldehyde

Crimmins and Ellis88 � 8 steps from known intermediate used to prepare11-acetoxy-4-deoxtasbestinin D

� Non-racemic synthesis

Sofiyev, Navarro and Trauner89 � 13 steps from known compounds� Biomimetic synthesis� No protecting groups used

1198 | Nat. Prod. Rep., 2010, 27, 1186–1203 This journal is ª The Royal Society of Chemistry 2010

Dow

nloa

ded

by D

UK

E U

NIV

ER

SIT

Y o

n 01

Oct

ober

201

0Pu

blis

hed

on 2

2 Ju

ne 2

010

on h

ttp://

pubs

.rsc

.org

| do

i:10.

1039

/B91

9366

AView Online


Table 1 (Contd. )


Seden et al.90 � 16 steps (longest liner sequence) from3-benzoyloxypropanal


Hamel et al.91 � 24 steps (longest liner sequence) from knowncompound

� Non-racemic synthesis� Biological activity: potent in vitro antiproliferative

activity

Niethe, Fischer and Blechert92 � 19 steps (longest linear sequence) from alanine� Non-racemic synthesis� Established absolute configuration of natural

product� Biological activity: activity against malaria causing

plasmodia and some trypanosomes

Hupp and Tepe93 � 14 steps from known compound� Racemic synthesis� Biological activity: cytotoxicity

Xie et al.94 � 19 steps (longest linear sequence) from alanine� Non-racemic synthesis� Established absolute configuration of natural

product� Biological activity: activity against malaria causing

plasmodia and some trypanosomes

Jiang et al.95 � 16 steps (longest linear sequence) fromcommercially available (+)-dehydro-epiandrosterone

� Non-racemic synthesis� Biological activity: cytotoxic against human solid

tumour cell lines

Ard�a et al.96 � 16 steps (longest linear sequence) from L-glutamicacid


This journal is ª The Royal Society of Chemistry 2010 Nat. Prod. Rep., 2010, 27, 1186–1203 | 1199

Dow

nloa

ded

by D

UK

E U

NIV

ER

SIT

Y o

n 01

Oct

ober

201

0Pu

blis

hed

on 2

2 Ju

ne 2

010

on h

ttp://

pubs

.rsc

.org

| do

i:10.

1039

/B91

9366

AView Online


Table 1 (Contd. )


Liu, Cui and Nan97 � 15 steps (longest linear sequence) from knowncompound

� Non-racemic synthesis� revision of structure

Lewis, Daniels and Lindsley98 � 3 steps from known compounds� Non-racemic synthesis� Revision of stereochemistry� Biological activity: antileishmanial

Eade et al.99 � 6 steps from known compound� Racemic synthesis� Biomimetic synthesis

Paterson, Razzak and Anderson100 � 17 steps from known compound� Non-racemic synthesis� Biological activity: ornithine decarboxylase

induction inhibitors

Li et al.101 � 11 steps from known compound� Non-racemic synthesis� Biological activity: antifungal

Smith et al.102 � Data for the synthetic material doesn’t match thatreported for each natural product

� 25 steps from known compound� Non-racemic� Potent cytotoxicity

Dow

nloa

ded

by D

UK

E U

NIV

ER

SIT

Y o

n 01

Oct

ober

201

0Pu

blis

hed

on 2

2 Ju

ne 2

010

on h

ttp://

pubs

.rsc

.org

| do

i:10.

1039

/B91

9366

AView Online

7 Largazole and the trichodermamides

Along with cortistatin A, largazole 156 proved to be one of the

hottest targets of the year. In both cases the high level of interest

was underpinned by some very impressive biological activity – in

1200 | Nat. Prod. Rep., 2010, 27, 1186–1203

the case of largazole it was nanomolar GI50 values against

a number of cancer cell lines, with �15-fold differential activity

for transformed vs. non-transformed cells. The structure eluci-

dation by Luesch69 was quickly followed by several total

syntheses, including those of Luesch,70,71 Williams,72 Phillips,73



Table 2 New total syntheses of marine natural products previously prepared that were reported in 2008

Compound Reference Compound Reference

Aaptamine Larghi et al.103 (�)-Agelastatin A Yoshimitsu et al.104

Aigialomycin D Chrovian et al.105 Amaminol B Jacobs et al.106

(�)-Amathaspiramide F Sakaguchi et al.107 Amphidinolide J Barbazanges et al.108

Attenols A and B Fuwa et al.109 (-)-Brevenal Ebine et al.110

Chondramide C Eggert et al.111 (�)-Cylindricine C Flick et al.112

Dictyopterene A Hohn et al.113 (�)-Dysibetaine Isaacson et al.114

Eicosanoid Kumaraswamy and Padmaja115 Et-743 Fishlock and Williams116

(�)-Flustramines A and C, (�)-flustramide A, and (�)- and(+)-debromoflustramines A

Kawasaki et al.117 (�)-Hirsutene and (�)-1-desoxyhypnophilin

Jiao et al.118

(+)-Isolaurepan Tripathi and Kumar119

Lamellarins O, P, Q and R Fukuda et al.120

Malyngamide U and its 20-epimer Feng et al.121

Manzacidins A and C Oe et al.122

(+)-Monocerin Kwon et al.123

Pachastrissamine (jaspine B) Passiniemi and Koskinen124

(+)-Phorboxazole A Smith III et al.125

Preclathridines A and C, andisonaamines A and C

Alifanov et al.126

(+)-Psymberin (irciniastatin A) Smith III et al.127 Siphonarienal and siphonarienone Lum et al.128

Solandelactones A, B, E and F White et al.129 (+)-Spongistatin 1 Smith III et al.130

(+)-Tedanolide and (+)-13-deoxytedanolide

Dunetz et al.131 (�)-Tridachiahydropyrone Sharma et al.132

Dow

nloa

ded

by D

UK

E U

NIV

ER

SIT

Y o

n 01

Oct

ober

201

0Pu

blis

hed

on 2

2 Ju

ne 2

010

on h

ttp://

pubs

.rsc

.org

| do

i:10.

1039

/B91

9366

AView Online

and Cramer.74 Further syntheses continued at a steady rate

through 2008, and by the end of year a further three had been

recorded (by Ghosh,75 Ye,76 and Doi77). Perhaps not surprisingly

given the relative simplicity of the target, key strategic questions

revolved around the timing of the thioester incorporation and the

position of macrocyclization. Most groups arrived at over-

lapping solutions, and the position of macrocyclization is shown

in Scheme 22, along with the almanac of key building blocks

employed in the various approaches (157 / 160).

The Luesch synthesis involved the coupling of thiazolyl nitrile

162 and a-methylcysteine 163 to give thiazolylthiazoline 159 in

51% yield. Removal of the Boc carbamate and acylation of the

amine with acid 158 under standard EDCI conditions produced

164 in 94% yield (over 2 steps) and was followed by coupling with

Boc-valine under Yamaguchi mixed anhydride conditions to

yield the precursor to the macrocyclization, 165. Removal of the

methyl ester (LiOH, aq. THF) and the Boc group (TFA) was

followed by HATU-mediated cyclization to give the desired

macrocycle 166 in 64% yield (over 3 steps). The synthesis was

then completed by appending the thioester side chain by cross-

metathesis between 164 and 157 in the presence of 30 mol%

Grubbs 2nd-generation catalyst, to give largazole in 41% yield.

The Williams synthesis involved acylation of alcohol 167 with

Fmoc-valine to produce 168 (Scheme 22). Removal of the Fmoc

carbamate was followed by coupling to acid 169 in the presence

of PyBOP, to give 170 in 78% yield (over 3 steps). Treatment with

TFA in CH2Cl2 removed the Boc and TMSE protecting groups,

and was followed by macrolactamization with HATU to give 171

in 77% yield (over 2 steps). Liberation of the thiol with TFA–

iPr3SiH, followed by acylation with capryloyl chloride, gave

largazole in 89% yield for these two steps.

The Phillips group and the Cramer group arrived at remark-

ably similar syntheses in an independent fashion (Scheme 23).

Readily accessible allylic alcohol 158 was acylated with Fmoc

valine and after removal of the Fmoc group, thiazolylthiazoline

acid 169 could be coupled to the amine to give 174. Acidic

conditions cleaved the acid-sensitive Boc carbamate and tert-

butyl ester, and macrocyclization was readily achieved with


either PyAOP (Phillips, 50% over 2 steps) or HATU (Cramer,

68–78% over 2 steps). The syntheses were then completed by

cross-metathesis with olefin 157 in the presence of either Grubbs

2nd-generation catalyst 175 (Phillips, 41%) or the Grela catalyst

176 (Cramer, 54%). An alternative macrocyclization substrate

was reported by Ghosh as a part of their total synthesis of lar-

gazole (see also Scheme 23). Treatment of 177 with TFA

removed the tert-butyl ester and Boc carbamate, and the inter-

mediate amino acid salt could by cyclised with HATU/HOAt to

give largazole directly in 40% yield.

Both the Zakarian and Joulli�e groups have completed total

syntheses of the 4H-5,6-dihydro-1,2-oxazine-containing natural

product trichodermamide B, and the Joulli�e group has also

completed trichodermamide A (Scheme 24).78,79 The Zakarian

synthesis is predicated on the formation of the oxazine by

application of an enolate nitrosation followed by a Lewis acid

mediated hetero-Cope rearrangement as the key reaction, and

the synthesis commenced with a Diels–Alder reaction between

179 and vinylidene carbonate to give 180 in 64% yield. Hydro-

lysis of the carbonate was accompanied by a surprising inversion

of the stereochemistry at the b-hydroxy position to give 181, and

after removal of the methoxy groups and protection of the

alcohols as TBS ethers, 181 was obtained. Wittig olefination,

hydroboration–oxidation and conversion to the methyl ester

gave 184 (via 183) and set the stage for the key transformation.

Deprotonation of the ester and conversion to the silylketene

acetal 185 was followed by treatment with isoamyl nitrite in the

presence of TiCl4 to give 186 in an excellent 82% yield over the

two steps. A sequence of seven steps advanced material to 187,

which was readily reacted with aminocoumarin 188 to yield 189.

Removal of the benzylidene acetal with Zn(OTf)2 and EtSH,

followed by mesylation of the less hindered alcohol, gave 190.

SN2 displacement of the mesylate was readily achieved with LiCl

in DMF, and the synthesis was completed by removal of the

TBDPS protecting group with aqueous HF.

The Joulli�e synthesis employed (�)-quinic acid 192 as a start-

ing material, and a 13-step sequence led to 193. Epoxidation with

in situ-formed CF3CO3H and acetonide formation gave 194.

Nat. Prod. Rep., 2010, 27, 1186–1203 | 1201


Dow

nloa

ded

by D

UK

E U

NIV

ER

SIT

Y o

n 01

Oct

ober

201

0Pu

blis

hed

on 2

2 Ju

ne 2

010

on h

ttp://

pubs

.rsc

.org

| do

i:10.

1039

/B91

9366

AView Online

Reduction of the lactone in two steps was accompanied by

migration of the TBDPS group to the primary alcohol, which

facilitated the protecting group and redox reorganizations

required to arrive at ketone 195. Upon reaction with hydroxyl-

amine, an intermediate oxime was presumably formed that

underwent intramolecular O-alkylation with the epoxide to

provide oxazine 196 as a single diastereomer in 65% yield. A

three-step sequence of TBDPS protection, acetonide cleavage

and Corey–Winter olefination gave 197. Oxidation-state

manipulations over five steps gave 198, and at this juncture the

synthesis could be completed by a sequence that was analogous

to that described by Zakarian.

A large number of other total syntheses of marine natural

products were reported in the review period, and papers

describing first total syntheses are presented in Table 1. New

total syntheses of compounds previously prepared are summa-

rized in Table 2.

8 Acknowledgements

We would like to thank Professor John Blunt and Professor

Murray Munro (University of Canterbury, Christchurch, New

Zealand) for a copy of the 2008 version of the MarinLit data-

base80 which facilitated data collection for this review. Members

of the Morris group are thanked for their assistance in drawing

structures.

9 References

1 J. W. Blunt, B. R. Copp, M. H. G. Munro, P. T. Northcote andM. R. Prinsep, Nat. Prod. Rep., 2010, 27, 165.

2 Literature searching was performed by using MarinLit, SciFinder,Web of Science, and a variety of publishing house search engineswith combinations of ‘marine’, ‘natural products’, ‘synthesis’, and‘total synthesis’.

3 H.-D. Arndt and M. Riedrich, Angew. Chem., Int. Ed., 2008, 47,4785–4788.

4 E. Delfourne, Anticancer Agents Med. Chem., 2008, 8, 910–916.5 M. Joullie, S. Berritt and E. M. Forbeck, Curr. Opin. Drug Discovery

Dev., 2008, 11, 829–852.6 J. i. Kobayashi, J. Antibiot., 2008, 61, 271–284.7 M. Lachia and C. J. Moody, Nat. Prod. Rep., 2008, 25, 227–253.8 I. Mancini, G. Guella and A. Defant, Mini-Rev. Med. Chem., 2008,

8, 1265–1284.9 K. C. Nicolaou, M. O. Frederick and R. J. Aversa, Angew. Chem.,

Int. Ed., 2008, 47, 7182–7225.10 Y. Usami, H. Ichikawa and M. Arimoto, Int. J. Mol. Sci., 2008, 9,

401–421.11 M. J. Abad Martinez, L. M. B. Del Olmo and P. B. Benito, Stud.

Nat. Prod. Chem., 2008, 35, 101–134.12 D. C. Behenna, J. L. Stockdill and B. M. Stoltz, Angew. Chem., Int.

Ed., 2008, 47, 2365–2386.13 J. Cossy, C. R. Chim., 2008, 11, 1303–1305.14 R. D. Little and G. A. Nishiguchi, Stud. Nat. Prod. Chem., 2008, 35,

3–56.15 B. R. Moser, J. Nat. Prod., 2008, 71, 487–491.16 P. A. Roethle and D. Trauner, Nat. Prod. Rep., 2008, 25, 298–317.17 S. J. Shaw, Mini-Rev. Med. Chem., 2008, 8, 276–284.18 T. Chou, O. Kamo and D. Uemura, Tetrahedron Lett., 1996, 37,

4023–4026.19 D. Uemura, T. Chou, T. Haino, A. Nagatsu, S. Fukuzawa,

S.-z. Zheng and H.-s. Chen, J. Am. Chem. Soc., 1995, 117, 1155–1156.

20 C. E. Stivala and A. Zakarian, J. Am. Chem. Soc., 2008, 130, 3774–3776.

21 S. Nakamura, F. Kikuchi and S. Hashimoto, Angew. Chem., Int. Ed.,2008, 47, 7091–7094.

22 B. M. Trost and F. D. Toste, J. Am. Chem. Soc., 2000, 122, 714–715.

1202 | Nat. Prod. Rep., 2010, 27, 1186–1203

23 J. A. McCauley, K. Nagasawa, P. A. Lander, S. G. Mischke,M. A. Semones and Y. Kishi, J. Am. Chem. Soc., 1998, 120, 7647–7648.

24 F. Matsuura, J. Hao, R. Reents and Y. Kishi, Org. Lett., 2006, 8,3327–3330.

25 F. Matsuura, R. Peters, M. Anada, S. S. Harried, J. Hao andY. Kishi, J. Am. Chem. Soc., 2006, 128, 7463–7465.

26 N. Fusetani, T. Sugawara and S. Matsunaga, J. Org. Chem., 1992,57, 3828–3832.

27 M. E. Green, J. C. Rech and P. E. Floreancig, Angew. Chem., Int.Ed., 2008, 47, 7317–7320.

28 P. J. Kocienski, R. Narquizian, P. Raubo, C. Smith and F. T. Boyle,Synlett, 1998, 1432–1434.

29 P. E. Floreancig, Synlett, 2007, 191–203.30 W. Tu and P. E. Floreancig, Org. Lett., 2007, 9, 2389–2392.31 J. I. C. Pedro de Armas, C. G. Francisco, R. Hern�andez,

J. A. Salazar and E. Su�arez, J. Chem. Soc., Perkin Trans. 1, 1989,405–411.

32 H. A. Reichard, J. C. Rieger and G. C. Micalizio, Angew. Chem., Int.Ed., 2008, 47, 7837–7840.

33 A. C. Hart and A. J. Phillips, J. Am. Chem. Soc., 2006, 128, 1094–1095.

34 J. A. Henderson and A. J. Phillips, Angew. Chem., Int. Ed., 2008, 47,8499–8501.

35 I. Navarro, J.-F. o. Basset, S. v. Hebbe, S. M. Major, T. Werner,C. Howsham, J. BraIckow and A. G. M. Barrett, J. Am. Chem.Soc., 2008, 130, 10293–10298.

36 K. J. Hale, M. G. Hummersone, S. Manaviazar and M. Frigerio,Nat. Prod. Rep., 2002, 19, 413–453.

37 D. J. Newman, Anticancer Agents from Natural Products, 2005, 137–150.

38 P. A. Wender, V. A. Verma, T. J. Paxton and T. H. Pillow, Acc.Chem. Res., 2008, 41, 40–49.

39 B. M. Trost and G. Dong, Nature, 2008, 456, 485.40 G. E. Keck, M. B. Kraft, A. P. Truong, W. Li, C. C. Sanchez,

N. Kedei, N. E. Lewin and P. M. Blumberg, J. Am. Chem. Soc.,2008, 130, 6660.

41 P. A. Wender, B. A. DeChristopher and A. J. Schrier, J. Am. Chem.Soc., 2008, 130, 6658.

42 A. E. Wright, J. C. Botelho, E. Guzman, D. Harmody, P. Linley,P. J. McCarthy, T. P. Pitts, S. A. Pomponi and J. K. J. Reed,J. Nat. Prod., 2007, 70, 412.

43 W. Youngsaye, J. T. Lowe, F. Pohlki, P. Ralifo and J. S. Panek,Angew. Chem., Int. Ed., 2007, 46, 9211.

44 D. W. Custar, T. P. Zabawa and K. A. Scheidt, J. Am. Chem. Soc.,2008, 130, 804–805.

45 O. A. Ulanovskaya, J. Janjic, M. Suzuki, S. S. Sabharwal,P. T. Schumacker, S. J. Kron and S. A. Kozmin, Nat. Chem. Biol.,2008, 4, 418–424.

46 V. V. Vintonyak, B. Kunze, F. Sasse and M. E. Maier, Chem. Eur. J.,2008, 14, 11132–11140.

47 S. K. Woo, M. S. Kwon and E. Lee, Angew. Chem., Int. Ed., 2008,47, 3242.

48 H. Fuwa, S. Naito, T. Goto and M. Sasaki, Angew. Chem., Int. Ed.,2008, 47, 4737–4739.

49 I. Paterson and N. A. Miller, Chem. Commun., 2008, 4708.50 R. Kartika, T. R. Gruffi and R. E. Taylor, Org. Lett., 2008, 10, 5047.51 F. Guella, F. Dini and F. Pietra, Angew. Chem., Int. Ed., 1999, 38,

1134–1136.52 K. C. Nicolaou, H. Zhang, A. Ortiz and P. Dagneau, Angew. Chem.,

Int. Ed., 2008, 47, 8605–8610.53 K. C. Nicolaou, A. Ortiz and H. Zhang, Angew. Chem., Int. Ed.,

2009, 48, 5648–5652.54 K. C. Nicolaou, H. Zhang and A. Ortiz, Angew. Chem., Int. Ed.,

2009, 48, 5642–5647.55 C. F. Nising and S. Braese, Angew. Chem., Int. Ed., 2008, 47, 9389–

9391.56 S. Aoki, Y. Watanabe, M. Sanagawa, A. Setiawan, N. Kotoku and

M. Kobayashi, J. Am. Chem. Soc., 2006, 128, 3148–3149.57 S. Aoki, Y. Watanabe, D. Tanabe, A. Setiawan, M. Arai and

M. Kobayashi, Tetrahedron Lett., 2007, 48, 4485–4488.58 Y. Watanabe, S. Aoki, D. Tanabe, A. Setiawan and M. Kobayashi,

Tetrahedron, 2007, 63, 4074–4079.59 R. A. Shenvi, C. A. Guerrero, J. Shi, C.-C. Li and P. S. Baran, J. Am.

Chem. Soc., 2008, 130, 7241–7243.



Dow

nloa

ded

by D

UK

E U

NIV

ER

SIT

Y o

n 01

Oct

ober

201

0Pu

blis

hed

on 2

2 Ju

ne 2

010

on h

ttp://

pubs

.rsc

.org

| do

i:10.

1039

/B91

9366

AView Online

60 K. C. Nicolaou, Y.-P. Sun, X.-S. Peng, D. Polet and D. Y. K. Chen,Angew. Chem., Int. Ed., 2008, 47, 7310–7313.

61 H. M. Lee, C. Nieto-Oberhuber and M. D. Shair, J. Am. Chem. Soc.,2008, 130, 16864–16866.

62 S. Yamashita, K. Iso and M. Hirama, Org. Lett., 2008, 10, 3413–3415.

63 M. Dai and S. J. Danishefsky, Tetrahedron Lett., 2008, 49, 6610–6612.

64 M. Dai, Z. Wang and S. J. Danishefsky, Tetrahedron Lett., 2008, 49,6613–6616.

65 E. M. Simmons, A. R. Hardin, X. Guo and R. Sarpong, Angew.Chem., Int. Ed., 2008, 47, 6650–6653.

66 L. Kurti, B. Czako and E. J. Corey, Org. Lett., 2008, 10, 5247–5250.67 N. Kotoku, Y. Sumii, T. Hayashi and M. Kobayashi, Tetrahedron

Lett., 2008, 49, 7078–7081.68 D. T. Craft and B. W. Gung, Tetrahedron Lett., 2008, 49, 5931–5934.69 K. Taori, V. J. Paul and H. Luesch, J. Am. Chem. Soc., 2008, 130,

1806–1807.70 Y. Ying, K. Taori, H. Kim, J. Hong and H. Luesch, J. Am. Chem.

Soc., 2008, 130, 8455–8459.71 Y. Ying, Y. Liu, S. R. Byeon, H. Kim, H. Luesch and J. Hong, Org.

Lett., 2008, 10, 4021–4024.72 A. Bowers, N. West, J. Taunton, S. L. Schreiber, J. E. Bradner and

R. M. Williams, J. Am. Chem. Soc., 2008, 130, 11219–11222.73 C. G. Nasveschuk, D. Ungermannova, X. Liu and A. J. Phillips,

Org. Lett., 2008, 10, 3595–3598.74 T. Seiser, F. Kamena and N. Cramer, Angew. Chem., Int. Ed., 2008,

47, 6483–6485.75 A. K. Ghosh and S. Kulkarni, Org. Lett., 2008, 10, 3907–3909.76 Q. Ren, L. Dai, H. Zhang, W. F. Tan, Z. S. Xu and T. Ye, Synlett,

2008, 2379–2383.77 Y. Numajiri, T. Takahashi, M. Takagi, K. Shin-ya and T. Doi,

Synlett, 2008, 2483–2486.78 C.-D. Lu and A. Zakarian, Angew. Chem., Int. Ed., 2008, 47, 6829–

6831.79 X. Wan and M. M. Joullie, J. Am. Chem. Soc., 2008, 130, 17236–

17237.80 MarinLit Database, Department of Chemistry, University of

Canterbury: http://www.chem.canterbury.ac.nz/marinlit/marinlit.shtml.

81 B. W. Gung and A. O. Omollo, J. Org. Chem., 2008, 73, 1067–1070.82 A. C. Giddens, L. Nielsen, H. I. Boshoff, D. Tasdemir, R. Perozzo,

M. Kaiser, F. Wang, J. C. Sacchettini and B. R. Copp, Tetrahedron,2008, 64, 1242–1249.

83 T. J. Greshock, A. W. Grubbs, P. Jiao, D. T. Wicklow, J. B. Gloerand R. M. Williams, Angew. Chem., Int. Ed., 2008, 47, 3573–3577.

84 V. Kumar and A. K. Shaw, J. Org. Chem., 2008, 73, 7526–7531.85 S. Ghosh, S. U. Kumar and J. Shashidhar, J. Org. Chem., 2008, 73,

1582–1585.86 C. K. Skepper, D. S. Dalisay and T. F. Molinski, Org. Lett., 2008,

10, 5269–5271.87 J. Cordes, C. Wessel, K. Harms and U. Koert, Synthesis, 2008, 2217–

2220.88 M. T. Crimmins and J. M. Ellis, J. Org. Chem., 2008, 73, 1649–1660.89 V. Sofiyev, G. Navarro and D. Trauner, Org. Lett., 2008, 10, 149–

152.90 P. T. Seden, J. P. H. Charmant and C. L. Willis, Org. Lett., 2008, 10,

1637–1640.91 C. Hamel, E. V. Prusov, J. Gertsch, W. B. Schweizer and

K. H. Altmann, Angew. Chem., Int. Ed., 2008, 47, 10081–10085.92 A. Niethe, D. Fischer and S. Blechert, J. Org. Chem., 2008, 73, 3088–

3093.93 C. D. Hupp and J. J. Tepe, Org. Lett., 2008, 10, 3737–3739.94 W. Xie, D. Ding, G. Li and D. Ma, Angew. Chem., Int. Ed., 2008, 47,

2844–2848.95 B. Jiang, H. P. Shi, M. Xu, W. J. Wang and W. S. Zhou,

Tetrahedron, 2008, 64, 9738–9744.


96 A. Arda, R. G. Soengas, M. I. Nieto, C. Jimenez and J. Rodriguez,Org. Lett., 2008, 10, 2175–2178.

97 S. Liu, Y.-M. Cui and F.-J. Nan, Org. Lett., 2008, 10, 3765–3768.98 J. A. Lewis, R. N. Daniels and C. W. Lindsley, Org. Lett., 2008, 10,

4545–4548.99 S. J. Eade, M. W. Walter, C. Byrne, B. Odell, R. l. Rodriguez,

J. E. Baldwin, R. M. Adlington and J. E. Moses, J. Org. Chem.,2008, 73, 4830–4839.

100 I. Paterson, M. Razzak and E. A. Anderson, Org. Lett., 2008, 10,3295–3298.

101 S. Li, S. Liang, Z. S. Xu and T. Ye, Synlett, 2008, 569–574.102 A. B. Smith, III, M. O. Duffey, K. Basu, S. P. Walsh,

H. W. Suennemann and M. Frohn, J. Am. Chem. Soc., 2008, 130,420.

103 E. L. Larghi, B. V. Obrist and T. S. Kaufman, Tetrahedron, 2008, 64,5236–5245.

104 T. Yoshimitsu, T. Ino and T. Tanaka, Org. Lett., 2008, 10, 5457–5460.

105 C. C. Chrovian, B. Knapp-Reed and J. Montgomery, Org. Lett.,2008, 10, 811–814.

106 W. C. Jacobs and M. Christmann, Synlett, 2008, 247–251.107 K. Sakaguchi, M. Ayabe, Y. Watanabe, T. Okada, K. Kawamura,

T. Shiada and Y. Ohfune, Org. Lett., 2008, 10, 5449–5452.108 M. Barbazanges, C. Meyer and J. Cossy, Org. Lett., 2008, 10, 4489–

4492.109 H. Fuwa and M. Sasaki, Org. Lett., 2008, 10, 2549–2552.110 M. Ebine, H. Fuwa and M. Sasaki, Org. Lett., 2008, 10, 2275–2278.111 U. Eggert, R. Diestel, F. Sasse, R. Jansen, B. Kunze and M. Kalesse,

Angew. Chem., Int. Ed., 2008, 47, 6478–6482.112 A. C. Flick, M. J. A. Caballero and A. Padwa, Org. Lett., 2008, 10,

1871–1874.113 E. Hohn, J. Palecek and J. Pietruszka, Synlett, 2008, 971–974.114 J. Isaacson, M. Loo and Y. Kobayashi, Org. Lett., 2008, 10, 1461–

1463.115 G. Kumaraswamy and M. Padmaja, J. Org. Chem., 2008, 73, 5198–

5201.116 D. Fishlock and R. M. Williams, J. Org. Chem., 2008, 73, 9594–

9600.117 T. Kawasaki, M. Shinada, M. Ohzono, A. Ogawa, R. Terashima and

M. Sakamoto, J. Org. Chem., 2008, 73, 5959–5964.118 L. Jiao, C. Yuan and Z.-X. Yu, J. Am. Chem. Soc., 2008, 130, 4421–

4430.119 D. Tripathi and P. Kumar, Tetrahedron Lett., 2008, 49, 7012–7014.120 T. Fukuda, E. Sudo, K. Shimokawa and M. Iwao, Tetrahedron,

2008, 64, 328–338.121 J.-P. Feng, Z.-F. Shi, Y. Li, J.-T. Zhang, X.-L. Qi, J. Chen and

X.-P. Cao, J. Org. Chem., 2008, 73, 6873–6876.122 K. Oe, T. Shinada and Y. Ohfune, Tetrahedron Lett., 2008, 49, 7426–

7429.123 H. K. Kwon, Y. E. Lee and E. Lee, Org. Lett., 2008, 10, 2995–2996.124 M. Passiniemi and A. M. P. Koskinen, Tetrahedron Lett., 2008, 49,

980–983.125 A. B. Smith, T. M. Razler, J. P. Ciavarri, T. Hirose, T. Ishikawa and

R. M. Meis, J. Org. Chem., 2008, 73, 1192–1200.126 D. S. Ermolat’ev, V. L. Alifanov, V. B. Rybakov, E. V. Babaev and

E. V. Van der Eycken, Synthesis, 2008, 2083–2088.127 A. B. Smith, J. A. Jurica and S. P. Walsh, Org. Lett., 2008, 10, 5625–5628.128 T.-K. Lum, S.-Y. Wang and T.-P. Loh, Org. Lett., 2008, 10, 761–

764.129 J. D. White, C. M. Lincoln, J. Yang, W. H. C. Martin and

D. B. Chan, J. Org. Chem., 2008, 73, 4139–4150.130 A. B. Smith, T. Tomioka, C. A. Risatti, J. B. Sperry and

C. Sfouggatakis, Org. Lett., 2008, 10, 4359–4362.131 J. R. Dunetz, L. D. Julian, J. S. Newcom and W. R. Roush, J. Am.

Chem. Soc., 2008, 130, 16407–16416.132 P. Sharma, N. Griffiths and J. E. Moses, Org. Lett., 2008, 10, 4025–

4027.

Nat. Prod. Rep., 2010, 27, 1186–1203 | 1203


review01-natural product reports (2010), 27(8), 1186-1203

Documents