Total syntheses of amphidinolides B1, B4, G1, H1 and structure revision of amphidinolide H2

FULL PAPER

DOI: 10.1002/chem.200802067

Total Syntheses of Amphidinolides B1, B4, G1, H1 and Structure Revision of

Amphidinolide H2

Alois Fꢀrstner,* Laure C. Bouchez, Louis Morency, Jaques-Alexis Funel, Vilnis Liepins,

FranÅois-Hugues Porꢁe, Ryan Gilmour, Daniel Laurich, Florent Beaufils, and

Minoru Tamiya^[a]

Abstract: Dinoflagellates of the genus

Amphidinium produce a “library” of

closely related secondary metabolites

of mixed polyketide origin, which are

extremely scarce but highly promising

owing to the exceptional cytotoxicity

against various cancer cell lines. Be-

cause of the dense array of sensitive

functionalities on their largely con-

served macrocyclic frame, however,

these amphidinolides of the B, D, G

and H types elapsed many previous at-

tempts at their synthesis. Described

the promise of making “non-natural”

analogues available by diverted total

synthesis. This notion transpires for a

synthesis-driven structure revision of

amphidinolide H2. The successful route

hinges upon a highly productive Stille–

Migita cross-coupling reaction at the

congested and chemically labile 1,3-

diene site present in all such targets,

which required the development of a

modified chloride- and fluoride-free

protocol. The macrocyclic ring could

be formed with high efficiency and se-

lectivity by ring-closing metathesis

(RCM) engaging a vinyl epoxide unit

as one of the reaction partners. Be-

cause of the sensitivity of the targets to

oxidizing and reducing conditions as

well as to pH changes, the proper ad-

justment of the protecting group pat-

tern for the peripheral -OH functions

also constitutes a critical aspect, which

has to converge to silyl groups only

once the diene is in place. Tris(dime-

thylamino)sulfonium difluorotrimethyl-

silicate (TASF) turned out to be a suf-

ficiently mild fluoride source to allow

for the final deprotection without dam-

aging the precious macrolides.

herein is

a robust, convergent and

Keywords:

macrocyclization

natural products · Stille coupling

anticancer agents

·

hence general blueprint which allowed

not only to conquest five prototype

members of these series, but also holds

·

metathesis

Introduction

structural elements. Particularly distinguishing features are

vicinal one-carbon branches, exo-methylene groups, s-cis-

1,3-diene functions, alkenyl epoxides and, in many cases,

odd-numbered ring sizes.^[1]Low isolation yields, however,

limit the supply of material available from the natural sour-

ces and hence severely hamper the structure elucidation as

well as the in depth biological profiling of these compounds.

Since the preliminary data suggest that all known amphidi-

nolides are highly cytotoxic and some of them even reach

exceptional levels of potency, these marine natural products

constitute rewarding targets for total synthesis.^[3–9]

Much excitement surrounds the amphidinolides, a family of

more than 30 macrolides produced by dinoflagellate strains

of the genus Amphidinium.^[1]Even though many of these

taxonomically rather distinctive unicellular organisms live in

symbiosis with Okinawan Amphiscolops flatworms in the

natural habitat, they can be cultivated in the laboratory in

appropriate seawater media. Their prolific mixed polyketide

biosynthetic machinery^[2]is capable of producing a large va-

riety of molecular frameworks adorned with rather unusual

This is particularly true for the individual members of the

amphidinolide B, D, G and H series, some of which exhibit

IC₅₀values in the picomolar range.^[10–16]This impressive

level of activity allowed meaningful SAR studies to be per-

formed even with the very limited supply of the naturally

occurring “library” of compounds of this sort (Figure 1).

From these investigations it was concluded that the sensitive

s-cis-diene, the ketone at C-20, as well as the alkenyl epox-

ide are mandatory structural elements for high biological ac-

[a] Prof. A. Fꢀrstner, Dr. L. C. Bouchez, Dr. L. Morency,

Dr. J.-A. Funel, Dr. V. Liepins, Dr. F.-H. Porꢁe, Dr. R. Gilmour,

D. Laurich, Dr. F. Beaufils, Dr. M. Tamiya

Max-Planck-Institut fꢀr Kohlenforschung

45470 Mꢀlheim/Ruhr (Germany)

Fax : (+49)208-306-2994

E-mail: fuerstner@mpi-muelheim.mpg.de

Supporting information for this article is available on the WWW

under http://dx.doi.org/10.1002/chem.200802067.

Chem. Eur. J. 2009, 15, 3983 – 4010

ꢂ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

3983

tivity.^[12]Moreover, amphidinolide H1 (9) is known to inter-

fere with the actin cytoskeleton, forming a covalent adduct

with Tyr200 in the critical subdomain 4 of the protein by

opening of its alkenyl epoxide unit.^[17,18]This ligation results

in stabilization of filamentous actin (F-actin) in a phalloidin-

like manner, thus rendering 9 a potentially valuable probe

for chemical biology if the supply of this marine natural

product could be improved. Whether the interaction of 9

with actin is the cause for its truly impressive cytotoxicity

(IC₅₀= 0.52 ngmL^ꢀ1for KB human epidermoid carcinoma

cells),^[10]however, remains to be elucidated.

quired building blocks and optimized procedures for their

assembly, the flexibility inherent to the chosen route could

be garnered, bringing amphidinolide B1 (1), B4 (4), G1

(14), H1 (9) and the putative H2 (10) into reach. In the

latter case, however, the recorded data were inconsistent

with those of the natural product. Based on the acquired

knowledge about the structural subtleties of these com-

pounds we were able to propose a revised structure for this

congener, which matches the reported spectra of amphidino-

lide H2 very well.

Despite considerable interest in the amphidinolides of the

B, H and G groups ever since their isolation,^[19,20]these en-

ticing targets withstood total synthesis for more than a

decade. With the preparation of amphidinolide H1 (9), our

group reported in 2007 the first conquest of any such

target;^[8]more recently, a total synthesis of the regioisomeric

compound amphidinolide B1 (1) by Carter and co-workers

has followed.^[9]Outlined below is a full account of our work

in this area. By virtue of improved access routes to the re-

Results and Discussion

Strategic considerations: The delicacy of the targets tran-

spires, to some extend, from the structures of amphidinolide

B1 (1)^[13]and H1 (9)^[11]in the solid state (Figure 2). Their

rectangular shape allows a strong transannular hydrogen

bond to be formed between the epoxide O-atom and the

-OH at C-21; this interaction also persists in solution.^[11,21]

Figure 1. Naturally occuring “library” of amphidinolides of the B, D, G and H types. Highlighted in red are the structural changes relative to the parent

compound of each particular series.

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Chem. Eur. J. 2009, 15, 3983 – 4010

Total Syntheses of Amphidinolides

FULL PAPER

One might speculate that the

significant distortion of the ox-

irane ring observed in the crys-

tal structure of 9 is a result of

this

intramolecular

activa-

tion.^[11]In any case, the C-8 O

bond (1.470(3) ꢃ) is much

ꢀ

Figure 2. Hydrogen-bonding

interactions determining the

shape of amphidinolide H1 (9)

in the solid state, as evident

from the published X-ray

structure.^[11]

ꢀ

longer than its C-9 O counter-

part (1.448(3) ꢃ), hence facili-

tating attack by a (biological)

nucleophile^[17,18]or even forma-

tion of an allylic cation at this

site.

Scheme 1. Retrosynthetic analysis of amphidinolide H1 (9), representa-

tive for the chosen convergent approach towards all targets of this type

of natural product.

Another remarkable structural attribute is a second intra-

molecular hydrogen bond between the -OH group at C-22

and the oxygen atom at C-18 serving as the acceptor.^[11]This

tight contact constrains the Northeastern sector of 9 in an

envelope-boat shaped eight-membered ring and forces the

neighboring s-cis-1,3-diene out of planarity (ꢀ35.6(5)8). This

twist might actually help stabilizing this unusual structural

element, which is expected to be sensitive to isomerization

to the thermodynamically more favorable internal 1,3-diene

if coplanarity were reached.

lowing a literature route (Scheme 2).^[25]Subsequent reduc-

tion set the stage for a Sharpless epoxidation^[26]to give ep-

oxide 19 which could be regioselectively opened distal to

the -OH group on treatment with Dibal-H in toluene (d.r.

>20:1).^[27]However, it was imperative to quench the reac-

tion with tBuOH at ꢀ608C to avoid cleavage of the primary

TBS ether and hence secure good yields, in particular when

working on a larger scale. Elaboration of 20 into the trisily-

lated product 21 followed by Swern oxidation^[28]of the pri-

mary -OTES ether afforded aldehyde 22, which was subject-

ed to a syn-selective boron glycolate aldol reaction with 23

to give 24 in good yield (d.r. >20:1).^[29,30]Following an O-si-

lylation with premixed TBSOTf and 2,6-lutidine, the result-

ing product 25 was transformed into the corresponding thio-

ester 26, which readily afforded the required methyl ketone

27 on exposure to Me₂CuLi.^[31]Selective removal of the sec-

ondary TES group allowed the unsaturated ester motif to be

installed and hence completed the preparation of 29 as a

fully functional surrogate of the “Southeastern” AB sector

common to all amphidinolides of the H group. As we had to

learn during the course of this investigation that the removal

of the -OPMB group from any advanced intermediates is

difficult once the 1,3-diene function has been installed, an

analogous building block 30 carrying only silyl groups has

also been prepared by straightforward protecting group in-

terchange.

Itaconic acid monoester 31 served as the substrate for the

preparation of the second key fragment (Scheme 3). Its

asymmetric hydrogenation using the excellent phosphite-

based methodology pioneered by Reetz and co-workers al-

lowed multigram amounts of optically pure 33 (97% ee) to

be prepared with low-catalyst loadings (0.15 mol%).^[32]The

necessary adjustment of the oxidation states of the termini

upon elaboration into aldehyde 34, however, required a

number of protecting group manipulations. Even though

these operations are high yielding and can be performed on

large scale,^[8]we decided to develop an alternative route to

this key intermediate. Albeit an auxiliary^[33,34]rather than a

chiral catalyst forms its basis, the sequence is distinctly

shorter (35 ! 37 ! 34). Aldehyde 34 was then homologat-

ed with the aid of the Bestmann–Ohira reagent 42^[35]to give

alkyne 38, which underwent a smooth carboalumination/io-

The individual amphidinolides of the B, D, G, and H

series are largely isomeric to each other (Figure 1), showing

up to three structural “point mutations” in the various sec-

tors of a conserved backbone; the seco-acid then forms

either a 26-membered (B, D, and H series) or a 27-mem-

bered lactone ring (G series).^[1,10–16]To cope with this struc-

tural diversity, any general synthetic approach must be

highly convergent. As exemplified in Scheme 1 for amphidi-

nolide H1 (9),^[10]we envisaged to assemble the basic skele-

ton from four building blocks A–D by esterification, an

aldol reaction, metal-catalyzed cross-coupling, and olefin

metathesis; proper modifications of these fragments should

allow for the preparation of any of the targets shown in

Figure 1 by following this basic blueprint. At the outset of

the project, however, it was by no means obvious in which

order these crucial operations should be executed. While re-

lated aldol reactions had already served in different pub-

lished model studies,^[19,20]we were somewhat concerned

about the cross-coupling step in view of a literature report,

wherein a highly advanced synthesis of 1 had to be aban-

doned because a late-stage Stille–Migita reaction^[22]meant

to install the 1,3-diene met with complete failure.^[20a]Like-

wise, inter- as well as intramolecular metathesis reactions of

alkenyl epoxides are surprisingly rare.^[23,24]As the oxirane in

9 is highly distorted and its reactivity is key—at least in

part—for the biological activity of this particular natural

product, the likelihood of productive macrocyclization at

ꢀ

the C6 C7 double bond adjacent to this reactive functionali-

ty was difficult to forecast. Therefore, the orchestration of

the final assembly process had to evolve on the basis of the

knowledge gathered en route to the targets.

Preparation of the building blocks: Our venture began with

Roche ester 17, which was converted into enoate 18 by fol-

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3985

A. Fꢀrstner et al.

Scheme 2. a) TBSCl, imidazole, DMF; b) Dibal-H, CH₂Cl₂, ꢀ788C; c)

DMSO, (COCl)₂, Et₃N, CH₂Cl₂, ꢀ788C RT; d) (iPr)₂NEt, LiCl,

(EtO)₂P(O)CH₂COOEt, MeCN, 69% (over four steps); e) Dibal-H,

CH₂Cl₂, ꢀ788C, 78%; f) (+)-DET, Ti(OiPr)₄cat., tBuOOH, MS 4 ꢃ,

!

AHCTUNGTRENNUNG

CH₂Cl₂, ꢀ208C, 74% (93% de); g) i) Dibal-H, toluene, ꢀ408C; ii)

tBuOH/THF, ꢀ608C ! RT, 78%; h) i) TBDPSCl, imidazole, CH₂Cl₂,

91%; ii) PPTS, EtOH, 558C; iii) TESCl, imidazole, CH₂Cl₂, 87% (over

both steps); i) DMSO, (COCl)₂, (iPr)₂NEt, CH₂Cl₂, ꢀ788C ! RT, 68 %;

j) 23, Bu₂BOTf, toluene, ꢀ50 ! ꢀ308C, 82%; k) TBSOTf, 2,6-lutidine,

CH₂Cl₂, 08C, 81%; l) EtSH, nBuLi, THF, 08C, 87%; m) CuI, MeLi

(2 equiv), Et₂O, ꢀ60 ! ꢀ108C, 89%; n) PPTS, EtOH, 56%; o) 28, DCC,

DMAP, CH₂Cl₂, 75%; p) DDQ, CH₂Cl₂, 52%; q) TESCl, imidazole,

DMAP, DMF, 458C, 79%. DET=diethyl tartrate, DMAP=4-dimethyl-

aminopyridine, TBDPS=tert-butyldiphenylsilyl, PPTS=pyridinium p-tolu-

enesulfonate, TES=triethylsilyl, TBS=tert-butyldimethylsilyl, MS=mo-

lecular sieves.

Scheme 3. a) [RhACHTNUTRGNEG(UN cod)₂]BF₄(0.15 mol%), 32 (0.3 mol%), H₂(1 atm),

1,2-dichloroethane, 99% (97% ee); b) i) LDA, LiCl, THF, ꢀ788C; ii)

tert-butyl-(2-iodoethoxy)diphenylsilane, ꢀ78 ! 08C, 98%; c) BH₃·NH₃,

LDA, THF, 08C ! RT, 96%; d) DMSO, (COCl)₂, Et₃N, CH₂Cl₂, ꢀ788C

! RT, 94 %; e) 42, NaOMe, THF, 67%; f) i) Me₃Al, [Cp₂ZrCl₂], 1,2-di-

chloroethane; ii) I₂, THF, ꢀ208C, 71–97%; g) TBAF, THF, 98%; h)

DMP, NaHCO₃, aq. CH₂Cl₂, 08C ! RT, 98 %. TBAF =tetra n-butylam-

monium fluoride, DMP=Dess Martin periodinane.

erationally simple and high yielding route. Subsequent

Dibal-H reduction followed by Sharpless epoxidation of the

resulting allylic alcohol installed the oxirane in 52 with high

diastereocontrol (98% de). A regioselective and nicely

scaleable palladium catalyzed silylstannation of the alkyne

unit in 53 with commercial Bu₃SnSiMe₃,^[37]followed by con-

dination with formation of 39.^[36]This product as well as al-

dehyde 41 derived thereof were then used as appropriate

surrogates of fragment D in the assembly process.

The original approach to the third key fragment C bor-

rowed the chiral methyl branch from (S)-citronellal (43, ee

>99%) (Scheme 4). After conversion of the aldehyde to an

alkyne, two consecutive chemoselective ozonolysis reactions

were necessary to adjust the carbon backbone of the “chiral

pool” derived material to the current needs.^[8]Even though

this sequence can be performed on larger scale, the high vol-

atility of the intermediates makes their purification tedious

and adversely affects the reproducibility of the route. As a

consequence, an alternative approach based on Myers auxil-

iary ent-35^[33]was developed which avoids such inconvenien-

ces. Once the methyl branch was set by asymmetric alkyla-

tion, product 48 could be elaborated into ester 46 by an op-

ꢀ

comitant cleavage of the C Si and O Si bonds in 54 with

TBAF in DMSO constitutes the key element of the chosen

route to stannane 55 as the envisaged surrogate of fragment

C.

Intelligence gathering: With a good supply of the required

building blocks secured, the development of a reliable as-

sembly process became the immediate next goal. In the light

of an important literature precedent, which reports the fail-

ure of an attempted late-stage Stille–Migita reaction for the

formation of the sensitive s-cis-1,3-diene motif of the targets

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Chem. Eur. J. 2009, 15, 3983 – 4010

Total Syntheses of Amphidinolides

FULL PAPER

It was only after extensive investigation that a modified

procedure could be found that allowed this critical transfor-

mation to be performed without any of these deleterious

side reactions occurring (Scheme 5). Specifically, a combina-

ꢀ

+

Scheme 5. a) [Pd

82%; b) DMP, NaHCO₃, CH₂Cl₂, 08C ! RT; c) [Ph₃PCH₃]Br, Na[N-

(SiMe₃)₂], THF, 08C, 65%; d) TBAF, THF, 87%; e) DMP, NaHCO₃, aq.

ACHTNUGTERNN(NUG Ph₃P)₄] (10 mol%), CuTC, Ph₂PO₂NBu₄, DMF,

AHCTUNGTRENNUNG

CH₂Cl₂, 08C ! RT; 75 %; f) 29, LDA, THF, ꢀ788C, 52%; g) 60,

Scheme 4. a) 42, NaOMe, THF; b) O₃, CH₂Cl₂, ꢀ788C, then Me₂S; c) i)

TBSOTf, Et₃N, CH₂Cl₂, ꢀ208C; ii) O₃, CH₂Cl₂, ꢀ788C, then Me₂S; e)

(EtO)₂P(O)CH₂COOEt, NaH, THF, 69%; or: 25% (over five steps a) !

e), see main text); f) LDA, LiCl, THF, then 47, ꢀ78 ! 08C, 97%; g)

(10 mol%); C₆H₆, 73%. CuTC=copper thiophene-2-carboxylate

.

BH₃NH₃, LDA, THF, 08C ! RT, 80%; h) TsCl, Et₃N, DMAP, CH₂Cl₂,

tion of [Pd

ACHTUNGTRENNUNG

08C ! RT, 72%; i) KCN, DMSO, 808C, 67%; j) Dibal-H, CH₂Cl₂,

ꢀ788C; k) TBAF, THF, 08C ! RT, 66% (over both steps); l) Dibal-H,

(CuTC),^[39]and [Ph₂PO₂]^ꢀ

AHCTUNGTRENNUNG

THF, ꢀ788C, 82%; m) (+)-DET, Ti

ACHTUNGTNER(NUGN OiPr)₄cat., tBuOOH, MS 4 ꢃ,

CH₂Cl₂, ꢀ208C, 58% (98% de); n) TBSCl, imidazole, DMAP, CH₂Cl₂,

tive. Although the use of each individual ingredient has

precedence in the extensive literature on Stille–Migita reac-

tions, their combination is unique and allows to cope with

fragile functionalities as well as with different C- and O-silyl

protecting groups.^[41]Only this particular chloride- and fluo-

ride-free recipe afforded the desired cross-coupling product

56 in excellent yield, uncontaminated with isomerized diene.

As the reaction can be performed at ambient temperature,

the risk of thermal decomposition of the sensitive material

is also minimized. It is worth mentioning that this new pro-

cedure has already served very well in other highly demand-

ing cases in our laboratory.^[41–43]

Compound 56 was then transformed to the intact “West-

ern” sector of amphidinolide H1 by oxidation of the epoxy

alcohol with Dess–Martin periodinane,^[44]Wittig olefination,

cleavage of the silyl ether on the other terminus, and oxida-

tion. Fragment coupling of the resulting aldehyde 57 was ac-

complished on treatment with the kinetic lithium enolate of

ketone 29, affording aldol (S)-58 as a single isomer in 52%

unoptimized yield. The excellent level of stereoinduction is

ascribed to the 1,4-anti directing effect exerted by the

98%; o) Bu₃SnSiMe₃, [Pd(Ph₃P)₄] (2 mol%), 1,2-dimethoxyethane

AHCTUNGTRENNUNG

(DME), sealed tube, 1008C, 79–85%; p) TBAF, DMSO, 808C, 79%.

in question,^[20a]it was planned to address this critical step

early on. Our initial attempts to effect this transformation,

however, reiterated the difficulties inherent to this particular

transformation. Specifically, all our efforts to join the sensi-

tive and sterically hindered coupling partners 39 and 55 by

following the well established protocols were in vain.^[38]

Whereas the use of different palladium catalysts without fur-

ther additives led to poor conversions, all attempts to boost

the reactivity with the aid of copper co-catalysts and/or vari-

ous fluoride sources resulted in hardly tractable mixtures.

Even though not fully analyzed, inspection of the resulting

crude material showed that oxidative dimerization of the

stannane, isomerization of the coupling product to the more

stable internal 1,3-diene, partial cleavage of the silyl protect-

ing groups, and destruction of the fragile epoxy alcohol had

interfered.

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3987

A. Fꢀrstner et al.

-OPMB substituent flanking the enolate.^[45,46]This hypothe-

sis was corroborated by the fact that the corresponding

ketone 30 bearing an -OTES ether at C-21 instead of the

-OPMB group, upon enolization and reaction with aldehyde

57, gave a poor 2:1 ratio of the two possible aldol diastereo-

mers 61 (Scheme 6). Not only was this mixture difficult to

separate, but the Mosher analysis^[47]showed that the major

isomer had the undesirable R configuration, opposite to the

one produced in the -OPMB case.

correct adjustment of the protecting groups is critical. Be-

cause of the sensitivity of the material, the final deprotec-

tion steps require notably mild conditions, whereas the aldol

reaction needs bias from an adjacent donor site able to

ligate the metal enolate intermediate.

The necessary compromise between these opposing needs

was reached by changing the order of the fragment coupling

events. Specifically, the Stille–Migita reaction was postponed

until after the aldol step and elaboration of the proper pro-

tecting group regimen. To this end, the lithium enolate of 29

was reacted with the iodine-containing aldehyde 41 to give

aldol 62 in good yield and appreciable selectivity (d.r.

>10:1) (Scheme 7). Once the newly formed alcohol had

been masked as a TBS ether, the protecting group at O-21

in 63 was swapped from PMB to TES. Gratifyingly, the

cross-coupling of the elaborate vinyl iodide 64 thus formed

Scheme 6. a) LDA, THF, ꢀ788C, then 57, 50–60% (d.r. ꢁ2:1).

Although only a few metathesis reactions of vinyl epox-

ides had previously been reported,^[23]exposure of 58 to cata-

lytic amounts of the second generation Grubbs carbene

complex 60^[48,49]at ambient temperature afforded the de-

sired 26-membered cycloalkene 59 in 73% yield as a single

E isomer (³J_H6,H7=18 Hz) (Scheme 5). Interestingly, the re-

action proceeded only in benzene as the solvent, whereas

the use of CH₂Cl₂resulted in marginal conversion under

otherwise identical conditions. This provides a striking illus-

tration of our previous observation that second generation

ruthenium carbene catalysts may exhibit (much) higher re-

activity in aromatic media as compared to the widely used

chlorinated solvents.^[50]

With the macrocycle closed, the completion of the total

synthesis of amphidinolide H required only the cleavage of

the oxygen protecting groups. Whereas the silyl ethers could

be deprotected with the aid of TASF as a particularly mild

fluoride source,^[51–53]all attempts to remove the PMB ether

were met with failure. The destruction of the valuable mate-

rial is ascribed to an uncontrolled oxidation of the diene

that occurs at a competitive rate on treatment with either

DDQ or CAN.^[54,55]This notion is corroborated by the fact

the acyclic diene 58 was equally destroyed, whereas depro-

tection of methyl ketone 29 devoid of the diene afforded

the corresponding alcohol without incident (Scheme 2). Un-

fortunately, acidic or reductive conditions previously used in

the literature for the cleavage of PMB ethers equally met

with failure when applied to 59.^[54]

Scheme 7. a) LDA, THF, ꢀ788C, 70%; b) TBSOTf, 2,6-lutidine, CH₂Cl₂,

08C ! RT, 79–94%; c) DDQ, CH₂Cl₂/H₂O, 55–62%; d) TESCl, imida-

Total syntheses of amphidinolide H1 and G1: Although the

synthetic venture summarized above had ultimately failed,

important lessons could be drawn from it. Whereas the

cross-coupling and the metathesis events, which seemed

problematic at the outset, could be cleanly effected under

optimized conditions, it became obvious that the choice and

zole, DMAP, DMF, 458C, 79%; e) 55, [PdACTHNUTRGNEUNG(Ph₃P)₄] (0.7 equiv), CuTC,

ꢀ

+

Ph₂PO₂NBu₄

,

DMF, 89%; f) DMP, NaHCO₃, CH₂Cl₂, 08C; g)

(SiMe₃)₂], THF, 08C, 65% (over both steps); h) 60

[Ph₃PCH₃]Br, Na[NAHCTUNGTRENNUNG

(10 mol%), C₆H₆, 68–72%; i) TASF, aq. THF/DMF (10:1), 08C ! RT,

55%; j) HCl cat., CHCl₃, 9/14 ꢁ3:1. TASF=tris(dimethylamino)sulfoni-

um difluorotrimethylsilicate.

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Chem. Eur. J. 2009, 15, 3983 – 4010

Total Syntheses of Amphidinolides

FULL PAPER

with stannane 55 worked remarkably well under the previ-

ously optimized conditions. However, it was necessary to in-

crease the catalyst loading to ensure complete conversion of

these encumbered partners at ambient temperature. The re-

sulting product 65 was then converted into vinyl oxirane 66,

which underwent a clean RCM reaction to give 67 as the re-

quired E isomer only. Because of the sensitivity of the com-

pound, it was again imperative to perform the macrocycliza-

tion at < 308C. Finally, treatment of 67 with excess TASF

allowed us to discard all silyl ethers, thus affording amphidi-

nolide H1 in analytically pure form. Its spectroscopic prop-

erties were in good accord with the published data (cf.

Tables 1–3 in the Experimental Section).^[10,56]Moreover, syn-

thetic 9 could be equilibrated with the ring expanded 27-

membered congener amphidinolide G1 (14) under slighly

acidic conditions.^[10]Since these two isomers are separable

by HPLC, a total synthesis of the latter has also been ach-

ieved.^[56]

extremely scarce metabolite of a recently collected Amphi-

dinium strain (Y-100) exhibits exceptional potency, although

only two cancer cell lines have been screened so far.^[15]

The modified polyhydroxylated Eastern sector to be in-

corporated into its frame was again obtained by a syn-selec-

tive glycolate aldol reaction^[29]between 23 and aldehyde 69,

which was prepared by alkylation of 35 with (R)-propenox-

ide^[57]as the matched electrophile,^[58]followed by appropri-

ate oxidation state management (Scheme 8). The subsequent

elaboration of product 70 followed the established route,

except that the attachment of the ester moiety to C-25 had

to occur with inversion of configuration (74 ! 75).^[59]

A

high yielding Mitsunobu reaction^[60]served this purpose

well. Upon deprotonation with LDA in Et₂O at low temper-

ature, the resulting methyl ketone 75 added to aldehyde 41

to give both diastereomeric aldol products 76 in a 3.2:1

ratio.^[61]The reason why this particular transformation

shows significantly lower selectivity than the corresponding

aldol reaction en route to amphidinolide H1 is not entirely

clear. Since the two isomers were separable by routine chro-

matography, however, no attempt was made to further opti-

mize this transformation. Rather, (S)-76 was advanced to

the cyclization precursor 80 by applying the successful se-

quence of protecting group swap at O-21 and Stille–Migita

cross-coupling to install the 1,3-diene; in line with our ex-

Amphidinolide B4: Next, we set out to probe the generality

of the synthesis blueprint underlying the successful conquest

of amphidinolide H1. Amphidinolide B4 (4)^[15]was chosen

as target for the initial foray, because it constitutes a fairly

close relative; it only lacks the hydroxy group at C-26 and

hence requires adjustment of a single building block. This

Scheme 8. a) LDA, LiCl, THF ꢀ788C ! RT, then (R)-propenoxide, ꢀ58C, 98% (85% de); b) TESCl, Et₃N, DMAP, CH₂Cl₂; c) BH₃·NH₃, LDA, THF,

08C ! RT, 80% (over both steps); d) TPAP, NMO, CH₂Cl₂; e) 23, Bu₂BOTf, Et₃N, toluene, ꢀ408C, 62% (over both steps); f) TESCl, imidazole,

CH₂Cl₂, 80%; g) EtSH, nBuLi, THF, 08C, 90%; h) CuI, MeLi (2 equiv), Et₂O, ꢀ608C, quant.; i) PPTS, EtOH, ꢀ158C, 89%; j) acid 28, DIAD, PPh₃, tol-

uene, 91%; k) LDA, Et₂O, ꢀ788C, then 41, 58% (d.r. 3.2:1); l) TBSOTf, 2,6-lutidine, CH₂Cl₂, 08C, 81%; m) DDQ, CH₂Cl₂/H₂O, 73%; n) TESCl, imida-

ꢀ

zole, DMAP, DMF, 81% (over both steps); o) 55, [Pd

ACHTUNGTRENNUNG

q) Ph₃P=CH₂, THF, 08C, 44% (over both steps); r) 60 (10 mol%), C₆H₆, 84%; s) TASF, aq. THF/DMF 10:1, 08C, 58%. DIAD=diisopropylazodicar-

boxylate, TPAP=tetrapropylammonium perruthenate, NMO=N-methylmorpholine-N-oxide.

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3989

A. Fꢀrstner et al.

pectations, this crucial frag-

ment coupling event again pro-

ceeded in excellent yield using

the newly developed proto-

col.^[41]After transformation of

the hydroxy epoxide in 79 to

the corresponding vinyl oxir-

ane 80, the material was sub-

jected to RCM, which pro-

duced the required macrocycle

81 in 84% yield as a single ste-

reoisomer. Finally, the total

synthesis of amphidinolide B4

(4) was completed by removal

of the peripheral silyl ethers

with the aid of TASF.^[51–53]The

analytical and spectroscopic

data of the synthetic samples

were in excellent agreement

with the reported spectra of

this precious marine natural

product (cf. Experimental Sec-

tion).^[15]

Amphidinolide B1: Amphidi-

nolide B1 (1)^[9,13,14,20]is a more

stringent test for the generality

of the chosen approach than

the previous example, because

it features a tertiary alcohol

rather than a simple methyl

branch at C-16. This site flanks

Scheme 9. a) LDA, THF/Et₂O, ꢀ788C, 54%; b) LiBH₄, THF, MeOH, 90%; c) TESCl, imidazole, DMAP,

DMF, 88%; d) i) nBuLi, Bu₃Sn–SnBu₃, CuCN, MeI; ii) I₂, CH₂Cl₂, 90% (over both steps); e) TESCl, Et₃N,

imidazole, DMAP, 84%; f) DMSO, (COCl)₂, Et₃N, CH₂Cl₂, ꢀ788C ! RT, quant.; g) 75, LDA, Et₂O, 45%; h)

TBSOTf, 2,6-lutidine, CH₂Cl₂, 08C, 86%; i) DDQ, CH₂Cl₂/H₂O, 0 8C ! RT, 92%; j) TESCl, imidazole,

ꢀ

DMAP, DMF, 75%; k) 55, [Pd

N

CH₂Cl₂, 08C ! RT; m) PPh₃=CH₂, THF, 08C, 52% (over two steps); n) 60 (10 mol%), C₆H₆, 91%; o) TASF,

aq. DMF, 08C, 93%.

the sensitive 1,3-diene moiety and hence provides additional

steric impediment for the Stille–Migita coupling, notably

when the -OH carries a bulky silyl protecting group. From

the biological point of view, 1 retains one of the top posi-

tions amongst the amphidinolides known to date (IC₅₀=

0.00014 mgmL^ꢀ1(L1210 murine lymphoma); IC₅₀=

0.0042 mgmL^ꢀ1(KB human epidermoid carcinoma); IC₅₀=

0.122 mgmL^ꢀ1(HCT116 human colon cancer)).^[13,14]

The modified Northern segment to be incorporated into

the framework of this target was prepared as shown in

Scheme 9. An Evans aldol reaction of 82 with alkynyl

ketone 83 furnished 84 as the major isomer (d.r. 7.2:1).^[30]

Reduction with LiBH₄followed by bis-silylation set the

reaction was much improved and occurred in essentially

quantitative yield when the corresponding di-TES ether 88

was employed. Even though this requires reprotection of 87

and hence renders the sequence one step longer, this variant

is prefered for its higher efficiency.

With aldehyde 89 in hand, the assembly of amphidinolide

B1 was accomplished by following the route outlined above.

Thereby, it was the aldol reaction with methyl ketone 75

which was the least productive step of the entire sequence.

In contrast, the challenging Stille–Migita cross-coupling,

when performed under the newly developed conditions,^[41]

was insensitive to the increased steric bulk in the electro-

philic component 92, delivering the desired 1,3-diene prod-

uct 93 in remarkably high yield. Likewise, the cyclization of

the macrolactone ring by RCM (94 ! 95) occurred un-

eventfully and stereoselectively. Synthetic amphidinolide B1

(1) matched the data of the natural sample in every regard

(see the Experimental Section).^[9,13,14]

stage for

a carbostannation/iodination of the terminal

alkyne in 86. In contrast to the literature, however, this

transformation was best performed with a Gilman-type stan-

nyl cuprate rather than the “higher order” stannyl cuprates

previously recommended,^[62]which led to significant decom-

position in our case.^[63]Under the optimized conditions, the

reaction was exceptionally clean and afforded 90% yield

over two steps. Since the primary TES-ether of the substrate

was cleaved during the iodination, the resulting alcohol 87

could be directly converted into the corresponding aldehyde

89 with the aid of Dess–Martin periodinane (57%)^[44]or by

Swern oxidation (55%).^[28]Interestingly, however, the Swern

Amphidinolide H2—Preparation and structure revision: A

subset of the amphidinolides of the B/H/G types, that is

compounds 5, 10, 13, 15, is reported to show a stereochemi-

cal relationship between the methyl branch at C-16 and the

hydroxyl group at C-18 opposite to that of amphidinolide

H1.^[1]To demonstrate that our approach can also cope with

3990

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Chem. Eur. J. 2009, 15, 3983 – 4010

Total Syntheses of Amphidinolides

FULL PAPER

products of this type, we undertook the total synthesis of

amphidinolide H2 (10).^[12]

As evident from Figure 3, substantial deviations were re-

ꢀ

corded for the “south-western” C-6 C-13/C-28 sector. This

The required fragment ent-41 was prepared by following

the sequence depicted in Scheme 3 using the enantiomeric

auxiliary ent-35. Not unexpectedly, addition of alkali eno-

lates of 30 to this aldehyde afforded the—in this case unde-

sired—aldol (S)-96 as the major product.^[64]Gratifyingly,

however, the corresponding boron enolate, derived from 30

on treatment with Cy₂BCl and Et₃N, furnished the required

compound (R)-96 in a workable 4:1 ratio (Scheme 10).^[45]

After removal of the minor isomer by flash chromatography,

the product was elaborated into compound 99 by following

the established route; the configurational changes did not

diminish the efficiency of the Stille–Migita fragment cou-

pling at all (97 ! 98). In contrast, the macrocyclization of

99 was somewhat less efficient and also gave small amounts

of the isomeric (Z)-alkene 100 (E/Z 5.2:1). This outcome il-

lustrates how subtle changes at remote sites of a given cycli-

zation precursor can substantially alter the stereochemical

course of ring-closing metathesis reactions catalyzed by

Grubbs-type ruthenium carbene complexes.^[65]Removal of

the protecting groups with TASF then furnished 10 pro-

posed to represent amphidinolide H2. However, the record-

ed spectra of this compound unmistakably deviated from

result was unexpected because this region is strictly con-

served within all amphidinolides of the B/D/G/H series

known to date (cf. Figure 1).^[1]As evident from the X-ray

structures of 1^[13]and 9,^[11]however, the C-6 C-13 segment

ꢀ

entertains a close transannular relationship with the poly-

hydroxylated sector of the molecule through a strong meri-

dial hydrogen bond engaging the epoxide

O atom

(Figure 2). Therefore we contemplated that the observed

ꢀ

mismatch at C-6 C-13 may actually report a stereochemical

misassignment in the transannular region of this particular

macrolide, residing somewhere between C-16 and C-23.

Under this premise, it seemed likely that the hydroxyl group

at C-21 might be a “hot-spot” since the epoxide directly

connects to this site. Moreover, the shift difference of no

less than Dd=ꢀ1 ppm of the aldol at C-18, which is known

to engage in a hydrogen bond with the -OH group at C-

22,^[11]also raises doubts about the assignment of this latter

chiral center.^[68]In view of these data and in consideration

of the other known amphidinolides (Figure 1),^[1]we pre-

sumed that structures 101 or 102, which solely differ from

each other by the configuration of C-16, might possibly rep-

resent amphidinolide H2. Among them, 102 seemed more

likely, because the methyl branches C-30 and C-31 in 10 also

show appreciable deviations from the reported values

(Figure 3).

1

the reported H and ¹³C NMR data of the natural product

(see Table 8 in the Experimental Section for the full data

set).^[12,66,67]

Compound 102 was hence prepared in a stereochemically

unambiguous manner for comparison with the natural prod-

uct (Scheme 11). This goal was attained by using the antipo-

dal auxiliary ent-23 for a syn-glycolate aldol reaction with

aldehyde 22.^[29]With the resulting product 103 in hand, it

sufficed to follow the customary route to the required cycli-

zation precursor 109. The only modification lies in the aldol

Scheme 10. a) 30, Cy₂BCl, Et₃N, ꢀ78 ! ꢀ208C, then H₂O₂, pH 7 buffer,

58% (d.r. 4:1); b) TBSOTf, 2,6-lutidine, CH₂Cl₂, 08C, 89%; c) 55, [Pd-

ACHTUNGTRENNUNG(Ph₃P)₄] (0.7 equiv), CuTC, Ph₂PO₂NBu₄, DMF, 87%; d) DMP,

NaHCO₃, CH₂Cl₂, 08C ! RT; e) PPh₃=CH₂, THF, 08C, 57% (over both

steps); f) 60 (10 mol%), C₆H₆, 56% (E/Z 5.2:1); g) TASF, aq. DMF, 08C,

46%.

Figure 3. Characteristic shift differences (Dd_C) between the ¹³C NMR

data of amphidinolide H2 and synthetic 10, which corresponds to the

originally proposed structure. The regions showing the biggest mismatch

are highlighted in red (for the full data set, see Table 8 in the Experimen-

tal Section). Two possible revised structures that might represent the nat-

ural product, cf. main text.

ꢀ

+

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3991

A. Fꢀrstner et al.

Conclusion

The delicacy and dense array of functional groups decorat-

ing the conserved carbon framework of the amphidinolides

of the B/D/G/H types impeded their synthesis for many

years. Gratifyingly, however, we were able to devise a

robust entry into this class of extremely scarce but expetion-

ally potent anticancer agents of marine origin. The conver-

gency of the chosen route holds the promise that each

member of this family should be available upon suitable

modification of the required four basic building blocks. This

notion is supported by the fact that a set of five representa-

tive members has been prepared by such simple adaptations

without need to change the underlying synthesis blueprint

to any significant extent. The appreciable overall yields illus-

trate the reliability of the approach, even though not all

steps were fully optimized for each individual analogue pre-

pared during this campaign. Moreover, the fact that the syn-

thesis can be readily diverted from a given to a conceived

target was instrumental for the structure revision of amphi-

dinolide H2. The inherent flexibility expressed in these ex-

amples should enable a more profound and systematic edit-

ing of the molecular architecture and hence could power a

detailed evaluation of the cytotoxicity profile and actin-

binding capacity of these valuable lead compounds.^[69]Al-

though dealing with a different type of amphidinolides, our

first attempts along such lines are outlined in the accompa-

nying papers.^[70,71]

Key to success of this synthetic endeavour was a careful

adjustment of the protecting groups as well as the develop-

ment of a highly productive protocol for Stille–Migita cross-

coupling of alkenyl iodides,^[41–43]which allowed the conspicu-

ous but very sensitive s-cis-1,3-diene unit of the targets to be

installed with high efficiency, despite the bulk of the reac-

tion partners. It is anticipated that this method should pay

dividends in other demanding settings too. Moreover, the re-

markable ease of formation of the macrocyclic frame by

RCM at the activated alkenyl oxirane site constitutes yet an-

other triumph for Grubbs-type second-generation cata-

lysts,^[48–50]and augurs well for further metathesis reactions of

vinyl epoxides,^[23]which remained a relatively unexplored

class of alkenes despite the vast literature on metathesis in

general that has accumulated during the last decade.^[24]

Scheme 11. a) Bu₂BOTf, Et₃N, toluene, ꢀ508C, then aldehyde 22, 82%;

b) TBSOTf, 2,6-lutidine, 08C; c) EtSH, nBuLi, THF, 08C, 61% (over

both steps); d) CuI, MeLi (2 equiv), Et₂O, ꢀ60 ! ꢀ208C; e) PPTS,

EtOH, 69% (over both steps); f) acid 28, DCC, DMAP, CH₂Cl₂, 73%; g)

DDQ, CH₂Cl₂/H₂O, 0 8C ! RT; h) TESCl, imidazole, DMAP, DMF,

508C, 65% (over both steps); i) LDA, THF, ꢀ788C, then aldehyde 57,

49%; j) 60 (10 mol%), C₆H₆, 54%; k) TASF, aq. THF/DMF 4:1, 08C,

80%.

reaction, which was best performed with the TES-ether de-

rivative 108 rather than its O-PMB congener 107. As this

avoids a subsequent protecting group interchange at O-21,

the fragment coupling can be performed with excellent se-

lectivity (d.r. >20:1) using the more advanced aldehyde 57,

which already contains the sensitive 1,3-diene entity. The

ring-closing metathesis and ultimate silyl cleavage per-

formed well. It was gratifying to see that the NMR spectra

of the resulting product 102 recorded at 600 MHz were in

excellent agreement with the published data of amphidino-

lide H2 (see Table 8 in the Experimental Section).^[12]Even

though we are aware that the ultimate proof would require

preparation of all possible stereoisomers and their direct

comparison with an authentic sample, the striking match

provides compelling evidence that the stereostructure of am-

phidinolide H2 needs to be revised from 10 to 102.^[67]

Experimental Section

General: All reactions were carried out under Ar in flame-dried glass-

ware. The solvents used were purified by distillation over the drying

agents indicated and were transferred under Ar: THF, Et₂O (Mg/anthra-

cene), CH₂Cl₂, Et₃N, CH₃CN, DMSO, (CaH₂), hexane, toluene (Na/K),

DMF (Desmodur 15, dibutyl tin dilaurate), MeOH, EtOH (Mg). Flash

chromatography (FC): Merck silica gel 60 (230–400 mesh). NMR: Spec-

tra were recorded on Bruker DPX 300, AMX 300, AV 400, AV 400,

DPX 600 and AVIII 600 spectrometer in the solvents indicated; chemical

shifts (d) are given in ppm relative to TMS, coupling constants (J) in Hz.

The solvent signals were used as references and the chemical shifts con-

verted to the TMS scale (CDCl₃: d_C=77.0 ppm; residual CHCl₃in

CDCl₃: d_H=7.26 ppm; CD₂Cl₂: d_C=53.8 ppm; residual ¹H: d_H=

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Total Syntheses of Amphidinolides

FULL PAPER

5.32 ppm; CD₃OD d_C=49.0 ppm; residual ¹H: d_H=3.30 ppm;

[D₈]acetone: d_C=29.8 ppm; residual ¹H: d_H=2.05 ppm). Where indicat-

ed, the signal assignments are unambiguous; the numbering scheme is ar-

bitrary as shown in the inserts. The assignments are based upon 1D and

2D spectra recorded using the following pulse sequences from the

Bruker standard pulse program library: DEPT; COSY (cosygs, cosydqtp,

and cosygpqf); HSQC (invietgssi, and hsqcedetgpsisp².2) optimized for

1020, 999, 971, 945, 837, 790, 665 cm^ꢀ1; HRMS (ESI): m/z: calcd for

C₁₆H₂₄SSi [M⁺+H]: 325.1291, found: 325.1293.

Compound 51: KCN (400 mg, 6.1 mmol) was added to a solution of tosy-

late 50 (1.0 g, 3.08 mmol) in DMSO (15 mL) and the resulting mixture

was stirred for 12 h at 808C. For work up, the mixture was diluted with

sat. aq. NaHCO₃(200 mL) and Et₂O (200 mL), the aqueous layer was ex-

tracted with Et₂O (2ꢄ150 mL), the combined organic phases were

washed with brine (2ꢄ150 mL), dried over Na₂SO₄and evaporated. Pu-

rification of the residue by flash chromatography (hexanes/tert-butyl

methyl ether 20:1) provided product 51 as a yellow oil (369 mg, 67%).

¹H NMR (400 MHz, CDCl₃): d=2.41 (dd, J=16.7, 5.8 Hz, 1H), 2.32–2.24

(m, 2H), 2.18 (dd, J=16.9, 6.8 Hz, 1H), 2.02 (app. oct., J=6.1 Hz, 1H),

1.07 (d, J=6.6 Hz, 3H), 0.07 ppm (s, 9H); ¹³C NMR (100 MHz, CDCl₃):

d=118.4, 103.1, 87.6, 34.1, 30.2, 26.3, 23.3, 19.0, 14.1, 0.01 ppm; IR (film):

¹J

tions via ⁿJ

time of 120 ms; NOESY (noesygpph). IR: Magna IR750 (Nicolet) or

Spectrum One (Perkin-Elmer) spectrometer, wavenumbers (n˜) in cm^ꢀ1

ACHTUNGTRENNUNG

.

MS (EI): Finnigan MAT 8200 (70 eV), ESI-MS: ESQ3000 (Bruker), ac-

curate mass determinations: Bruker APEX III FT-MS (7 T magnet) or

Mat 95 (Finnigan). Melting points: Bꢀchi melting point apparatus B-540

(corrected). Elemental analyses: H. Kolbe, Mꢀlheim/Ruhr. All commer-

cially available compounds (Fluka, Lancaster, Aldrich) were used as re-

ceived.

n˜ =2963, 2247, 2176, 1458, 1426, 1345, 1250, 1035, 996, 842, 760, 699 cm^ꢀ1

;

HRMS (EI): m/z: calcd for C₁₀H₁₇NSi [M⁺+H]: 180.1207, found:

180.1208.

Preparation of the building blocks of type C

Aldehyde 45: Dibal-H (1m in CH₂Cl₂, 4 mL, 4 mmol) was added to a so-

lution of nitrile 51 (369 mg, 2.06 mmol) in CH₂Cl₂(10 mL) at ꢀ788C.

After stirring for 1 h at this temperature, the reaction was quenched with

a cold (08C) sat. aq. solution of Rochelle salt (80 mL) and the mixture

slowly warmed to room temperature over a period of 4 h. The separated

aqueous layer was extracted with Et₂O (2ꢄ100 mL), the combined organ-

ic phases were washed with brine (2ꢄ100 mL), dried over Na₂SO₄and

evaporated. The resulting crude aldehyde was dissolved in THF (5 mL)

and treated with a solution of TBAF (1m in THF, 3 mL, 3 mmol). After

stirring for 2 h, all volatile materials were evaporated and the residue pu-

rified by flash chromatography (hexanes/tert-butyl methyl ether 20:1) to

give aldehyde 45 as a colorless oil (149 mg, 66%). ¹H NMR (400 MHz,

CDCl₃): d=9.79 (t, J 1.8 Hz, 1H), 2.68–2.58 (m, 1H), 2.40–2.15 (m, 4H),

2.00 (t, J=2.7 Hz, 1H), 1.06 ppm (d, J=6.4 Hz, 3H); ¹³C NMR

(100 MHz, CDCl₃): d=201.9, 82.0, 70.4, 49.7, 27.5, 25.7, 19.8 ppm.

Compound 48: iPr₂NH (22 mL, 15.12 mmol) and nBuLi (1.6m solution in

hexane, 9 mL, 14.5 mmol) were successively added to a suspension of

flame-dried LiCl (1.34 g, 31.5 mmol) in THF (15 mL) at 08C. The yellow

slurry was stirred for 15 min at this temperature and for 20 min at ambi-

ent temperature before it was cooled to ꢀ788C. A solution of ent-35

(900 mg, 4.2 mmol) in THF (9 mL) was added via cannula and stirring

continued for 45 min at ꢀ788C. To complete the enolization, the mixture

was stirred at 08C for 15 min and another 15 min at room temperature.

The mixture was then cooled to ꢀ788C before iodide 47 (1.5 g,

6.3 mmol) was added neat. The reaction was allowed to reach 08C and

stirred at this temperature for 18 h. For work up, sat. aq. NH₄Cl (60 mL)

was added and the mixture extracted with EtOAc (2ꢄ50 mL). The com-

bined organic layers were dried over Na₂SO₄and evaporated, and the

residue purified by flash chromatography (hexanes/EtOAc 7:3) to give

product 48 as a colorless syrup (1.26 g, 97%). [a]²_D⁰= +13.8 (c=0.5,

CHCl₃); ¹H NMR (400 MHz, C₆D₆, rotamers; signals of the minor rota-

mer are marked *): d=7.13 (d, J=7.1 Hz, 2H), 7.05–6.87 (m, 3H), 4.41

(brs, 1H, OH), 4.35 (d, J=6.8 Hz, 1H), 4.16 (d, J=7.8 Hz, 1H)*, 3.71

(m, 1H), 2.69 (s, 3H)*, 2.41–2.38 (m, 1H), 2.31 (dd, J=16.6, 6.3 Hz, 1H),

2.22 (s, 3H), 2.11 (dd, J=16.9, 7.8 Hz, 1H), 1.04 (d, J=6.6 Hz, 3H)*,

0.84 (d, J=6.6 Hz, 3H), 0.76 (d, J=6.8 Hz, 3H), 0.51 (d, J=6.6 Hz,

3H)*, 0.03 (s, 9H)*, ꢀ0.01 ppm (s, 9H); ¹³C NMR (100 MHz, C₆D₆): d=

175.9, 175.5*, 143.1, 142.4*, 128.3, 128.1*, 127.8, 127.5, 126.6*, 125.2,

106.8*, 105.9, 85.4*, 85.2, 75.8, 75.2*, 59.8, 58.1*, 36.1, 35.6*, 27.2, 21.0,

20.3*, 17.2, 15.2*, 1.1*, 0.28 ppm; HRMS (ESI): m/z: calcd for

C₁₉H₃₀NO₂Si [M⁺]: 332.2042, found: 322.2045.

Compound 46: (EtO)₂P(O)CH₂COOEt (3.0 mL, 15 mmol) was added to

a suspension of NaH (360 mg, 15 mmol) in THF (15 mL) at 08C and the

resulting mixture stirred for 1.5 h at ambient temperature. A solution of

aldehyde 45 (1.5 g, 13.6 mmol) in THF (15 mL) was introduced and stir-

ring continued for 1 h. The reaction was then carefully quenched with an

aqueous solution of citric acid (10% w/w, 10 mL), the mixture was ex-

tracted with CH₂Cl₂(2ꢄ20 mL), the combined organic phases were dried

over Na₂SO₄and evaporated, and the residue purified by flash chroma-

tography (hexanes/EtOAc 10:1) to give ester 46 as a colorless oil (1.69 g,

69%). [a]²_D⁰= +25 (c=0.4, CHCl₃); ¹H NMR (400 MHz, CDCl₃): d=

6.91 (dt, J=15.6, 7.4 Hz, 1H), 5.85 (dt, J=15.6, 1.5 Hz, 1H), 4.18 (q, J=

7.1 Hz, 2H), 2.39–2.30 (m, 1H), 2.22–2.09 (m, 3H), 1.99 (t, J=2.7 Hz,

1H), 1.87 (ttd, J=6.7, 6.7, 6.7 Hz, 1H), 1.29 (t, J=7.1 Hz, 3H), 1.02 ppm

(d, J=6.7 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃): d=166.6, 147.1, 123.2,

82.4, 69.9, 60.3, 38.4, 32.0, 25.4, 19.5, 14.5 ppm; IR (film): n˜ =3307, 2960,

2929, 2205, 1716, 1654, 1458, 1368, 1319, 1265, 1200, 1160, 1043, 983,

837 cm^ꢀ1; HRMS (ESI): m/z: calcd for C₁₁H₁₆O₂Na [M⁺+Na]: 203.1048,

found 203.10469.

Compound 50: nBuLi (1.6m solution in hexanes, 78.8 mL, 126 mmol) was

added dropwise to a solution of iPr₂NH (18.3 mL, 132 mmol) in THF

(50 mL) at 08C. The mixture was stirred at room temperature for 10 min

and then cooled again to 08C before BH₃·NH₃(4.75 g, 153.8 mmol, 90%)

was added in portions. After stirring of the slurry at room temperature

for 1 h, a solution of compound 48 (10.2 g, 30.7 mmol) in THF (60 mL)

was added at 08C and the mixture stirred at ambient temperature for 2 h.

For work up, the reaction was quenched at 08C with aq. HCl (1m,

18 mL). Extraction with Et₂O (3ꢄ120 mL), drying of the organic layers

over Na₂SO₄, evaporation of the solvents and purification of the residue

by flash chromatography (pentanes/diethyl ether 1:1) afforded alcohol 49

(4.2 g, 80%) which was immediately used in the next step.

AHCTUNGERTG(NNUN 5S,E)-5-Methyloct-2-en-7-yn-1-ol: Dibal-H (1m in hexanes, 106 mL,

106 mmol) was added over 30 min to a solution of ester 46 (7.62 g,

42.3 mmol) in THF (100 mL) at ꢀ788C and the resulting mixture was

stirred for 1 h at this temperature. The reaction was

quenched by the careful addition of MeOH (50 mL)

and the mixture was allowed to warm to ambient tem-

To a solution of 49 thus obtained in CH₂Cl₂(30 mL) at 08C were succes-

sively added Et₃N (5.1 mL, 36.1 mmol), DMAP (0.1 g) and tosyl chloride

(5.5 g, 28.9 mmol). The resulting mixture was stirred overnight before the

reaction was quenched with sat. aq. NH₄Cl (40 mL). A standard extrac-

tive work up followed by flash chromatography (hexanes/tert-butyl

methyl ether 4:1) afforded tosylate 50 as a pale yellow oil (5.75 g, 72%).

[a]²_D⁰= +9.0 (c=0.3, CHCl₃); ¹H NMR (400 MHz, CDCl₃): d=7.71 (d,

J=8.0 Hz, 2H), 7.26 (d, J=8.0 Hz, 2H), 3.85 (m, 2H), 2.32 (s, 3H), 2.16

(m, 2H), 1.94 (app. oct., J=6.3 Hz, 1H), 0.89 (d, J=6.8 Hz, 3H),

0.01 ppm (s, 9H); ¹³C NMR (100 MHz, CDCl₃): d=144.7, 132.9, 129.8,

127.9, 103.6, 86.7, 73.3, 32.3, 23.4, 21.6, 15.8, ꢀ0.01 ppm; IR (film): n˜ =

2962, 2174, 1598, 1495, 1457, 1362, 1291, 1249, 1188, 1175, 1097, 1036,

perature. A sat. aq. solution of Rochelleꢅs salt was

added (200 mL) and the mixture was vigorously stirred

for 2 h to reach a clean phase separation. The aqueous

phase was extracted with tert-butyl methyl ether (3ꢄ50 mL), the com-

bined organic extracts were washed with brine (100 mL), dried over

MgSO₄and evaporated. Flash chromatography of the residue (pentanes/

Et₂O 2:1) afforded the title compound as colorless oil (4.80 g, 82%).

[a]²_D⁰= +18 (c=0.25, CHCl₃); ¹H NMR (400 MHz, CDCl₃): d=5.71–

5.60 (m, 2H), 4.10–4.08 (m, 2H), 2.20–2.12 (m, 3H), 2.10 (dd, J=6.0,

3.3 Hz, 1H), 1.96 (t, J=2.6 Hz, 1H), 1.75 (oct, J=6.7 Hz 1H), 1.3 (brs,

1H), 0.99 ppm (d, J=7.0 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃): d=

131.1, 130.8, 83.1, 69.5, 63.8, 38.6, 32.6, 25.7, 19.3 ppm; IR (film): n˜ =

Chem. Eur. J. 2009, 15, 3983 – 4010

ꢂ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

www.chemeurj.org

3993

A. Fꢀrstner et al.

3310, 2956, 2928, 2857, 1461, 1252, 1000, 971 cm^ꢀ1; HRMS (ESI): m/z:

calcd for C₉H₁₄ONa [M⁺+Na]: 161.09423, found: 161.09422.

(pentanes/Et₂O 2:1) to furnish stannane 55 as a yellow oil (55 mg, 79%).

1

[a]²_D⁰= ꢀ6.1 (c=0.64, CHCl₃); H NMR (400 MHz, CDCl₃): d=5.64 (td,

J=2.8, 1.3, 1H), 5.16 (brd, J=2.8 Hz, 1H), 3.92 (brd, J=12.1 Hz, 1H),

3.64 (brd, J=12.1 Hz, 1H), 2.97 (ddd, J=8.4, 6.1, 2.3 Hz, 1H), 2.89 (ddd,

J=4.3, 2.3, 1.8 Hz, 1H), 2.45–2.41 (m, 2H), 2.29 (dd, J=13.4, 6.4, 1H),

2.13 (dd, J=13.4, 7.4, 1H), 1.75–1.63 (m, 2H), 1.53–1.41 (m, 5H), 1.36–

1.26 (m, 7H), 0.93 (d, J=6.5 Hz, 3H), 0.87–0.84 ppm (m, 15H);

¹³C NMR (100 MHz, CDCl₃): d=154.2, 126.7, 61.7, 59.0, 54.7, 49.7, 38.6,

30.8, 29.3, 27.6, 20.9, 19.7, 13.8, 9.8 ppm; IR (film): n˜ =3417, 2955, 2926,

2871, 1458, 1376, 1247, 1073, 913 cm^ꢀ1; MS (EI): m/z (%): 393 (16), 389

(100), 329 (40), 251 (19), 217 (23), 175 (59), 137 (31); HRMS (ESI): m/z:

calcd for C₂₁H₄₂O₂SnNa [M⁺+Na]: 469.2100, found: 469.2098.

Compound 52: A suspension of powdered, flame-dried molecular sieves

(4 ꢃ, 2.0 g) in CH₂Cl₂(70 mL) was stirred for 3 h. The resulting mixture

was cooled to ꢀ208C before l-(+)-DET (236 mL, 12 mol%) and Ti-

ACHTUNGTRENNUNG(OiPr)₄(340 mL, 10 mol%) were introduced, followed by the dropwise

addition of tBuOOH (4.20 mL, 45.1 mmol, dried over activated molecu-

lar sieves for 3 h prior to use). After stirring for 30 min, a solution of

(5S,2E)-5-methyloct-2-en-7-yn-1-ol (2.84 g, 20.5 mmol) in CH₂Cl₂

(20 mL), which had also been stirred over activated MS 4 ꢃ for 3 h prior

to use, was added and the mixture was stirred at ꢀ208C for 14 h. After

reaching 08C, the mixture was slowly poured into a cold (08C) solution

of FeSO₄·7H₂O (7.0 g) and citric acid (2.5 g) in H₂O (23 mL). After stir-

ring for 30 min, the aqueous phase was extracted with CH₂Cl₂(2ꢄ

50 mL), the combined extracts were washed with brine (50 mL), dried

over MgSO₄and evaporated, and the residue purified by flash chroma-

tography (pentanes/Et₂O 2:1) to give 52 as a colorless oil (1.84 g, 58%).

Preparation of type D building blocks

Compound 33: A solution of phosphite 32 (271 mg, 0.52 mmol) and [Rh-

AHCTUNTGREG(NNUN cod)₂]BF₄(106 mg, 0.26 mmol) in 1,2-dichloroethane (5 mL) was trans-

ferred via cannula to a degassed solution of itaconic acid monomethyl

ester 31 (25.0 g, 173.4 mmol) in 1,2-dichloroethane (300 mL). Hydrogen

gas was bubbled through the mixture over a period of 4 h. For work-up,

the mixture was purged with Ar for 5 min to remove any remaining H₂,

the flask was fitted with a distillation head and the product isolated by

distillation under reduced pressure (10^ꢀ3mbar, b.p. 76–788C). Yellow oil

[a]²_D⁰

=

ꢀ27.1 (c=0.6, CHCl₃); ¹H NMR (400 MHz, CDCl₃): d=3.92

(brd, J=12.6 Hz, 1H), 3.68–3.60 (m, 1H), 3.00 (ddd, J=7.2, 5.2, 2.3 Hz,

1H), 2.93–2.91 (m, 1H), 2.22 (ddd, J=16.7, 6.4, 2.6 Hz, 1H), 2.21 (ddd,

J=16.7, 6.4, 2.6 Hz, 1H), 1.98 (t, J=2.6 Hz, 1H), 1.96–1.90 (m, 1H),

1.72–1.65 (m, 2H), 1.52 (ddd, J=13.6, 8.2, 6.4 Hz, 1H), 1.08 ppm (d, J=

7.0 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃): d=82.6, 69.9, 61.6, 58.7, 54.5,

37.8, 30.7, 26.1, 19.5 ppm; IR (film): n˜ =3422, 3296, 1460, 1428, 1075,

1025, 703 cm^ꢀ1; HRMS (ESI): m/z: calcd for C₉H₁₄O₂Na [M⁺+Na]:

177.0891, found 177.0891.

(18.7 g, 99%, 97% ee); [a]_D²⁰

=

ꢀ10.3 (c=1.0, CHCl₃);¹H NMR

(400 MHz, C₆D₆): d=10.21 (br. s, 1H), 3.36 (s, 3H), 2.84–2.92 (m, 1H),

2.67 (dd, J=16.7, 8.0 Hz, 1H), 2.36 (dd, J=16.7, 6.0 Hz, 1H), 1.19 ppm

(d, J=7.2 Hz, 3H). The analytical and spectroscopic data are consistent

with those previously reported.^[72]

Compound 53: Imidazole (1.36 g, 20.0 mmol), DMAP (170 mg,

1.34 mmol) and TBSCl (2.40 g, 16.0 mmol) were added to a solution of

the compound 52 (2.06 g, 13.36 mmol) in CH₂Cl₂(40 mL) and the result-

ing mixture was stirred overnight. A standard extractive work up fol-

lowed by flash chromatography (hexanes/tert-butyl methyl ether 20:1) af-

forded product 53 as a colorless oil (3.54 g, 98%). [a]²_D⁰= ꢀ8.1 (c=0.83,

CHCl₃); ¹H NMR (400 MHz, CDCl₃): d=3.75 (dd, J=11.9, 3.7 Hz, 1H),

3.69 (dd, J=11.9, 4.4 Hz, 1H), 2.86–2.82 (m, 2H), 2.24 (ddd, J=16.7, 6.2,

2.6 Hz, 1H), 2.16 (ddd, J=16.7, 6.7, 2.6 Hz, 1H), 1.96 (t, J=2.6 Hz, 1H),

1.95–1.88 (m, 1H), 1.72–1.65 (m, 1H), 1.46 (ddd, J=13.8, 8.4, 5.2 Hz,

1H), 1.07 (d, J=6.7 Hz, 3H), 0.89 (s, 9H), 0.07 (s, 3H), 0.06 ppm (s,

3H); ¹³C NMR (100 MHz, CDCl₃): d=82.8, 69.7, 63.6, 58.9, 55.0, 38.0,

30.8, 26.1, 26.0, 19.4, 14.1, ꢀ5.1, ꢀ5.2 ppm; IR (film): n˜ =2956, 2929,

2857, 1472, 1463, 1252, 1109, 1088, 833, 776 cm^ꢀ1; MS (EI): m/z (%): 181

(3), 129 (4), 101 (10), 117 (100), 75 (58); HRMS (ESI): m/z: calcd for

C₁₅H₂₈O₂SiNa [M⁺+Na]: 291.1752, found: 291.1751.

tert-Butyl(2-iodoethoxy)diphenylsilane:

A solution of 2-iodoethanol

(10.0 g, 58 mmol), TBDPSCl (17.9 mL, 69.8 mmol) and imidazole (4.7 g,

69.8 mmol) in CH₂Cl₂(70 mL) was stirred for 18 h. Water (30 mL) was

added and the mixture extracted with CH₂Cl₂(2ꢄ30 mL), the combined

organic phases were dried over Na₂SO₄and evaporated, and the crude

material purified by flash chromatography (hexanes) to yield the title

compound as a white solid (23.0 g, 97%). ¹H NMR (400 MHz, CDCl₃):

d=7.71 (dd, J=8.3, 2.4 Hz, 4H), 7.40–7.47 (m, 6H), 3.90 (t, J=6.7 Hz,

2H), 3.25 (t, J=6.7 Hz, 2H), 1.11 ppm (s, 9H); ¹³C NMR (100 MHz,

CDCl₃): d=135.2, 129.4, 127.4, 64.2, 26.4, 6.41 ppm; MS (EI): m/z (%):

309 (100); HRMS (ESI): m/z: calcd for C₁₈H₂₃IOSiNa [M⁺+Na]:

433.0455, found: 433.0450.

Compound 36: nBuLi (1.6m solution in hexane, 5.6 mL, 8.9 mmol) was

added to a suspension of flame-dried LiCl (806 mg, 19.2 mmol) and

iPr₂NH (1.3 mL, 0.96 mmol) in THF at 08C. The resulting yellow slurry

was stirred for 15 min at 08C and 20 min at ambient temperature before

it was cooled to ꢀ788C. A solution of compound 35 (1.0 g, 4.52 mmol) in

THF (25 mL) was added via cannula, the reaction was stirred for 45 min

at ꢀ788C, warmed to 08C for 15 min and then stirred at ambient temper-

ature for another 15 min before it was again cooled to ꢀ788C. tert-

Butyl(2-iodoethoxy)diphenylsilane (1.31 g, 3.2 mmol) was added neat and

the mixture was warmed to 08C and stirred at this temperature for 18 h.

The reaction was quenched with sat. aq. NH₄Cl (40 mL) and the aqueous

phase extracted with EtOAc (2ꢄ40 mL). The combined organic layers

were dried over Na₂SO₄and evaporated, and the residue was purified by

flash chromatography (hexanes/EtOAc 3:2) to give amide 36 as a color-

less syrup (2.23 g, 98%). ¹H NMR (400 MHz, CDCl₃, 7:1 mixture of ro-

tamers; peaks of the minor rotamer are marked *): d=7.67 (t, J=7 Hz,

4H)*, 7.61–7.65 (m, 4H), 7.23–7.44 (m, includes the minor rotamer peak,

11H), 4.52 (d, J=7.6 Hz, 1H), 4.48 (d, J=7.6 Hz, 1H)*, 4.38–4.36 (m,

1H, OH), 3.65 (m, 1H)*, 3.56 (m, 1H), 3.50 (m, 1H), 2.91 (m, 1H), 2.82

(s, 3H)*, 2.80 (s, 3H), 1.74 (m, 1H), 1.46 (m, 1H), 1.19 (m, 2H), 0.98 (d,

J=6.1 Hz, 3H), 0.97 (d, J=6.1 Hz, 3H)*, 0.96 (s, 9H)*, 0.95 (s, 9H), 0.79

(d, J=6.1 Hz, 3H), 0.77 ppm (d, J=6.1 Hz, 3H)*; ¹³C NMR (100 MHz,

CDCl₃): d=178.6, 147.4*, 142.17, 135.14, 133.35*, 129.33, 129.29*, 128.3*,

127.9, 127.3, 126.6*, 125.9, 75.4, 61.01, 40.98, 36.35, 32.25, 28.7, 26.60*,

26.50, 22.26, 18.12, 16.5, 13.9, 11.07 ppm; IR (film): n˜ =3371, 2931, 2858,

1618, 1472, 1427, 1106, 1084, 907, 729, 699 cm^ꢀ1; HRMS (ESI): m/z: calcd

for C₃₁H₄₁NO₃SiNa [M⁺+Na]: 526.2736, found: 526.2747. ent-36 was pre-

pared analogously using ent-35 as the substrate.

Compound 54: Bu₃Sn-SiMe₃(1.50 mL, 4.46 mmol) was added to a solu-

tion of alkyne 53 (1.0 g, 3.73 mol) in degassed 1,2-dimethoxyethane

(DME, 10 mL). [PdACHTUNGTRENNUNG(PPh₃)₄] (86 mg, 2 mol%) was then added, the

Schlenck tube was sealed and heated to 1008C overnight. Celite was

added to the black mixture and all volatile materials were evaporated.

The loaded Celite was added to the top of a silica gel column and the

product was eluded with pentanes/Et₂O (1:0 ! 75:1) to afford a yellow

oil contaminated with PPh₃. To remove this impurity, the residue was dis-

solved in CH₃CN (5 mL) before MeI (1.2 mL, 18.6 mmol, 5.0 equiv) was

added. The mixture was stirred for 0.5 h before it was filtered though a

pad of silica gel (washed with pentanes) to afford pure 54 as a colorless

oil (1.42 g, 85%). [a]²_D⁰= ꢀ1.3 (c=0.65, CHCl₃); ¹H NMR (400 MHz,

CDCl₃): d=6.27 (brs, 1H), 3.77 (dd, J=15.7, 4.6 Hz, 1H), 3.68 (dd, J=

15.7, 6.0 Hz, 1H), 2.82–2.77 (m, 2H), 2.30 (dd, J=17.0, 8.9 Hz, 1H), 2.17

(dd, J=17.0, 9.6 Hz, 1H), 1.76–1.64 (m, 2H), 1.52–1.42 (m, 6H), 1.37–

1.26 (m, 6H), 1.20–1.10 (m, 1H), 0.94–0.86 (m, 27H), 0.09 (s, 9H), 0.08

(s, 3H), 0.07 ppm (s, 3H); ¹³C NMR (100 MHz, CDCl₃): d=164.0, 146.0,

64.0, 59.5, 56.1, 55.3, 38.4, 30.4, 29.4, 27.7, 26.0, 19.4, 18.5, 13.9, 11.4, 0.4,

ꢀ5.1, ꢀ5.2 ppm; IR (film): n˜ =2955, 2928, 2856, 1463, 1247, 832,

776 cm^ꢀ1; MS (EI): m/z (%): 575 (54), 417 (67), 291 (45), 235 (35), 193

(43), 177 (36), 117 (20), 73 (100); HRMS (ESI): m/z: calcd for

C₃₀H₆₄O₂Si₂SnNa [M⁺+Na]: 655.3353, found: 655.3358.

Compound 55: A solution of TBAF (1m in THF, 720 mL, 0.72 mmol) was

added to a solution of 54 (100 mg, 0.16 mmol) in DMSO (2 mL). The

mixture was stirred at 808C for 45 min, cooled to ambient temperature

and adsorbed on silica, which was loaded on top of a silica gel column

Compound 37: nBuLi (1.6m solution in hexanes, 76.9 mL, 124.8 mmol)

was added dropwise to a solution of iPr₂NH (17.7 mL, 131 mmol) in THF

3994

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ꢂ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Chem. Eur. J. 2009, 15, 3983 – 4010

Total Syntheses of Amphidinolides

FULL PAPER

(150 mL) at 08C. The mixture was stirred at room temperature for

10 min before it was cooled to 08C. BH₃·NH₃(4.3 g, 124.8 mmol, 90%)

was added in portions and the resulting slurry was warmed to room tem-

perature over 1 h. A solution of amide 36 (15.8 g, 31.3 mmol) in THF

(20 mL) was added via cannula at 08C and the mixture allowed to warm

to room temperature over a period of 2 h once the addition was com-

plete. The reaction was quenched at 08C with aq. HCl (1m, 21 mL), the

aqueous layer was extracted with Et₂O (3ꢄ150 mL), the combined organ-

ic phases were dried over Na₂SO₄and evaporated, and the residue puri-

fied by flash chromatography (hexanes/EtOAc 4:1) to give alcohol 37 as

a colorless oil (10.3 g, 96%). [a]²_D⁰= ꢀ3.0 (c=0.95, CHCl₃). ¹H NMR

(400 MHz, CDCl₃): d=7.69–7.66 (m, 4H), 7.44–7.39 (m, 6H), 3.79–3.67

(m, 2H), 3.53–3.45 (m, 2H), 2.33 (brs, 1H), 1.85 (qd, J=13.2, 6.7 Hz,

1H), 1.64 (ddd, J=7.6, 6.6, 5.2 Hz, 1H), 1.53–1.40 (m, 1H), 1.06 (s, 9H),

0.90 ppm (d, J=6.7 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃): d=135.7,

133.7, 129.9, 127.8, 68.4, 62.7, 36.9, 34.0, 27.0, 19.3, 17.3 ppm; IR (film):

n˜ =3346, 2930, 2857, 1427, 1106, 1086, 699 cm^ꢀ1; HRMS (ESI): m/z: calcd

for C₂₁H₃₀O₂SiNa [M⁺+Na]: 365.1902, found: 365.1907. The recorded an-

alytical and spectroscopic data were consistent with those previously re-

ported in the literature.^[73]

added and the layers were separated. The aqueous phase was extracted

with CH₂Cl₂(2ꢄ40 mL), the combined extracts were washed with brine,

dried over MgSO₄and evaporated. Purification of the residue by flash

chromatography (hexanes/tert-butyl methyl ether 30:1) afforded vinyl

iodide 39 as a colorless oil (5.06 g, 94%). [a]_D²⁰

= +12.8 (c=0.71,

CHCl₃); ¹H NMR (400 MHz, CDCl₃): d=7.67–7.63 (m, 4H), 7.43–7.36

(m, 6H), 5.91 (brs, 1H), 3.59–3.55 (m, 2H), 2.67 (q, J=9.2 Hz, 1H), 1.69

(d, J=1.2 Hz, 3H), 1.64–1.52 (m, 2H), 1.04 (s, 9H), 0.99 ppm (d, J=

9.2 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃): d=151.7, 135.7, 134.0, 129.7,

127.8, 75.4, 61.8, 39.9, 37.7, 27.0, 20.5, 19.6, 19.3 ppm; IR (film): n˜ =3070,

2959, 2930, 1427, 1104, 699 cm^ꢀ1; MS (EI): m/z (%): 421 (100), 309 (68),

249 (16), 215 (15), 211 (15), 199 (32), 183 (21); HRMS (ESI): m/z: calcd

for C₂₃H₃₁IOSiNa [M⁺+Na]: 501.1083, found: 501.1081.

Compound 40: A solution of TBAF in THF (1m, 2.5 mL, 2.5 mmol) was

added to a solution of 39 (1.0 g, 2.09 mmol) in THF (6 mL). After stirring

for 1.5 h, the mixture was carefully evaporated (308C, 400 mbar) and the

residue purified by flash chromatography (pentanes/Et₂O 1:0 ! 30:1 !

10:1) to afford alcohol 40 as a colorless oil (502 mg, 98%). [a]²_D⁰= +24.0

(c=0.3, CHCl₃); ¹H NMR (400 MHz, CDCl₃): d=5.99–5.98 (m, 1H),

3.59 (ddd, J=16.8, 10.6, 6.4 Hz, 2H), 2.62 (qd, J=13.6, 6.8 Hz, 1H), 1.76

(d, J=1.0 Hz, 3H), 1.71–1.49 (m, 3H), 1.05 ppm (d, J=6.8 Hz, 3H);

¹³C NMR (100 MHz, CDCl₃): d=151.7, 75.4, 61.0, 40.3, 37.6, 37.6, 20.4,

19.6 ppm; IR (film): n˜ =3330, 2960, 2929, 2873, 1377, 1267, 1046, 774,

660 cm^ꢀ1; HRMS (ESI): m/z: calcd for C₇H₁₃IO [M⁺]: 240.0014, found:

240.0011.

Compound 34: A solution of DMSO (1.5 mL, 21.8 mmol) in CH₂Cl₂

(10 mL) was added dropwise to

a solution of (COCl)₂(930 mL,

10.5 mmol) in CH₂Cl₂(30 mL) at ꢀ788C. After stirring for 10 min, a solu-

tion of alcohol 37 (2.8 g, 8.06 mmol) in CH₂Cl₂(15 mL) was introduced

and stirring continued for 1 h at ꢀ788C before Et₃N (8.0 mL, 56.4 mmol)

was added and the mixture allowed to warm to ambient temperature.

After 1 h, the reaction was quenched with brine (40 mL), the aqueous

phase was extracted with tert-butyl methyl ether (2ꢄ30 mL), the com-

bined organic extracts were dried over MgSO₄, and the solvent was

evaporated to afford aldehyde 34 (2.6 g, 94% crude) as a pale yellow oil

Aldehyde 41: A mixture containing alcohol 40 (502 mg, 2.10 mmol) and

solid NaHCO₃(1.76 g, 21.0 mmol) in CH₂Cl₂(8.0 mL) was stirred for

30 min at ambient temperature before Dess–Martin periodinane (980 mg,

2.30 mmol) was introduced and stirring continued for 1.5 h. The solvent

was evaporated and the residue suspended in pentanes (10 mL). The re-

sulting mixture was then filtered through a pad of Celite and the filtrate

was evaporated. This operation was repeated twice to afford the crude al-

dehyde which was then purified by flash chromatography (hexanes/tert-

butyl methyl ether 30:1) to give analytically pure 41 as a pale yellow oil

which was used in the next step without further purification. [a]_D²⁰

=

+3.5 (c=1.1, CHCl₃); ¹H NMR (400 MHz, CDCl₃): d=9.68 (d, J=

1.6 Hz, 1H), 7.67–7.64 (m, 4H), 7.46–7.37 (m, 6H), 3.77–3.66 (m, 2H),

2.58 (qdd, J=8.4, 7.0, 1.6 Hz, 1H), 2.01 (ddd, J=12.7, 6.8, 5.6 Hz, 1H),

1.62 (m, 1H), 1.09 (d, J=7.0 Hz, 3H), 1.05 ppm (s, 9H); ¹³C NMR

(100 MHz, CDCl₃): d=205.0, 135.7, 133.7, 129.8, 127.8, 61.3, 43.6, 33.6,

26.9, 19.3, 13.2 ppm; IR (film): n˜ =2931, 2857, 1726, 1427, 1105, 1087,

699 cm^ꢀ1; MS (EI): m/z (%): 283 (87), 253 (25), 205 (62), 199 (100), 175

(57), 139 (30); HRMS (ESI): m/z: calcd for C₂₁H₂₈O₂SiNa [M⁺+Na]:

363.1750, found: 363.1751.

(492 mg, 98%). [a]_D²⁰

=

+25.0 (c=1.0, CHCl₃); ¹H NMR (400 MHz,

CDCl₃): d=9.69 (d, J=2.0 Hz, 1H), 6.08–6.07 (m, 1H), 3.02 (qd, J=13.8,

6.8 Hz, 1H), 2.56 (ddd, J=16.6, 6.8, 2.0 Hz, 1H), 2.52 (ddd, J=16.6, 7.6,

2.0 Hz, 1H), 1.81 (d, J=1.0 Hz, 3H), 1.10 ppm (d, J=7.0 Hz, 3H);

¹³C NMR (100 MHz, CDCl₃): d=201.2, 150.3, 76.5, 48.8, 37.7, 21.5,

19.6 ppm; IR (film): n˜ =2964, 2928, 1721, 1377, 1277, 777 cm^ꢀ1; HRMS

(ESI): m/z: calcd for C₇H₁₁IO+Na [M⁺+Na]: 260.9752, found: 260.9755.

Alkyne 38: A solution of NaOMe (6.55 g, 80 mmol) in MeOH (15 mL)

was added to a solution of 42 (15.4 g, 80 mmol) in THF (80 mL) at

ꢀ788C. The resulting mixture was stirred at this temperature for 0.5 h

before a solution of the crude aldehyde 34 (7.0 g, 20 mmol) in THF

(50 mL) was slowly introduced. The mixture was stirred for 0.5 h at

ꢀ788C before it was stirred overnight at ambient temperature. Water

(50 mL) was added and the mixture extracted with tert-butyl methyl

ether (2ꢄ50 mL). The combined organic phases were dried over Na₂SO₄

and evaporated, and the residue was purified by flash chromatography

(hexanes/tert-butyl methyl ether 15:1) to give alkyne 38 as a pale yellow

oil (4.5 g, 67%). [a]²_D⁰= +25.0 (c=1.1, CHCl₃); ¹H NMR (400 MHz,

CDCl₃): d=7.70–7.66 (m, 4H), 7.45–7.36 (m, 6H), 3.86–3.74 (m, 2H),

2.74 (qdd, J=9.3, 6.9, 2.4 Hz, 1H), 1.99 (d, J=2.4 Hz, 1H), 1.69 (ddd, J=

9.3, 6.8, 1.1 Hz, 2H), 1.19 (d, J=6.9 Hz, 3H), 1.05 ppm (s, 9H); ¹³C NMR

(100 MHz, CDCl₃): d=135.7, 134.2, 129.7, 127.7, 88.9, 68.4, 61.7, 39.6,

27.0, 22.3, 21.0, 19.4 ppm; IR (film): n˜ =3307, 2932, 2858, 1427, 1107,

1088, 699 cm^ꢀ1; MS (EI): m/z (%): 279 (100), 201 (93), 183 (23), 171 (10),

137 (10); HRMS (ESI): m/z: calcd for C₂₂H₂₈OSiNa [M⁺+Na]: 359.1804,

found: 359.1802.

Compound 84: A solution of LDA (0.8m in THF, 5.8 mL, 4.6 mmol) was

added to a solution of (R)-3-acetyl-4-benzyloxazolidin-2-one (82; 1.0 g,

4.6 mmol) in Et₂O (42 mL) at ꢀ788C and the resulting mixture was

stirred at this temperature for 1 h. Ketone 83 (185 mg, 2.71 mmol) was

added and stirring continued for 30 min. The reaction was then quenched

with aq. sat. NH₄Cl (20 mL) and warmed to ambient temperature. The

aqueous layer was extracted with tert-butyl methyl ether (3ꢄ50 mL), the

combined organic phases were dried (Na₂SO₄) and evaporated, and the

residue purified by flash chromatography (EtOAc in pentanes, 10 ! 15

! 20% v/v) to afford product 84 as a white solid (394 mg, 54%). M.p.

114–1168C; [a]²_D⁰= ꢀ95.0 (c=1.0, CHCl₃); ¹H NMR (400 MHz, CDCl₃):

d=7.27–7.22 (m, 5H), 4.77–4.71 (m, 1H), 4.43 (s, 1H), 4.27–4.19 (m,

2H), 3.78 (d, J=17.4 Hz, 1H), 3.31 (dd, J=13.4, 3.2 Hz, 1H), 2.96 (d, J=

17.4 Hz, 1H), 2.86 (dd, J=13.5, 9.3 Hz, 1H), 2.46 (s, 1H), 1.61 ppm (d,

J=0.6 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃): d=171.9, 153.2, 134.8,

129.5, 129.0, 127.5, 86.6, 70.9, 66.3, 65.3, 55.0, 46.8, 37.8, 29.6 ppm; IR

(film): n˜ =3502, 3293, 2991, 1771, 1679, 1379 cm^ꢀ1; MS (EI): m/z (%): 287

(5) [M⁺], 269 (13), 241 (8), 219 (7), 178 (11), 86 (100); HRMS (ESI): m/

z: calcd for C₁₆H₁₇NO₄+Na [M⁺+Na]: 310.10498, found: 310.10476.

Vinyl iodide 39:

A solution of AlMe₃(2.0m in heptane, 21.2 mL,

42.4 mmol) was added to a suspension of [Cp₂ZrCl₂] (4.64 g, 15.9 mmol)

in 1,2-dichloroethane (70 mL). After stirring for 0.5 h, a solution of

alkyne 38 (3.56 g, 10.57 mmol) in 1,2-dichloroethane (15 mL) was added

dropwise. The resulting yellow solution was stirred for 24 h at ambient

temperature before the mixture was cooled to ꢀ208C and a solution of

iodine (16.10 g, 63.5 mmol) in THF (60 mL) was slowly introduced. After

stirring for 20 min at ꢀ208C and 30 min at 08C, the reaction was careful-

ly quenched with water (10 mL). A sat. aq. Na₂SO₃solution was then

Compound 85: MeOH (0.22 mL, 5.5 mmol) and LiBH₄(119 mg,

5.5 mmol) were successively added to

a solution of compound 84

(391 mg, 1.37 mmol) in THF (14 mL) at 08C. The mixture was stirred at

ambient temperature for 2 h before the reaction was quenched with aq.

sat. NH₄Cl (10 mL) and diluted with tert-butyl methyl ether (20 mL) and

HCl (2m, 0.05 mL). The aqueous layer was extracted with tert-butyl

methyl ether (3ꢄ20 mL), the combined organic phases were dried

(Na₂SO₄) and evaporated, and the residue was purified by flash chroma-

Chem. Eur. J. 2009, 15, 3983 – 4010

ꢂ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

www.chemeurj.org

3995

A. Fꢀrstner et al.

tography (Et₂O/pentanes 1:1) to afford diol 85 as a colorless oil (141 mg,

90%). [a]²_D⁰= +11.2 (c=1.2, CH₂Cl₂); ¹H NMR (400 MHz, CDCl₃): d=

4.15 (td, J=10.4, 3.2 Hz, 1H), 3.89 (dt, J=11.0, 4.3 Hz, 1H), 3.14 (brs,

2H), 2.48 (s, 1H), 1.98 (ddd, J=14.3, 9.8, 4.3 Hz, 1H), 1.52 (s, 3H),

1.08 ppm (ddd, J=14.6, 4.6, 3.5 Hz, 1H); ¹³C NMR (100 MHz, CDCl₃):

d=87.0, 71.9, 68.6, 60.5, 43.3, 30.5 ppm; IR (film): n˜ =3362, 3299, 2934,

1424, 1372, 1090 cm^ꢀ1; HRMS (EI): m/z: calcd for C₆H₁₀O₂: 114.06808,

found: 114.06805.

m/z (%): 368 (1) [M⁺], 339 (97), 325 (18), 295 (11), 211 (32), 129 (100);

HRMS: m/z: calcd for C₁₃H₂₅IO₂SiNa [M⁺+Na]: 391.05607, found:

391.05628.

Preparation of the building blocks of type AB

A

Dibal-H

(1.0m solution in hexane, 91.8 mL, 91.8 mmol) was slowly added to a so-

lution of compound 18 (10.8 g, 39.9 mmol) in CH₂Cl₂

(100 mL) at ꢀ788C. After 30 min at ꢀ788C, the reaction

was quenched with MeOH (until effervescence ceased) at

ꢀ788C and then poured into a sat. aq. solution of cold

(08C) Rochelleꢅs salt. The mixture was stirred overnight at

room temperature, leading to a clean phase separation.

The aqueous phase was extracted with EtOAc (3ꢄ

100 mL), the combined organic portions were dried

(Na₂SO₄) and evaporated, and the residue purified by flash chromatogra-

phy (hexanes/EtOAc 4:1) to give the title compound as a colorless oil

(7.13 g, 78%). The material must be stored at low temperature

Compound 86: Imidazole (204 mg, 3.0 mmol), DMAP (489 mg,

4.0 mmol) and TESCl (0.368 mL, 2.2 mmol) were successively added to a

solution of diol 85 (115 mg, 1.0 mmol) in DMF (1 mL). After stirring for

15 h, the reaction was quenched with aq. sat. NH₄Cl (1 mL), the aqueous

layer was extracted with Et₂O (3ꢄ10 mL), the combined extracts were

dried (Na₂SO₄) and evaporated, and the residue purified by flash chro-

matography (5% v/v Et₂O in pentanes) to afford compound 86 as a col-

orless oil (302 mg, 88%). ¹H NMR (300 MHz, CDCl₃): d=3.82 (t, J=

7.6 Hz, 2H), 2.39 (s, 1H), 1.91 (s, 2H), 1.46 (s, 3H), 0.94 (td, J=8.0 Hz,

18H), 0.62 ppm (s, 12H); ¹³C NMR (75 MHz, CDCl₃): d=87.8, 71.9, 67.4,

59.5, 47.6, 47.6, 31.4, 6.9, 6.8, 6.1, 4.4 ppm; IR (film): n˜ =3311, 2954, 2877,

1118, 1089, 1003 cm^ꢀ1; MS (EI): m/z (%): 313 (100) [M⁺ꢀEt], 285 (57),

217 (74), 189 (47), 115 (55), 87 (59); HRMS (ESI): m/z: calcd for

C₁₈H₃₈O₂Si₂+Na [M⁺+Na]: 365.23026, found: 365.23030.

(ꢂꢀ208C). [a]²_D⁰

=

+10.7 (c=0.65, CHCl₃); ¹H NMR (400 MHz,

CDCl₃): d=5.68–5.63 (m, 2H), 4.11–4.08 (m, 2H), 3.50 (dd, J=9.7,

6.2 Hz, 1H), 3.41 (dd, J=9.7, 7.0 Hz, 1H), 2.34 (app. sept., J=6.6 Hz,

1H), 1.9 (brs, 1H), 1.00 (d, J=6.7 Hz, 3H), 0.89 (s, 9H), 0.04 ppm (s,

6H); ¹³C NMR (100 MHz, CDCl₃): d=135.7, 128.9, 68.1, 64.0, 39.1, 26.1,

18.5, 16.5, ꢀ5.2 ppm; IR (film): n˜ =3342, 2956, 2929, 2857, 1471, 1463,

1252, 1085, 833, 773 cm^ꢀ1; MS (EI): m/z (%): 230 (<1), 173 (7), 115 (3),

105 (81), 89 (14), 75 (100); HRMS (ESI): m/z: calcd for C₁₂H₂₆O₂SiNa

[M⁺+Na]: 253.1595, found: 253.1594.

Compound 88: nBuLi (1.6m in hexanes, 0.75 mL, 1.2 mmol) was added to

a solution of hexabutylditin (0.61 mL, 1.22 mmol) in THF (3 mL) at

ꢀ788C. Once the addition was complete, the mixture was stirred at

ꢀ408C for 30 min before CuCN (104 mg, 1.16 mmol) was introduced and

stirring continued at ꢀ208C for 2 min. The resulting red solution was

cooled to ꢀ788C and a solution of compound 86 (100 mg, 0.29 mmol) in

THF (1 mL) was added. The reaction was quenched after 3 h with aq.

sat. NH₄Cl (5 mL), the aqueous layer was extracted with Et₂O (3ꢄ

10 mL), the combined organic phases were dried (Na₂SO₄), filtered and

evaporated. The remaining oil was dissolved in CH₂Cl₂(5 mL) and a sa-

turated solution of I₂in CH₂Cl₂was added dropwise until the pink color

persisted. The solvent was evaporated and the residue was purified by

flash chromatography (1 ! 30% v/v Et₂O in hexanes) to afford product

87 (106 mg, 90%, two steps) as a colorless oil.

AHCTUNGTERG(NNUN (2S,3S)-3-((S)-1-(tert-Butyldimethylsilyloxy)propan-2-yl)oxiran-yl)me-

thanol (19): A suspension of powdered MS 4 ꢃ (ꢁ1.0 g) in CH₂Cl₂

(20 mL) was stirred under Ar for 3 h before it was cooled to ꢀ208C and

l-(+)-DET (0.36 mL, 2.1 mmol) and TiACHTNUGTRENUNG(OiPr)₄(0.51 mL 1.71 mmol) were

introduced. After stirring for 20 min, a solution of tBuOOH (6.32 mL,

34.8 mmol), which had been pretreated with powdered MS 4 ꢃ for 3 h

prior to use, was added and the resulting mixture stirred for 20 min

before a solution of (R,E)-5-(tert-butyldimethylsilyloxy)-4-methylpent-2-

en-1-ol (4.0 g, 17.5 mmol) in CH₂Cl₂(30 mL, pre-dried with activated MS

4 ꢃ for 3 h) was added via cannula. The mixture was stirred for 15 h at

ꢀ208C, then warmed to 08C, and poured into a cold (08C) solution of

FeSO₄·7H₂O (9.15 g) and citric acid (3.0 g) in water (40 mL). This mix-

ture was stirred for 0.5 h before it was extracted with CH₂Cl₂(3ꢄ20 mL),

the combined organic phases were dried (Na₂SO₄) and evaporated, and

the residue purified by flash chromatography (hexanes/EtOAc 2:1) to

yield product 19 as a colorless oil (3.2 g, 74%). [a]²_D⁰= ꢀ15.8 (c=0.57,

Imidazole (5 mg, 0.076 mmol), DMAP (0.5 mg, 0.0038 mmol) and TESCl

(0.007 mL, 0.041 mmol) were added to

a solution of compound 87

(14 mg, 0.038 mmol) in CH₂Cl₂(0.1 mL) and the resulting mixture stirred

for 2 h. The reaction was quenched with aq. sat. NH₄Cl (3 mL), the aque-

ous phase extracted with Et₂O (3ꢄ5 mL), the combined organic layers

were dried (Na₂SO₄) and evaporated, and the residue was purified by

flash chromatography (5% v/v Et₂O in hexanes) to afford product 88

1

CHCl₃); H NMR (400 MHz, CDCl₃): d = 3.91 (d, J=12.6 Hz, 1H), 3.63

(11 mg, 84%) as

a

colorless oil. [a]_D²⁰

=

+6.8 (c=1.23, CH₂Cl₂);

(d, J=5.1 Hz, 2H), 3.61–3.57 (m, 1H), 2.99 (ddd, J=4.8, 2.6, 2.6 Hz,

1H), 2.92 (dd, J=7.0, 2.6 Hz, 1H), 1.78 (brs, 1H), 1.68–1.58 (m, 1H),

0.95 (d, J=7.0 Hz, 3H), 0.89 (s, 9H), 0.052 (s, 3H), 0.048 ppm (s, 3H);

¹³C NMR (100 MHz, CDCl₃): d=65.3, 62.1, 57.7, 57.2, 38.00, 26.0, 18.5,

13.0, ꢀ5.3 ppm; IR (film): n˜ =3439, 2955, 2929, 2857, 1472, 1252, 1095,

832, 773 cm^ꢀ1; HRMS (ESI): m/z: calcd for C₁₂H₂₆O₃SiNa [M⁺+Na]:

269.1545, found: 269.1543.

¹H NMR (400 MHz, CDCl₃): d=6.29 (s, 1H), 3.64–3.58 (m, 1H), 3.49–

3.42 (m, 1H), 1.95–1.88 (m, 1H), 1.84 (s, 3H), 1.81–1.74 (m, 1H), 1.39 (s,

3H), 0.95 (t, J=7.9 Hz, 9H), 0.94 (t, J=7.9 Hz, 9H), 0.63–0.54 ppm (m,

12H); ¹³C NMR (100 MHz, CDCl₃): d=151.6, 78.6, 77.9, 59.0, 44.4, 27.8,

21.7, 7.1, 6.8, 6.7, 4.0 ppm; IR (film): n˜ =2954, 2876, 1091, 1002 cm^ꢀ1; MS

(EI): m/z (%): 484 (1) [M⁺], 455 (18), 427 (11), 325 (100), 217 (24), 115

(38); HRMS (ESI): m/z: calcd for C₁₉H₄₁IO₂Si₂Na [M⁺+Na]: 507.15821,

found: 507.15824.

Compound 20:

123 mmol) was added dropwise to

A

solution of Dibal-H (1.0m in hexanes, 123 mL,

solution of epoxide 19 (7.6 g,

a

Compound 89: A solution of DMSO (0.13 mL, 1.9 mmol) in CH₂Cl₂

(0.5 mL) was added dropwise to a solution of oxalyl chloride (0.11 mL,

0.9 mmol) in CH₂Cl₂(2 mL) at ꢀ788C. After stirring for 30 min, a solu-

tion of 88 (150 mg, 0.31 mmol) in CH₂Cl₂(0.5 mL) was slowly introduced

and stirring continued for 3 h at ꢀ788C. (iPr)₂NEt (0.6 mL, 3.72 mmol)

was added and the mixture allowed to warm to 08C. After 1 h, the reac-

tion was quenched with sat. aq. NH₄Cl, the aqueous layer was extracted

with Et₂O (3ꢄ10 mL), the combined organic phases were dried (Na₂SO₄)

and the solvent evaporated. The crude product was purified by flash

chromatography (10% v/v Et₂O in hexanes) to afford product 89

30.84 mmol) in toluene (25 mL) at ꢀ788C over the course of 1 h. The

temperature was then raised to ꢀ408C and stirring continued for 4 h

before the reaction was carefully quenched at ꢀ608C with a solution of

tBuOH in THF (1:1, 25 mL). The resulting mixture was poured into an

ice-cold solution of Rochelleꢅs salt (85 g in 250 mL water) and vigorously

stirred for 2 h until a clear separation of the phases was reached. The

aqueous layer was extracted with tert-butyl methyl ether, the combined

organic phases were dried over Na₂SO₄and evaporated, and the residue

was purified by flash chromatography (hexanes/EtOAc 1:1) to give prod-

uct 19 as a colorless oil (5.98 g, 78%). [a]²_D⁰= +3.1 (c=0.43, CHCl₃);

¹H NMR (400 MHz, CDCl₃): d=3.79–3.70 (m, 1H), 3.59–3.51 (m, 2H),

3.44–3.35 (m, 2H), 1.86–1.74 (m, 1H), 1.48–1.32 (m, 2H), 0.89 (s, 9H),

0.88 (d, J=6.7 Hz, 3H), 0.06 ppm (s, 6H); ¹³C NMR (100 MHz, CDCl₃):

71.1, 69.5, 67.5, 39.4, 34.2, 26.0, 18.4, 18.0, ꢀ5.3, ꢀ5.4 ppm; IR (film): n˜ =

3350, 2929, 2857, 1471, 1251, 1077, 832, 773 cm^ꢀ1; HRMS (ESI): m/z:

calcd for C₁₂H₂₈O₃SiNa [M⁺+Na]: 271.1699, found: 271.1698.

(123 mg, quant.) as a colorless oil. [a]_D²⁰

= +25.7 (c=0.9, CH₂Cl₂);

¹H NMR (300 MHz, CDCl₃): d=9.63 (t, J=2.9 Hz, 1H), 6.51 (s, 1H),

2.63 (dd, J=15.2, 2.7 Hz, 1H), 2.42 (dd, J=15.2, 3.1 Hz, 1H), 1.90 (d, J=

0.8 Hz, 3H), 1.49 (s, 3H), 0.95 (t, J=7.7 Hz, 9H), 0.62 ppm (q, J=7.9 Hz,

6H); ¹³C NMR (75 MHz, CDCl₃): d=201.9, 150.5, 79.5, 77.9, 53.8, 27.7,

21.6, 7.0, 6.6 ppm; IR (film): n˜ =2955, 2876, 1723, 1003 cm^ꢀ1; MS (EI):

3996

www.chemeurj.org

ꢂ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Chem. Eur. J. 2009, 15, 3983 – 4010

Total Syntheses of Amphidinolides

FULL PAPER

A

J=10.0, 7.5 Hz, 1H), 2.58–2.47 (m, 1H), 1.90 (ddd, J=14.1, 8.7, 5.8 Hz,

1H), 1.68 (ddd, J=14.1, 7.9, 3.5 Hz, 1H), 1.10 (d, J=7.0 Hz, 3H), 1.05 (s,

9H), 0.86 (t, J=8.0 Hz, 9H), 0.47 ppm (q, J=8.0 Hz, 6H); ¹³C NMR

(100 MHz, CDCl₃): 205.3, 135.7, 133.6, 133.5, 129.9, 129.8, 127.9, 70.8,

68.0, 43.3, 35.9, 27.0, 19.4, 13.9, 6.9, 5.0 ppm; IR (film): n˜ =2956, 2933,

2876, 1727, 1428, 1106, 1006, 823, 736 cm^ꢀ1; HRMS (ESI): m/z: calcd for

C₂₈H₄₄O₃Si₂+Na [M⁺+Na]: 507.2727, found: 507.2725.

latridecan-6-ol: Imidazole (4.95 g, 72.56 mmol) and TBDPSCl (18.79 mL,

72.56 mmol) were added to a solution of diol 19 (18.0 g, 72.56 mmol) in

CH₂Cl₂(500 mL) and the reaction was stirred at

(2ꢄ200 mL), and the organic phases were dried

(Na₂SO₄) and evaporated. Purification of the resi-

due by flash chromatography (hexanes/tert-butyl

Aldol product 24: Et₃N (211 mg, 0.29 mL, 2.09 mmol) and Bu₂BOTf

(479 mg, 0.4 mL, 1.79 mmol) were sequentially added to a solution of 23

(529 mg, 1.5 mmol) in toluene (3 mL) at ꢀ508C. The resulting mixture

methyl ether 10:1) furnished the title compound as a colorless syrup

was stirred for 1.5 h before

a solution of aldehyde 22 (600 mg,

(32.0 g, 91%). [a]_D²⁰

=

+3.6 (c=0.5, CHCl₃); ¹H NMR (400 MHz,

1.24 mmol) in toluene (1.25 mL) was slowly introduced and stirring con-

tinued at ꢀ508C for 40 min. The mixture was then warmed to ꢀ308C

and stirred at that temperature for 1 h. For work up, the reaction was

quenched with phosphate buffer (pH 7, 5 mL) and diluted with MeOH

(5 mL) and THF (5 mL). The mixture was warmed to 08C before a solu-

tion of aq. H₂O₂(30% w/w, 1.2 mL) in MeOH (2 mL) was added. After

stirring for 1 h, the mixture was extracted with EtOAc (3ꢄ15 mL), the

combined extracts were washed with phosphate buffer solution (20 mL,

pH 7), the aqueous phase was extracted with Et₂O (3ꢄ10 mL), the com-

bined organic layers were dried over MgSO₄and evaporated, and the res-

idue purified by chromatography (hexanes/EtOAc 7:3) to give aldol

adduct 24 as a colorless oil (853 mg, 82%). ¹H NMR (400 MHz, CDCl₃):

d=7.59 (m, 4H), 7.35–7.20 (m, 11H), 7.12 (d, J=8.4 Hz, 2H), 6.76 (d,

J=8.8 Hz, 2H), 5.24 (d, J=1.3 Hz, 1H), 4.58 (m, 1H), 4.54 (d, J=

11.1 Hz, 1H), 4.46 (d, J=11.1 Hz, 1H), 4.09 (m, 4H), 3.70 (m, 2H), 3.65

(s, 3H), 3.52 (m, 2H), 3.35 (dd, J=9.8, 6.8 Hz, 1H), 3.18 (dd, J=13.4,

3.3 Hz, 1H), 2.63 (dd, J=13.4, 9.6 Hz, 1H), 1.94 (m, 1H), 1.49 (m, 1H),

0.97 (s, 9H), 0.94 (d, J=6.6 Hz, 3H), 0.80 (t, J=8.1 Hz, 9H), 0.43 ppm

(q, J=7.8 Hz, 6H); ¹³C NMR (100 MHz, CDCl₃): d=171.8, 159.0, 135.3,

135.2, 130.0, 129.9, 129.3, 129.2, 129.1, 128.6, 127.4, 127.3, 127.0, 113.4,

77.1, 76.4, 72.1, 70.3, 68.3, 66.5, 60.0, 55.3, 54.8, 37.3, 32.3, 26.7, 26.5, 20.7,

15.0, 13.8, 6.6, 4.7 ppm; IR (film): n˜ =2955, 2875, 1779, 1708, 1612, 1587,

1463, 1427, 1389, 1360, 1301, 1247, 1210, 1175, 1108, 1032, 1008, 906, 823,

CDCl₃): d=7.70–7.66 (m, 4H), 7.45–7.36 (m, 6H), 3.83–3.76 (m, 1H),

3.62 (dd, J=10.0, 4.4 Hz, 1H), 3.56 (dd, J=10.0, 6.6 Hz, 1H), 3.47–3.42

(m, 2H), 1.89–1.79 (m, 1H), 1.51–1.44 (m, 1H), 1.33–1.26 (m, 1H), 1.08

(s, 9H), 0.92–0.88 (m, 12H), 0.05 ppm (s, 6H); ¹³C NMR (100 MHz,

CDCl₃): d=135.7, 133.6, 133.5, 129.9, 127.8, 70.5, 69.1, 68.7, 37.8, 33.2,

27.1, 26.1, 19.4, 17.2, ꢀ5.3, ꢀ5.3 ppm; IR (film): n˜ =3452, 2955, 2929,

2857, 1471, 1428, 1105, 834, 699 cm^ꢀ1; HRMS (ESI): m/z: calcd for

C₂₈H₄₆O₃Si₂Na [M⁺+Na]: 509.2874, found: 509.2878.

Compound 21: Pyridinium p-toluenesulfonate (11.6 g, 46 mmol) was

added to a solution of (6R,8R)-2,2,8,11,11,12,12-heptamethyl-3,3-diphen-

yl-4,10-dioxa-3,11-disilatridecan-6-ol (32 g, 66 mmol) in EtOH (160 mL)

and the resulting mixture was stirred overnight before the solvent was

evaporated. The residue was taken up in tert-butyl methyl ether

(300 mL), the organic phase was washed with aq. sat. NaHCO₃(300 mL),

dried over Na₂SO₄and evaporated to give crude (2R,4R)-5-(tert-butyldi-

phenylsilyloxy)-2-methylpentane-1,4-diol, which was used in the next step

without further purification. For analytical purposes, a small fraction was

purified by flash chromatography (hexanes/tert-butyl methyl ether 30:1)

to give the diol as a colorless oil which analyzed as follows: [a]²_D⁰= +1.2

(c=0.43, CHCl₃); ¹H NMR (400 MHz, CDCl₃): d=7.68–7.63 (m, 4H),

7.45–7.34 (m, 6H), 3.83 (dd, J=4.1, 1.3 Hz, 2H), 3.57 (dd, J=10.9,

5.2 Hz, 1H), 3.47 (dd, J=10.9, 5.3 Hz, 1H), 2.17 (s, 1H), 1.91 (app.

quint., J=6.8 Hz, 1H), 1.72–1.61 (m, 1H), 1.56 (app. quint., J=6.4 Hz,

1H), 1.06 (s, 9H), 0.97 ppm (d, J=6.8 Hz, 3H); ¹³C NMR (100 MHz,

CDCl₃): 188.0, 135.8, 135.7, 133.5, 129.9, 127.8, 80.1, 67.7, 65.1, 42.8, 37.8,

34.4, 32.4, 26.9, 19.4, 17.6 ppm; IR (film): n˜ =3334, 2930, 2858, 1472,

1427, 1110, 699 cm^ꢀ1; HRMS (ESI): m/z: calcd for C₂₂H₃₂O₃SiNa [M⁺

+Na]: 395.2011, found: 395.2013.

740 cm^ꢀ1

;

HRMS (ESI): m/z: calcd for C₄₈H₆₅NO₈Si₂Na [M⁺+Na]:

862.4137, found: 862.4140.

Aldol product 103: Prepared analogously from aldehyde 22 (600 mg,

1.24 mmol) and amide ent-23 (529 mg, 1.5 mmol) as

a colorless oil

(853 mg, 82%). ¹H NMR (400 MHz, CDCl₃): d=7.59 (m, 4H), 7.32–7.22

(m, 11H), 7.18 (d, J=8.4 Hz, 2H), 6.81 (d, J=8.8 Hz, 2H), 5.22 (d, J=

0.9 Hz, 1H), 4.64 (m, 1H), 4.63 (d, J=12.0 Hz, 1H), 4.32 (d, J=12.0 Hz,

1H), 4.13 (m, 2H), 3.70 (m, 2H), 3.74 (s, 3H), 3.74 (m, 2H), 3.49 (dd, J=

12.8, 3.2 Hz, 1H), 3.48 (dd, J=9.6, 1.2 Hz, 1H), 2.77 (dd, J=14.2, 6.5 Hz,

1H), 1.97 (m, 1H, -OH), 178 (m, 1H), 1.18 (m, 1H), 0.97 (d, J=6.6 Hz,

3H), 0.96 (s, 9H), 0.79 (t, J=8.1 Hz, 9H), 0.40 ppm (q, J=7.8 Hz, 6H);

¹³C NMR (100 MHz, CDCl₃): d=170.3, 158.6, 152.3, 134.6, 134.2, 132.6,

132.5, 129.3, 129.2, 128.8, 128.6, 128.5, 128.0, 126.7, 126.6, 112.8, 112.8,

75.9, 71.4, 69.9, 67.6, 66.0, 54.8, 36.8, 31.8, 25.8, 18.2, 14.7, 5.8, 5.7, 5.6, 4.5,

3.9 ppm.

Imidazole (13.5 g, 198 mmol) and TESCl (49.7 g, 330 mmol) was added

to a solution of the crude diol (24.6 g, 66 mmol) in CH₂Cl₂(160 mL) and

the resulting mixture was stirred overnight. A standard extractive work

up followed by flash chromatography of the crude material (hexanes/

EtOAc 30:1) gave product 21 as a colorless oil (34.5 g, 87%). [a]_D²⁰

=

+19.1 (c=1, CHCl₃); ¹H NMR (400 MHz, CDCl₃): d=7.71–7.66 (m,

4H), 7.44–7.36 (m, 6H), 3.84–3.77 (m, 1H), 3.61 (dd, J=10.0, 4.8 Hz,

1H), 3.49 (dd, J=10.0, 5.6 Hz, 1H), 3.46 (dd, J=10.0, 6.9 Hz, 1H), 3.39

(dd, J=10.0, 6.7 Hz, 1H), 1.86–1.76 (m, 1H), 1.51–1.46 (m, 2H), 1.06 (s,

9H), 0.97 (t, J=8.0 Hz, 9H), 0.92 (d, J=6.7 Hz, 3H), 0.89 (t, J=8.0 Hz,

9H), 0.60 (q, J=8.0 Hz, 6H), 0.52 ppm (q, J=8.0 Hz, 6H); ¹³C NMR

(100 MHz, CDCl₃): 135.8, 134.0, 133.9, 129.7, 129.7, 127.8, 71.1, 69.0, 68.6,

38.7, 32.2, 27.0, 19.4, 17.0, 7.0, 6.9, 5.2, 4.7 ppm; IR (film): n˜ =2954, 2876,

1105, 1005, 735, 699 cm^ꢀ1; MS (EI): m/z (%): 571 (21), 543 (29), 411 (20),

367 (21), 313 (83), 285 (39), 257 (18), 253 (19), 213 (95), 199 (100).

Compound 25: 2,6-Lutidine (281 mg, 0.31 mL, 2.62 mmol) and TBSOTf

(629 mg, 550 mL, 2.38 mmol) were added to a solution of alcohol 24

(1.0 g, 1.19 mmol) in CH₂Cl₂(10 mL) at 08C. After stirring for 1 h, the

mixture was warmed to room temperature and the reaction quenched

with sat. aq. NH₄Cl (15 mL). A standard extractive work up followed by

flash chromatography (hexanes/tert-butyl methyl ether 4:1) gave product

Compound 22: (COCl)₂(0.73 mL, 8.93 mmol) was added to a solution of

DMSO (0.71 mL, 10.49 mmol) in CH₂Cl₂(25 mL) at ꢀ788C. After stir-

ring for 10 min, a solution of 21 (1.3 g, 2.10 mmol) in CH₂Cl₂(15 mL)

was added dropwise and the resulting mixture stirred at ꢀ788C over-

night. (iPr)₂NEt (ꢁ5 mL, 21 mmol) was slowly introduced and the mix-

ture was warmed to ambient temperature over the course of 2 h. The re-

action was quenched with water (20 mL), the aqueous phase was extract-

ed with CH₂Cl₂(3ꢄ20 mL), the combined organic layers were dried

(Na₂SO₄) and evaporated, and the residue was purified by flash chroma-

tography (hexanes/tert-butyl methyl ether 10:1) to yield aldehyde 22 as a

colorless oil (670 mg, 68%). [a]²_D⁰= +24.4 (c=0.4, CHCl₃); ¹H NMR

(400 MHz, CDCl₃,): d=9.62 (d, J=1.9 Hz, 1H), 7.67–7.63 (m, 4H), 7.46–

7.36 (m, 6H), 3.79–3.72 (m, 1H), 3.62 (dd, J=10.0, 4.7 Hz, 1H), 3.45 (dd,

25 as a colorless oil (833 mg, 81%). [a]_D²⁰

=

ꢀ13.0 (c=0.2, CHCl₃);

¹H NMR (400 MHz, CDCl₃): d=7.55 (m, 4H), 7.32–7.24 (m, 6H), 7.21–

7.14 (m, 5H), 7.03 (d, J=8.4 Hz, 2H), 6.73 (d, J=8.4 Hz, 2H), 5.2 (d, J=

1.3 Hz, 1H), 4.62 (d, J=11.6 Hz, 1H), 4.39 (d, J=11.6 Hz, 1H), 4.36 (m,

1H), 3.91 (m, 3H), 3.63 (s, 3H), 3.58 (m, 1H), 3.42 (dd, J=10, 4.8 Hz,

1H), 3.29 (dd, J=10, 7.6 Hz, 1H), 2.97 (dd, J=14.4, 3.2 Hz, 1H), 2.14

(dd, J=13.2, 2.8 Hz, 1H), 1.75 (m, 1H), 1.58 (m, 1H), 1.34 (m, 1H), 0.84

(s, 9H), 0.81 (d, J=6.7 Hz, 3H), 0.77 (s, 9H), 0.69 (t, J=8.4 Hz, 9H),

0.27 (q, J=8.5 Hz, 6H), 0.01 (s, 3H), ꢀ0.07 ppm (s, 3H); ¹³C NMR

(100 MHz, CDCl₃): d=171.8, 159.0, 135.3, 135.0, 133.3, 133.2, 130.0,

129.6, 129.2, 129.1, 128.9, 128.6, 127.3, 127.2, 126.9, 113.2, 77.9, 72.1, 70.3,

68.1, 65.8, 55.5, 54.8, 40.1, 37.0, 31.3, 30.0, 26.5, 25.8, 25.5, 25.3, 25.3, 18.9,

18.8, 12.7, 6.7, 6.5, 5.1, 4.6, ꢀ4.0, ꢀ4.1, ꢀ4.7 ppm; IR (film): n˜ =2955,

Chem. Eur. J. 2009, 15, 3983 – 4010

ꢂ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

www.chemeurj.org

3997

A. Fꢀrstner et al.

2931, 2857, 1682, 1614, 1514, 1463, 1428, 1389, 1250, 1112, 1079, 1038,

834, 776, 739, 702 cm^ꢀ1

Compound 72: Prepared analogously from compound 71 (2.34 g,

.

3.36 mmol) as a colorless oil (1.77 g, 90%). [a]_D²⁰

= +47.4 (c=1.2,

CH₂Cl₂); ¹H NMR (400 MHz, [D₆]acetone): d=7.38 (d, J=8.6 Hz, 2H),

6.93 (d, J=8.7 Hz, 2H), 4.62 (d, J=10.7 Hz, 1H), 4.43 (d, J=10.6 Hz,

1H), 3.95 (d, J=6.9 Hz, 1H), 3.91 (q, J=6.1 Hz, 1H), 3.85 (dd, J=6.9,

2.4 Hz, 1H), 3.80 (s, 3H), 2.93–2.85 (m, 2H), 1.68–1.60 (m, 1H), 1.50–

1.46 (m, 2H), 1.25 (t, J=7.2 Hz, 3H), 1.10 (d, J=5.9 Hz, 3H), 0.97 (t, J=

8.0 Hz, 9H), 0.94 (d, J=6.4 Hz, 3H), 0.92 (t, J=8.0 Hz, 9H), 0.63–

0.54 ppm (m, 12H); ¹³C NMR (100 MHz, [D₆]acetone): d=202.1, 160.5,

130.5, 130.4, 114.4, 89.1, 78.1, 73.3, 67.6, 55.5, 45.9, 30.3, 24.2, 22.9, 15.0,

14.4, 7.4, 7.3, 6.0, 5.8 ppm; IR (film): n˜ =2951, 2875, 1682, 1514, 1248,

1004 cm^ꢀ1; MS (EI): m/z (%): 555 (1) [M⁺ꢀEt], 387 (7), 325 (4), 233 (4),

213 (39), 121 (100); HRMS (ESI): m/z: calcd for C₃₀H₅₆O₅SSi₂Na [M⁺

+Na]: 607.32792, found: 607.32729.

Compound 71: Flame dried molecular sieves (4 ꢃ, 4.6 g) were added to a

solution of (2R,4R)-2-methyl-4-(trimethylsilyloxy)pentan-1-ol (2.0 g,

8.6 mmol)^[9]in CH₂Cl₂(86 mL). N-Methyl-morpholine-N-oxide (NMO,

1.5 g, 12.9 mmol) was added followed by tetrapropylammonium per-

ruthenate (TPAP, 151 mg, 0.43 mmol)^[74]and the resulting mixture was

stirred for 30 min before the reaction was filtered through a pad of silica

which was carefully rinsed with Et₂O/hexanes (3:7, 400 mL). The com-

bined filtrates were evaporated and the crude aldehyde 69 was used with-

out further purification.

Et₃N (1.4 mL, 9.8 mmol) and Bu₂BOTf (2.2 mL, 8.9 mmol) were succes-

sively added to a solution of compound 23 (3.48 g, 9.8 mmol) in toluene

(41 mL) at ꢀ508C. After stirring for 30 min at this temperature and for

2 h at ꢀ408C, a solution of crude 69 in toluene (41 mL) was added drop-

wise. Stirring was continued for 12 h before the reaction was quenched

with phosphate buffer (pH 7, 20 mL) and diluted with MeOH (20 mL)

and THF (20 mL). The solution was warmed to 08C before aq. H₂O₂

(30% w/w, 20 mL) in MeOH (20 mL) was slowly added. After stirring

for 60 min, the mixture was extracted with EtOAc (3ꢄ100 mL) and the

combined organic layers were washed with pH 7 buffer (100 mL). The

aqueous phase was extracted with Et₂O (3ꢄ100 mL), the combined or-

ganic layers were dried over Na₂SO₄, the solvent was evaporated, and the

residue purified by flash chromatography (EtOAc in hexanes, 20% !

30% v/v) to afford diol 70 (2.5 g, 62%) as a colorless oil.

Methyl ketone 27: MeLi (1.6m in Et₂O, 10.9 mL, 17.6 mmol) was added

to a suspension of CuI (1.7 g, 8.79 mmol) in Et₂O (7.0 mL) at ꢀ208C.

After stirring for 35 min, the resulting solution was cooled to ꢀ608C

before a solution of thioester 26 (1.2 g, 1.43 mmol) in Et₂O (5 mL) was

slowly added. Once the addition was complete, the mixture was allowed

to warm to ꢀ208C over a period of 2 h. The reaction was quenched with

sat. aq. NH₄Cl (10 mL) at ꢀ108C, the resulting mixture was warmed to

ambient temperature and stirred for 1 h. The aqueous phase was extract-

ed with tert-butyl methyl ether (3ꢄ10 mL), the combined organic layers

were dried over Na₂SO₄and evaporated, and the crude product purified

by flash chromatography (hexanes/EtOAc 9:1) to give ketone 27 as a col-

orless oil (1.0 g, 89%). [a]_D²⁰

=

+35.5 (c=0.5, CHCl₃); ¹H NMR

TESCl (2 mL, 12.19 mmol) and imidazole (1.8 g, 26.5 mmol) were added

to a solution of diol 70 (2.5 g, 5.3 mmol) in CH₂Cl₂(53 mL). After stirring

for 15 h, the reaction was quenched with aq. sat. NaHCO₃(20 mL), the

aqueous layer was extracted with CH₂Cl₂(3ꢄ20 mL), the combined or-

ganic phases were dried (Na₂SO₄) and evaporated, and the residue was

purified by flash chromatography (EtOAc in hexanes, 5 ! 10%) to

afford product 71 as a colorless oil (2.97 g, 80%). [a]²_D⁰= ꢀ33.2 (c=1.25,

CH₂Cl₂); ¹H NMR (300 MHz, CDCl₃): d=7.34–7.27 (m, 5H), 7.19–7.16

(m, 2H), 6.84 (d, J=8.6 Hz, 2H), 5.25 (d, J=6.0 Hz, 1H), 4.65 (d, J=

11.6 Hz, 1H), 4.51 (d, J=12.2 Hz, 1H), 4.49–4.44 (m, 1H), 4.11–4.06 (m,

2H), 3.97 (dd, J=5.8, 2.1 Hz, 1H), 3.80 (q, J=6.0 Hz, 1H), 3.75 (s, 3H),

3.11 (dd, J=13.0, 3.0 Hz, 1H), 2.39 (dd, J=13.5, 13.3 Hz, 1H), 1.61–1.42

(m, 3H), 1.09 (d, J=6.0 Hz, 3H), 0.94 (t, J=7.8 Hz, 9H), 0.93 (t, J=

7.7 Hz, 9H), 0.89 (d, J=6.2 Hz, 3H), 0.64–0.55 ppm (m, 12H); ¹³C NMR

(75 MHz, CDCl₃): d=171.9, 159.4, 152.9, 135.3, 130.1, 129.9, 129.3, 129.0,

127.3, 113.6, 77.0, 73.0, 67.2, 66.3, 56.0, 55.2, 44.3, 37.4, 33.5, 23.7, 14.8,

7.0, 6.9, 5.4, 5.0 ppm; IR (film): n˜ =2955, 2876, 1784, 1247 cm^ꢀ1; MS (EI):

m/z (%): 670 (1) [M⁺-Et], 440 (9), 348 (12), 213 (24), 121 (100); HRMS

(ESI): m/z: calcd for C₃₈H₆₁NO₇Si₂Na [M⁺+Na]: 722.38788, found:

722.38714.

(400 MHz, CDCl₃): d=7.57 (m, 4H), 7.37–7.27 (m, 6H), 7.16 (d, J=

8.4 Hz, 2H), 6.78 (d, J=8.4 Hz, 2H), 4.37 (d, J=11.2 Hz, 1H), 4.26 (d,

J=11.3 Hz, 1H), 3.73 (br.s, 3H), 3.68 (m, 1H), 3.63 (d, J=7 Hz, 1H),

3.56 (m, 1H), 3.48 (dd, J=9.8, 4.5 Hz, 1H), 3.30 (dd, J=9.8, 8.1 Hz, 1H),

2.0 (s, 3H), 1.82 (tdd, J=11.4, 2.0, 1.8 Hz, 1H), 1.52 (m, 1H), 1.26 (tdd,

J=11.4, 2.5, 1.5 Hz, 1H), 0.97 (s, 9H), 0.81 (s, 9H), 0.79 (d, J=6.7 Hz,

3H), 0.71 (t, J=7.8 Hz, 9H), 0.33 (q, J=7.8 Hz, 6H), ꢀ0.01 (s, 3H),

ꢀ0.06 ppm (s, 3H); ¹³C NMR (100 MHz, CDCl₃): d=209.6, 158.9, 135.3,

135.2, 133.2, 129.3, 129.3, 129.2, 127.2, 113.3, 89.9, 77.5, 72.2, 70.0, 67.8,

54.9, 40.7, 31.0, 26.5, 26.0, 25.8, 25.4, 18.8, 18.1, 11.8, 6.4, 4.5, ꢀ4.1,

ꢀ4.9 ppm; IR (film): n˜ =2954, 2858, 1715, 1613, 1515, 1462, 1428, 1388,

1249, 1111, 1037, 1066, 832, 777, 739, 702 cm^ꢀ1; HRMS (ESI): m/z: calcd

for C₄₅H₇₂O₃Si₅Na [M⁺+Na]: 815.45290, found: 815.45302.

Compound 73: Prepared analogously as a pale yellow oil (1.66 g, quant.).

[a]²_D⁰= +30.6 (c=1.1, CH₂Cl₂); ¹H NMR (300 MHz, [D₆]acetone): d=

7.32 (d, J=8.7 Hz, 2H), 6.93 (d, J=8.7 Hz, 2H), 4.43 (s, 2H), 3.95–3.86

(m, 2H), 3.80 (s, 3H), 3.74 (d, J=6.8 Hz, 1H), 2.15 (s, 3H), 1.59–1.43 (m,

3H), 1.10 (d, J=6.1 Hz, 3H), 0.96 (t, J=7.9 Hz, 9H), 0.94 (t, J=7.7 Hz,

9H), 0.90 (d, J=6.6 Hz, 3H), 0.66–0.56 ppm (m, 12H); ¹³C NMR

(100 MHz, [D₆]acetone): d=209.8, 160.5, 130.6, 130.5, 114.5, 89.6, 77.3,

73.1, 67.7, 55.5, 45.4, 33.7, 27.0, 24.0, 14.4, 7.4, 7.4, 7.3, 6.0, 5.8 ppm; IR

(film): n˜ =2954, 2874, 1715, 1514, 1248, 1004 cm^ꢀ1; MS (EI): m/z (%): 373

(2), 345 (1), 308 (2), 279 (6), 213 (36), 121 (100); HRMS (ESI): m/z:

calcd for C₂₉H₅₄O₅Si₂Na [M⁺+Na]: 561.340203, found: 561.339699.

Thioester 26: nBuLi (1.6m in hexane, 1.2 mL, 1.92 mmol) was added to a

solution of EtSH (144 mg, 0.17 mL, 2.32 mmol) in THF (9.0 mL) at 08C.

After stirring for 20 min, a solution of 25 (1.22 g, 1.29 mmol) in THF

(3.0 mL) was slowly introduced and stirring continued for 20 min. The re-

action was quenched with sat. aq. NH₄Cl (25 mL), the aqueous layer ex-

tracted with Et₂O (3ꢄ20 mL), the combined organic phases were dried

over MgSO₄and evaporated, and the residue quickly passed through a

plug of silica gel (hexanes/tert-butyl methyl ether 85:15) to give thioester

Compound 106: MeLi (2.2m in Et₂O, 1.06 mL, 2.34 mmol) was added to

a suspension of CuI (223 mg, 1.17 mmol) in Et₂O (2.0 mL) at ꢀ208C.

After 35 min, the colorless solution was cooled to ꢀ608C before a solu-

tion of thioester derivative 105 (160 mg, 0.19 mmol) in Et₂O (5 mL) was

slowly introduced. The mixture was allowed to warm to ꢀ208C over 2 h

before the reaction was quenched with sat. aq. NH₄Cl (10 mL) at ꢀ108C.

After stirring at ambient temperature for 1 h, the aqueous phase was ex-

tracted with tert-butyl methyl ether (3ꢄ10 mL), the combined organic

phases were dried over Na₂SO₄and evaporated, and the residue purified

by flash chromatography (hexanes/EtOAc 9:1) to give the corresponding

methyl ketone (127 mg, 82%) as a colorless oil. Pyridinium p-toluene sul-

fonate (36.2 mg, 0.14 mmol) was added to a solution of this product

(127 mg, 0.16 mmol) in EtOH (0.3 mL) and the mixture was stirred for

1 h before the reaction was quenched with a sat. aq. NaHCO₃(3 mL). A

standard extractive work up followed by flash chromatography (hexanes/

tert-butyl methyl ether 12:1) gave product 106 as a colorless oil (75 mg,

26 as

a

colorless oil (1.3 g, 87%). [a]_D²⁰

=

ꢀ58.0 (c=0.5, CHCl₃);

¹H NMR (400 MHz, CDCl₃): d=7.63 (m, 4H), 7.39 (m, 6H), 7.31 (d, J=

8.4 Hz, 2H), 6.86 (d, J=8.5 Hz, 2H), 4.57 (d, J=10.8 Hz, 1H), 4.36 (d,

J=10.8 Hz, 1H), 3.91 (d, J=7.2 Hz, 1H), 3.80 (s, 3H), 3.76 (dd, J=7.2,

1.6 Hz, 1H), 3.64 (m, 1H), 3.54 (dd, J=10.0, 4.4 Hz, 1H), 3.37 (dd, J=

9.6, 8.0 Hz, 1H), 2.89 (dq, J=13.2, 7.6 Hz, 1H), 2.78 (dq, J=13.2, 7.6 Hz,

1H), 1.85 (3d, J=11.2, 4, 2 Hz, 1H), 1.77 (m, 1H), 1.32 (m, 1H), 1.22 (t,

J=7.6 Hz, 3H), 1.03 (s, 9H), 0.93 (d, J=6.4 Hz, 3H), 0.86 (s, 9H), 0.80

(t, J=7.8 Hz, 9H), 0.39 (q, J=8 Hz, 6H), 0.02 (s, 3H), ꢀ0.06 ppm (s,

3H); ¹³C NMR (100 MHz, CDCl₃): d=201.9, 158.8, 135.3, 135.2, 133.2,

129.3, 129.27, 129.12, 127.2, 113.2, 88.1, 78.1, 72.0, 70.2, 67.9, 54.9, 40.5,

30.7, 29.3, 26.5, 25.8, 22.0, 18.8, 14.1, 12.0, 6.5, 4.5, ꢀ4.1, ꢀ4.9 ppm; IR

(film): n˜ =2931, 1683, 1515, 1464, 1250, 1110, 822, 741, 702 cm^ꢀ1; HRMS

(ESI): m/z: calcd for C₄₆H₇₄O₆Si₃Na [M⁺+Na]: 861.44024, found:

861.44061.

1

69%). H NMR (400 MHz, CDCl₃): d=7.64 (m, 4H), 7.40–7.33 (m, 6H),

7.19 (d, J=8.6 Hz, 2H), 6.81 (d, J=8.6 Hz, 2H), 4.35 (d, J=2.8 Hz, 2H),

3998

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Chem. Eur. J. 2009, 15, 3983 – 4010

Total Syntheses of Amphidinolides

FULL PAPER

3.77 (m, 1H), 3.77 (brs, 3H), 3.71 (m, 1H), 3.68 (m, 1H), 3.56 (dd, J=

14.0, 9.9 Hz, 1H), 3.45 (dd, J=14.0, 6.6 Hz, 1H), 2.13 (s, 3H), 1.79 (m,

2H), 1.77 (m, 1H), 1.22 (m, 1H), 1.01 (s, 9H), 0.90 (d, J=6.7 Hz, 3H),

0.98 (s, 9H), 0.02 (s, 3H), ꢀ0.06 ppm (s, 3H); ¹³C NMR (100 MHz,

CDCl₃): d=210.1, 135.2, 135.2, 129.5, 129.4, 127.4, 113.4, 95.4, 87.9, 77.0,

76.7, 76.3, 72.2, 69.1, 54.9, 33.9, 32.2, 27.0, 26.5, 25.7, 16.6, ꢀ4.5,

ꢀ5.0 ppm; IR (film): n˜ =3545, 2958, 2931, 2857, 1713, 1648, 1613, 1514,

1463, 1428, 1362, 1302, 1275, 1258, 1112, 835, 703 cm^ꢀ1; HRMS (ESI):

m/z: calcd for C₃₉H₅₈O₆Si₂Na [M⁺+Na]: 701.36595, found: 701.36641.

(ESI): m/z: calcd for C₄₇H₆₈O₇Si₂Na [M⁺+Na]: 823.4396, found:

823.4398.

Methyl ketone 29: A solution of pyridinium p-toluenesulfonate (251 mg,

1 mmol) and 27 (1.0 g, 1.26 mmol) in EtOH (3 mL) was stirred for 1 h

before the reaction was quenched with a sat. aq. NaHCO₃(5 mL). A

standard extractive work up followed by flash chromatography (hexanes/

tert-butyl methyl ether 12:1) of the crude product gave the TES-depro-

tected alcohol as a colorless oil (480 mg, 56%).

DCC (365 mg, 1.77 mmol) and DMAP (72 mg, 0.59 mmol) were added to

a solution of this compound (480 mg, 0.70 mmol) in CH₂Cl₂(3 mL) at

08C. The mixture was stirred for 30 min before acid 28 (393 mg,

2.8 mmol)^[75]was introduced and stirring continued for 12 h at ambient

temperature. For work up, all volatile materials were evaporated, the

product adsorbed on silica and purified by flash chromatography (hex-

anes/tert-butyl methyl ether 12:1) to give product 29 as a colorless oil

Compound 74: Pyridinium p-toluenesulfonate (PPTS, 47 mg, 0.19 mmol)

was added to a solution of 73 (1.66 g, 3.08 mmol) in EtOH (93 mL) at

ꢀ158C. After stirring for 3 h, the reaction was quenched with aq. sat.

NaHCO₃(20 mL), the aqueous layer was extracted with EtOAc (3ꢄ

100 mL), the combined organic phases were dried (Na₂SO₄) and evapo-

rated, and the residue purified by flash chromatography (15 ! 30% v/v

EtOAc in hexanes) to afford alcohol 74 as a colorless oil (1.15 g, 89%).

[a]²_D⁰= +21.4 (c=0.42, CH₂Cl₂); ¹H NMR (300 MHz, [D₆]acetone): d=

7.32 (d, J=8.7 Hz, 2H), 6.91 (d, J=8.7 Hz, 2H), 4.39 (d, J=2.8 Hz, 2H),

4.03 (dd, J=7.4, 2.0 Hz, 1H), 3.86–3.81 (m, 1H), 3.80 (s, 3H), 3.70 (d, J=

7.3 Hz, 1H), 3.41 (d, J=5.3 Hz, 1H), 2.13 (s, 3H), 1.70–1.52 (m, 2H),

1.32–1.22 (m, 1H), 1.11 (d, J=6.2 Hz, 3H), 0.93 (t, J=7.9 Hz, 9H), 0.87

(d, J=6.6 Hz, 3H), 0.65–0.53 ppm (m, 6H); ¹³C NMR (75 MHz,

[D₆]acetone): d=209.6, 160.4, 130.6, 114.4, 90.5, 75.1, 73.0, 65.2, 55.5,

44.2, 32.8, 26.2, 24.7, 14.6, 7.4, 6.0 ppm; IR (film): n˜ =3467, 2959, 2875,

1713, 1514, 1054 cm^ꢀ1; MS (EI): m/z (%): 288 (1), 213 (3), 201 (10), 121

(100); HRMS (ESI): m/z: calcd for C₂₃H₄₀O₅SiNa [M⁺+Na]: 447.25372,

found: 447.25359.

(405 mg, 75%). [a]_D²⁰

=

+11.5 (c=0.5, CHCl₃); ¹H NMR (400 MHz,

CDCl₃): d=7.63 (m, 4H), 7.43–7.32 (m, 6H), 7.20 (d, J=8.4 Hz, 2H),

6.82 (d, J=8.4 Hz, 2H), 6.75 (td, J=6.9, 1.3 Hz, 1H), 5.82 (ddt, J=17.3,

10.4, 6.6 Hz, 1H), 5.10 (m, 1H), 5.03 (ddt, J=17.1, 1.8, 1.4 Hz, 1H), 4.98

(ddt, J=10.4, 1.4, 1.2 Hz, 1H), 4.38 (d, J=11.6 Hz, 1H), 3.78 (br.s, 5H),

3.72 (d, J=5.7 Hz, 1H), 3.66 (d, J=4.8 Hz, 2H), 2.25 (td, J=7.2, 6.9 Hz,

2H), 2.18 (td, J=6.8, 6.6 Hz, 2H), 2.09 (s, 3H), 1.94 (3d, J=14.2, 9.8,

4.2 Hz, 1H), 1.82 (s(d), J=1.0 Hz, 3H), 1.59 (m, 2H), 1.01 (s, 9H), 0.87

(s, 9H), 0.86 (d, J=6.7 Hz, 3H), 0.02 (s, 3H), ꢀ0.03 ppm (s, 3H);

¹³C NMR (100 MHz, CDCl₃): d=210.1, 167.3, 159.0, 141.9, 137.2, 135.2,

133.0, 129.3, 129.0, 127.8, 127.3, 114.9, 113.4, 87.6, 76.6, 72.1, 71.8, 65.4,

54.9, 34.5, 32.5, 32.1, 27.8, 26.8, 26.3, 25.6, 18.83, 18.0, 13.4, 12.1, ꢀ4.5,

ꢀ5.0 ppm; IR (film): n˜ =3072, 2955, 2930, 2857, 1710, 1648, 1613, 1514,

1471, 1462, 1462, 1388, 1249, 1111, 1035, 913, 834, 740 cm^ꢀ1; HRMS

(ESI): m/z: calcd for C₄₇H₆₈O₇Si₂Na [M⁺+Na]: 823.4396, found:

823.4398.

Compound 75: PPh₃(1.5 g, 5.86 mmol) and DIAD (1.15 mL, 5.86 mmol)

were successively added to a solution of alcohol 74 (1.15 g, 2.71 mmol)

and acid 28 (713 mg, 5.08 mmol) in toluene (40 mL) at ꢀ208C. Once the

addition was complete, the mixture was stirred for 1 h at ambient temper-

ature before the reaction was quenched with aq. sat. NaHCO₃(20 mL).

The aqueous layer was extracted with EtOAc (3ꢄ30 mL), the combined

organic phases were dried (Na₂SO₄) and evaporated, and the residue pu-

rified by flash chromatography (5% v/v EtOAc in hexanes) to afford

ester 75 as a colorless oil (1.34 g, 91%). [a]²_D⁰= +29.4 (c=1.4, CH₂Cl₂);

¹H NMR (400 MHz, [D₆]acetone): d=7.33 (d, J=8.7 Hz, 2H), 6.92 (d,

J=8.7 Hz, 2H), 6.72 (tq, J=7.0, 1.3 Hz, 1H), 5.84 (ddt, J=17.0, 10.3,

6.3 Hz, 1H), 5.08–4.96 (m, 3H), 4.46 (d, J=11.0 Hz, 1H), 4.42 (d, J=

11.0 Hz, 1H), 3.89 (dd, J=6.0, 3.0 Hz, 1H), 3.80 (s, 3H), 3.77 (d, J=

6.3 Hz, 1H), 2.32–2.26 (m, 2H), 2.22–2.16 (m, 2H), 2.14 (s, 3H), 1.88–

1.82 (m, 1H), 1.80 (d, J=1.3 Hz, 3H), 1.64–1.57 (m, 1H), 1.56–1.49 (m,

1H), 1.20 (d, J=6.2 Hz, 3H), 0.94 (t, J=7.8 Hz, 9H), 0.88 (d, J=6.5 Hz,

3H), 0.65–0.59 ppm (m, 6H); ¹³C NMR (100 MHz, [D₆]acetone): d=

210.0, 167.7, 160.5, 141.6, 138.6, 130.6, 130.5, 129.2, 115.6, 114.5, 89.0,

77.7, 73.1, 69.2, 55.5, 41.2, 33.6, 33.3, 28.7, 27.1, 21.2, 13.9, 12.6, 7.4,

5.9 ppm; IR (film): n˜ =2954, 2876, 1707, 1514, 1249, 1078, 1005 cm^ꢀ1; MS

(EI): m/z (%): 308 (2), 279 (3), 213 (28), 201 (14), 121 (100); HRMS

(ESI): m/z: calcd for C₃₁H₅₀O₆SiNa [M⁺+Na]: 569.32689, found:

569.32657.

Compound 30: DDQ (797 mg, 3.51 mmol) was added to a solution of 29

(900 mg, 1.17 mmol) in CH₂Cl₂(6 mL). After stirring for 2 h, the reaction

was quenched with sat. aq. NaHCO₃(12 mL) and ice, the aqueous phase

was extracted with CH₂Cl₂(3ꢄ10 mL), the combined organic layers were

dried over Na₂SO₄and evaporated, and the residue purified by flash

chromatography (hexanes/tert-butyl methyl ether 4:1) to give the corre-

sponding alcohol as a colorless oil (400 mg, 52%), which was immediate-

ly used in the next step.

DMAP (100 mg, 0.77 mmol), imidazole (149 mg, 2.19 mmol) and TESCl

(553 mg, 0.62 mL, 3.67 mmol) were added to a solution of this alcohol

(400 mg, 587 mol) in DMF (7 mL) and the resulting mixture was stirred

at 458C for 3 d. The reaction was quenched with sat. aq. NH₄Cl (3ꢄ

20 mL), the aqueous phase extracted with EtOAc (4ꢄ10 mL), the com-

bined organic layers were dried over Na₂SO₄and evaporated, and the

residue was purified by flash chromatography (hexanes/tert-butyl methyl

ether 30:1) to give product 30 (370 mg, 79%) as a colorless oil. [a]_D²⁰

=

+20.1 (c=0.2, CHCl₃); ¹H NMR (400 MHz, C₆D₆): d=7.65 (m, 4H),

7.09 (m, 6H), 6.85 (td, J=6.9, 1.3 Hz, 1H), 5.54 (ddt, J=17.3, 10.4,

6.6 Hz, 1H), 5.33 (m, 1H), 4.87 (ddt, J=17.1, 1.8, 1.4 Hz, 1H), 4.79 (ddt,

J=10.4, 1.4, 1.2 Hz, 1H), 4.09 (d, J=5.1 Hz, 1H), 3.70 (m, 3H), 1.97 (m,

1H), 1.94 (s, 3H), 1.88 (m, 3H), 1.76 (s(d), J=1.3 Hz, 3H), 1.51 (m, 1H),

1.033 (s, 9H), 0.89 (d, J=6.7 Hz, 3H), 0.86 (m, 2H), 0.83 (t, J=7.9 Hz,

9H), 0.825 (s, 9H), 0.39 (q, J=8 Hz, 6H), ꢀ0.02 (s, 3H), ꢀ0.04 ppm (s,

3H); ¹³C NMR (100 MHz, C₆D₆): d=207.8, 167.7, 141.9, 138.0, 136.2,

134.1, 130.0, 129.0, 129.0, 128.0, 115.5, 82.1, 78.8, 72.6, 66.5, 35.8, 33.1,

32.9, 28.7, 28.0, 27.3, 26.5, 19.8, 18.7, 15.4, 7.3, 5.5, ꢀ3.5, ꢀ4.0 ppm; IR

(film): n˜ =2957, 1712, 1648, 1613, 1462, 1258, 1113, 1005, 837, 740,

Compound 107: Prepared analogously from acid 28 (90 mg, 0.64 mmol)

and alcohol 106 (100 mg, 0.16 mmol) as a colorless oil (90 mg, 73%).

[a]²_D⁰= ꢀ7.1 (c=0.95, CHCl₃); ¹H NMR (400 MHz, CDCl₃): d=7.67 (m,

4H), 7.43–7.38 (m, 6H), 7.26 (d, J=8.6 Hz, 2H), 6.87 (d, J=8.6 Hz, 2H),

6.79 (td, J=7.3, 1.3 Hz, 1H), 5.85 (ddt, J=16.9, 11.4, 6.6 Hz, 1H), 5.17

(m, 1H), 5.03 (ddt, J=16.9, 1.8, 1.4 Hz, 1H), 5.00 (ddt, J=10.4, 1.4,

1.2 Hz, 1H), 4.45 (d, J=11.6 Hz, 1H), 4.41 (d, J=11.6 Hz, 1H), 3.81 (s,

3H), 3.67 (m, 2H), 3.66 (2d, J=10.6, 5.6 Hz, 1H), 3.65 (2d, J=10.6,

5.6 Hz, 1H), 2.27 (td, J=7.2, 6.9 Hz, 2H), 2.22 (td, J=6.8, 6.6 Hz, 2H),

2.12 (s, 3H), 1.84 (s(d), J=1.0 Hz, 3H), 1.82 (m, 1H), 1.44 (m, 2H), 1.05

(s, 9H), 1.02 (d, J=6.7 Hz, 3H), 0.89 (s, 9H), 0.03 ppm (s, 3H), ꢀ0.03 (s,

3H); ¹³C NMR (100 MHz, CDCl₃): d=209.0, 167.7, 164.5, 160.2, 145.6,

141.9, 138.1, 137.5, 136.3, 136.3, 134.2, 130.3, 130.0, 128.6, 128.4, 127.8,

114.3, 88.6, 78.6, 73.0, 72.5, 66.6, 55.0, 53.6, 49.5, 34.5, 33.2, 33.1, 32.9,

32.7, 28.8, 28.5, 26.8, 27.3, 27.0, 26.6, 26.8, 19.7, 18.2, 17.6, 13.0, 12.6, ꢀ3.5,

ꢀ4.3 ppm; IR (film): n˜ =3072, 2955, 2930, 2857, 1710, 1648, 1613, 1514,

1471, 1462, 1462, 1388, 1249, 1111, 1035, 913, 834, 740 cm^ꢀ1; HRMS

702 cm^ꢀ1

;

HRMS (ESI): m/z: calcd for C₄₅H₇₄O₆Si₃Na [M⁺+Na]:

817.46785, found: 817.46854.

Compound 108: Prepared analogously from compound 107 as a colorless

oil (34 mg, 65% over two steps). [a]_D²⁰

=

ꢀ32.5 (c=0.9, CHCl₃);

¹H NMR (400 MHz, C₆D₆): d=7.72 (m, 4H), 7.15 (m, 6H), 6.95 (td, J=

6.9, 1.3 Hz, 1H), 5.66 (ddt, J=17.1, 10.0, 6.9 Hz, 1H), 5.33 (m, 1H), 4.93

(ddt, J=16.9, 1.8, 1.1 Hz, 1H), 4.88 (ddt, J=10.4, 1.6, 1.2 Hz, 1H), 4.19

(d, J=5.0 Hz, 1H), 3.74 (m, 2H), 3.67 (dd, J=13.5, 4.8 Hz, 1H), 2.04 (s,

3H), 1.98 (m, 1H), 1.84 (s(d), J=1.3 Hz, 3H), 1.37 (m, 1H), 1.18 (m,

4H), 1.18 (s, 9H), 1.03 (d, J=6.7 Hz, 3H), 0.92 (s, 9H), 0.73 (t, J=

Chem. Eur. J. 2009, 15, 3983 – 4010

ꢂ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

www.chemeurj.org

3999

A. Fꢀrstner et al.

7.9 Hz, 9H), 0.52 (q, J=8 Hz, 6H), 0.07 (s, 3H), ꢀ0.01 ppm (s, 3H);

¹³C NMR (100 MHz, C₆D₆): d=208.2, 167.7, 141.8, 138.1, 136.2, 134.1,

130.2, 128.9, 128.5, 128.0, 115.5, 81.8, 79.4, 72.2, 66.7, 41.9, 36.6, 34.0, 33.1,

32.7, 32.2, 29.6, 28.7, 28.2, 27.4, 27.3, 26.6, 21.0, 19.8, 18.8, 17.5, 14.8, 14.6,

13.0, 11.9, 7.4, 5.5, ꢀ3.2, ꢀ4.0 ppm; HRMS (ESI): m/z: calcd for

C₄₅H₇₄O₆Si₃Na [M⁺+Na]: 817.46785, found: 817.46854.

6.1 Hz, 1H), 3.82 (dd, J=10.8, 4.3 Hz, 1H), 3.79 (dd, J=10.8, 5.5 Hz,

1H), 3.27 (s, 3H), 2.91 (brd, J=3.4 Hz, 1H, OH), 2.91 (dd, J=7.4,

2.0 Hz, 1H), 2.89 (dd, J=17.9, 9.1 Hz, 1H), 2.68 (3d, J=6.4, 5.5, 2.1 Hz,

1H), 2.59 (dd, J=18.0, 2.6 Hz, 1H), 2.55 (m, 1H), 2.15 (3d, J=14.4, 10.0,

4.0 Hz, 1H), 2.09 (dd, J=13.6, 6.6 Hz, 1H), 2.07 (m, 2H), 2.03 (m, 2H),

1.93 (dd, J=13.6, 7.8 Hz, 1H), 1.91 (s(d), J=1.2 Hz, 3H), 1.88 (m, 1H),

1.80 (m, 1H), 1.79 (s(d), J=0.9 Hz, 3H), 1.76 (m, 1H), 1.69 (3d, J=14.4,

9.6, 3.2 Hz, 1H), 1.54 (3d, J=13.9, 6.4, 4.7 Hz, 1H), 1.35 (3d, J=13.2,

8.4, 4.0 Hz, 1H), 1.17 (s, 9H), 1.14 (m, 1H), 1.07 (d, J=6.7, 3H), 1.06 (d,

J=6.8, 3H), 1.03 (s, 9H), 0.88 (d, J=6.6 Hz, 3H), 0.14 (s, 3H), 0.12 ppm

(s, 3H); ¹³C NMR (100 MHz, C₆D₆): d=212.6, 167.5, 160.0, 144.8, 143.5,

137.7, 136.8, 136.0, 135.9, 133.9, 133.8, 130.1, 130.02, 130.01, 129.8, 128.8,

128.1, 125.5, 117.9, 115.4, 114.9, 114.1, 88.0, 77.0, 72.9, 72.8, 66.4, 65.8,

59.0, 58.9, 54.7, 47.3, 46.3, 42.7, 40.0, 39.2, 35.4, 33.7, 32.9, 29.9, 28.4, 27.0,

26.4, 19.7, 19.5, 19.2, 18.6, 14.9, 14.6, 12.8, ꢀ3.7, ꢀ4.3 ppm; IR (film): n˜ =

3390, 2927, 2876, 1711, 1608, 1514, 1462, 1425, 1390, 1252, 1125, 834, 702,

Fragment couplings: Aldol reactions and elaboration of the resulting ad-

ducts

Aldol product 62: A solution of LDA (1m in THF, 0.19 mL, 0.16 mmol)

was added to a solution of methyl ketone 29 (100 mg, 0.13 mmol) in THF

(0.5 mL) at ꢀ788C. After stirring for 2 h, a pre-cooled solution of alde-

691 cm^ꢀ1

;

HRMS (ESI): m/z: calcd for C₆₄H₉₄O₉Si₂Na [M⁺+Na]:

1085.63375, found: 1085.63386.

Compound 76: Prepared analogously from ketone 75 (300 mg,

0.55 mmol) and aldehyde 41 (170 mg, 0.71 mmol). Flash chromatography

(5 ! 10% v/v EtOAc in hexanes) of the crude product afforded (R)-76

(59 mg, 14%) and (S)-76 (191 mg, 44%) as a colorless oil each. Analyti-

cal and spectroscopic data of the major isomer (S)-76: [a]²_D⁰= +40.4 (c=

0.95, CH₂Cl₂); ¹H NMR (400 MHz, C₆D₆): d=7.20 (d, J=8.7 Hz, 2H),

6.95–6.91 (m, 1H), 6.77 (d, J=8.7 Hz, 2H), 5.87 (s, 1H), 5.67 (qt, J=

10.3, 6.2 Hz, 1H), 5.31–5.23 (m, 1H), 5.00–4.94 (m, 2H), 4.32 (d, J=

11.2 Hz, 1H), 4.27 (d, J=11.1 Hz, 1H), 4.13–4.06 (m, 1H), 4.01 (dd, J=

6.2, 3.4 Hz, 1H), 3.84 (d, J=6.2 Hz, 1H), 3.28 (s, 3H), 2.90 (d, J=3.4 Hz,

1H), 2.71 (dd, J=18.1, 9.1 Hz, 1H), 2.65–2.58 (m, 1H), 2.53 (dd, J=18.1,

2.5 Hz, 1H), 2.07–1.95 (m, 6H), 1.88–1.81 (m, 1H), 1.86 (d, J=1.1 Hz,

3H), 1.69 (d, J=1.0 Hz, 3H), 1.56–1.46 (m, 2H), 1.36–1.26 (m, 1H), 1.20

(d, J=6.2 Hz, 3H), 1.13–1.07 (m, 1H), 1.04 (d, J=6.7 Hz, 1H), 1.03 (t,

J=7.8 Hz, 9H), 0.85 (d, J=6.9 Hz, 3H), 0.73–0.66 ppm (m, 6H);

¹³C NMR (100 MHz, C₆D₆): d=213.1, 167.5, 160.2, 152.7, 141.3, 137.8,

130.1, 129.7, 129.0, 115.4, 114.2, 88.2, 77.2, 75.7, 73.2, 69.1, 65.3, 54.8, 47.2,

42.3, 40.8, 39.6, 33.7, 32.9, 28.4, 21.4, 21.2, 18.5, 14.4, 12.8, 7.4, 5.8 ppm;

IR (film): n˜ =3528, 2954, 2875, 1706, 1514, 1250, 1077 cm^ꢀ1; MS (EI): m/z

(%): 517 (1), 439 (6), 421 (3), 279 (2), 213 (32), 121 (100); HRMS (ESI):

m/z: calcd for C₃₈H₆₁IO₇SiNa [M⁺+Na]: 807.31235, found: 807.31209.

hyde 41 (40 mg, 0.17 mmol) was added via cannula at ꢀ788C. Stirring

was continued for 45 min at this temperature before the reaction was

quenched with aq. phosphate buffer (pH 7, 10 mL). The mixture was ex-

tracted with EtOAc (3ꢄ5 mL), and the combined organic layers were

dried over Na₂SO₄and evaporated. Purification of the residue by flash

chromatography (hexanes/tert-butyl methyl ether 4:1) gave aldol 62 as a

colorless oil (90 mg, 70%, d.r. >10:1). [a]_D²⁰

= +5 (c=0.2, CHCl₃);

¹H NMR (400 MHz, C₆D₆): d=7.78 (m, 4H, H26d), 7.26 (m, 6H, H26e,

H26f), 7.18 (d, J=8.5 Hz, 2H, H21c), 6.98 (tq, J=7.3, 1.4 Hz, 1H, H3),

6.75 (d, J=8.5 Hz, 2H, H21d), 5.86 (s(q), J=0.8, 1H, H14), 5.69 (ddt, J=

17.0, 10.4, 6.3 Hz, 1H, H6), 5.43 (m, 1H, H25), 4.98 (ddt, J=17.7, 1.7,

1.6 Hz, 1H, H7_Z), 4.95 (ddt, J=10.2, 1.8, 1.2 Hz, 1H, H7_E), 4.29 (d, J=

11.2 Hz, 1H, H21a), 4.24 (d, J=11.2 Hz, 1H, H21a’), 4.08 (m, 1H, H18),

4.01 (dd, J=6.1, 3.2 Hz, 1H, H22), 3.82 (dd, J=10.8, 4.2 Hz, 1H, H26a),

3.82 (d, J=6.1 Hz, 1H, H21), 3.79 (dd, J=10.8, 5.5 Hz, 1H, H26b), 3.26

(s, 3H, H21f), 2.86 (d, J=3.3 Hz, 1H, OH), 2.71 (dd, J=18.2, 9.2 Hz,

1H, H19a), 2.61 (ddq, J=9.2, 6.8, 5.5 Hz, 1H, H16), 2.51 (dd, J=18.2,

2.4 Hz, 1H, H19b), 2.14 (3d, J=14.2, 9.8, 4.2 Hz, 1H, H24a), 2.06 (m,

2H, H4), 2.01 (m, 2H, H5), 1.90 (s, 3H, H27), 1.86 (m, 1H, H23), 1.68

(s(d), J=1.0 Hz, 3H, H30), 1.68 (3d, J=14.2, 9.3, 3.4 Hz, 1H, H24b),

1.52 (3d, J=13.7, 9.5, 5.5 Hz, 1H, H17a), 1.16 (s, 9H, H26b), 1.11 (3d,

J=13.6, 9.2, 3.6 Hz, 1H, H17b), 1.06 (d, J=6.7 Hz, 3H, H32), 0.99 (s,

9H, H22b), 0.90 (d, J=6.8 Hz, 3H, H31), 0.12 (s, 3H, H22c), 0.15 ppm (s,

3H, H22d); ¹³C NMR (100 MHz, C₆D₆): d=212.8 (s, C20), 167.6 (s, C1),

160.1 (s, C21e), 152.7 (s, C15), 141.6 (d, C3), 137.7 (d, C6), 136.0 (d,

C26d), 135.9 (d, C26e), 133.8 (2 s, C26c), 130.0 (d, C21d), 129.6 (s, C21b),

128.7 (s, C2), 115.4 (t, C7), 114.2 (d, C21d), 88.0 (d, 21), 77.0 (d, C22),

75.6 (d, C14), 73.0 (t, C21a), 72.9 (d, C25), 66.4 (t, C26), 65.2 (d, C18),

54.8 (q, C21f), 47.2 (t, C19), 42.2 (t, C17), 39.5 (d, C16), 35.4 (t, C24),

33.8 (d, C23), 32.8 (t, C5), 28.4 (t, C4), 27.0 (q, C26b), 26.4 (q, C22b),

21.3 (q, C30), 19.5 (s, C26a), 18.6 (s, C22a), 18.5 (q, C31), 14.6 (q, C32),

12.8 (q, C27), ꢀ3.7 (q, C22c), ꢀ4.3 ppm (q, C22d); IR (film): n˜ =3480,

2930, 2857, 1708, 1613, 1514, 1462, 1428, 1388, 1250, 1115, 1036, 834, 777,

741, 702 cm^ꢀ1; HRMS (ESI): m/z: calcd for C₅₄H₇₉O₈Si₂INa [M⁺+Na]:

1061.42504, found: 1061.42498.

Analytical and spectroscopic data of the minor isomer (R)-76: [a]_D²⁰

=

+21.4 (c=0.92, CH₂Cl₂); ¹H NMR (400 MHz, C₆D₆): d=7.15 (d, J=

8.4 Hz, 2H), 6.95–6.92 (m, 1H), 6.77 (d, J=

8.7 Hz, 2H), 5.97 (s, 1H), 5.68 (qt, J=10.3,

6.1 Hz, 1H), 5.31–5.24 (m, 1H), 5.01–4.94

(m, 2H), 4.31 (d, J=11.4 Hz, 1H), 4.19 (d,

J=11.4 Hz, 1H), 3.99 (dd, J=6.8, 2.8 Hz,

1H), 3.92–3.85 (m, 1H), 3.82 (d, J=6.8 Hz,

1H), 3.30 (s, 3H), 2.80 (brs, 1H), 2.72–2.64

(m, 1H), 2.64 (dd, J=18.0, 2.9 Hz, 1H), 2.45

(dd, J=18.0, 8.9 Hz, 1H), 2.06–1.91 (m,

4H), 1.88 (s, 3H), 1.86–1.78 (m, 1H), 1.65

(d, J=1.0 Hz, 3H), 1.55–1.48 (m, 1H), 1.31–1.14 (m, 3H), 1.22 (d, J=

6.1 Hz, 3H), 1.07 (d, J=6.4 Hz, 3H), 1.04 (t, J=7.8 Hz, 9H), 0.82 (d, J=

7.0 Hz, 3H), 0.75–0.68 ppm (m, 6H); ¹³C NMR (100 MHz, C₆D₆): d=

212.4, 167.5, 160.1, 151.2, 141.2, 137.8, 130.1, 129.6, 129.0, 115.4, 114.2,

89.2, 76.9, 76.4, 73.3, 69.0, 65.5, 54.9, 46.8, 42.1, 41.3, 40.1, 33.0, 32.9, 28.4,

21.1, 20.2, 20.1, 13.8, 12.8, 7.4, 5.8 ppm; IR (film): n˜ =3528, 2955, 2932,

2875, 1705, 1514, 1249, 1075, 1036 cm^ꢀ1; MS (EI): m/z (%): 517 (1), 439

(8), 421 (3), 353 (1), 279 (2), 213 (33), 121 (100); HRMS (ESI): m/z:

calcd for C₃₈H₆₁IO₇SiNa [M⁺+Na]: 807.31235, found: 807.31198.

Compound 58: Prepared analogously from methyl ketone 29 (25 mg,

31 mmol) and aldehyde 57 (10 mg, 38 mmol) as a colorless oil (13 mg,

40%, d.r. >20:1). [a]²_D⁰= +12.3 (c=0.4, CHCl₃); ¹H NMR (600 MHz,

C₆D₆): d=7.79 (m, 4H), 7.21 (m, 6H), 7.15 (m, 2H), 6.99 (tq, J=7.4,

1.4 Hz, 1H), 6.75 (d, AB, J=8.7, 2H), 5.73 (s 1H), 5.69 (ddt, J=17.0,

10.3, 6.3, 1H), 5.50 (3d, J=17.2, 10.4, 7.5, 1H), 5.44 (m, 1H), 5.29 (3d,

J=17.2, 1.5, 0.5 Hz, 1H), 5.02 (3d, J=10.4, 1.6, 0.5 Hz, 1H), 5.00 (s, 1H),

4.99 (ddt, J=17.2, 1.7, 1.6 Hz, 1H), 4.95 (ddt, J=10.3, 1.9, 1.1 Hz, 1H),

4.93 (dd, J=2.4, 1.1 Hz, 1H), 4.37 (d, J=11.2 Hz, 1H), 4.26 (m, 1H),

4.24 (d, J=11.1 Hz, 1H), 4.03 (dd, J=6.1, 3.3 Hz, 1H), 3.86 (d, J=

Compound 90: Prepared analogously from ketone 75 (140 mg,

0.26 mmol) and aldehyde 89 (123 mg, 0.33 mmol) as

a colorless oil

(106 mg, 45%). [a]²_D⁰+38.5 (c=1.6, CH₂Cl₂); ¹H NMR (400 MHz,

=

C₆D₆): d=7.25 (d, J=8.7 Hz, 2H), 6.97–6.91 (m, 1H), 6.79 (d, J=8.7 Hz,

2H), 6.37 (d, J=0.8 Hz, 1H), 5.76–5.63 (m, 1H), 5.32–5.22 (m, 1H),

5.03–4.94 (m, 2H), 4.54–4.48 (m, 1H), 4.47 (d, J=11.0 Hz, 1H), 4.27 (d,

J=11.0 Hz, 1H), 4.04 (dd, J=6.1, 3.0 Hz, 1H), 3.89 (d, J=6.4 Hz, 1H),

3.45 (d, J=2.0 Hz, 1H), 3.29 (s, 3H), 3.08 (dd, J=17.5, 8.0 Hz, 1H), 2.52

4000

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ꢂ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Chem. Eur. J. 2009, 15, 3983 – 4010

Total Syntheses of Amphidinolides

FULL PAPER

(dd, J=17.5, 4.3 Hz, 1H), 2.07–1.98 (m, 6H), 1.93–1.85 (m, 2H), 1.89 (s,

6H), 1.56–1.45 (m, 3H), 1.30 (s, 3H), 1.22 (d, J=6.0 Hz, 3H), 1.04–0.99

(m, 1H), 1.04 (t, J=8.3 Hz, 9H), 0.92 (t, J=7.9 Hz, 9H), 0.75–0.65 (m,

6H), 0.55–0.47 ppm (m, 6H); ¹³C NMR (100 MHz, C₆D₆): d=211.4,

167.4, 160.0, 152.8, 141.2, 137.8, 130.1, 130.0, 129.0, 115.4, 114.1, 88.4,

80.0, 79.2, 76.9, 73.0, 69.2, 64.9, 54.8, 48.7, 47.4, 40.7, 33.6, 32.9, 28.4, 26.6,

22.1, 21.1, 14.4, 12.8, 7.4, 7.3, 6.8, 5.8 ppm; IR (film): n˜ =2955, 1707, 1515,

1250, 1077, 1009 cm^ꢀ1; MS (EI): m/z (%): 685 (1), 437 (2), 339 (6), 325

(6), 279 (3), 213 (34), 121 (100); HRMS (ESI): m/z: calcd for

C₄₄H₇₅IO₈Si₂Na [M⁺+Na]: 937.39374, found: 937.39384.

26.0, 23.8, 20.9, 19.5, 18.6, 18.4, 15.2, 14.6, 12.8, 7.19, 7.16, 5.22, 5.21, 5.18,

1.4, ꢀ3.7, ꢀ4.4 ppm.

Data of the minor diastereomer (S)-96: [a]_D²⁰

= +11.0 (0.1, CHCl₃);

¹H NMR (400 MHz, C₆D₆): d=7.63 (m, 4H), 7.07 (m, 6H), 6.85 (t, J=

6.1 Hz, 1H), 5.80 (s, 1H), 5.44 (ddt, J=16.1, 10.6, 5.5 Hz, 1H), 5.30 (m,

1H), 4.84 (ddt, J=18.9, 1.7, 1.6 Hz, 1H), 4.80 (ddt, J=11.6, 1.5, 1.0 Hz,

1H), 4.12 (d, J=4.6 Hz, 1H), 3.82 (m, 1H), 3.68 (m, 3H), 2.81 (d, J=

2.0 Hz, 1H), 2.46 (dd, J=17.9, 9.1 Hz, 1H), 2.59 (m, 1H), 2.45 (dd, J=

18.1, 2.5 Hz, 1H), 1.99–1.87 (m, 5H), 1.76 (s, 3H), 1.49 (s, 3H), 1.45 (m,

1H), 1.18 (m, 3H), 1.01 (s, 9H), 0.87 (d, J=6.6 Hz, 3H), 0.82 (s, 9H),

0.69 (t, J=8.0 Hz, 9H), 0.66 (d, J=6.8 Hz, 3H), 0.46 (q, J=7.8 Hz, 6H),

0.03 (s, 3H), ꢀ0.05 ppm (s, 3H).

Compound 109: Prepared analogously from methyl ketone 108 (34 mg,

42 mmol) and aldehyde 57 (11 mg, 42 mmol) as a colorless oil (21 mg,

49%). [a]²_D⁰= +11.0 (c=0.1, CHCl₃); ¹H NMR (600 MHz, C₆D₆): d=

7.79 (m, 4H), 7.27–7.22 (m, 6H), 7.06 (tq, J=7.3, 1.4 Hz, 1H), 5.72 (ddt,

J=16.9, 10.4, 6.3 Hz, 1H), 5.72 (s, 1H), 5.52 (3d, J=17.2, 10.3, 7.5 Hz,

1H), 5.52 (m, 1H), 5.29 (3d, J=17.2, 1.8, 1.6 Hz, 1H), 5.03 (3d, J=10.4,

1.6, 0.3 Hz, 1H), 5.00 (s(d), J=2.5 Hz, 1H), 5.00 (ddt, J=17.0, 1.6,

0.5 Hz, 1H), 4.96 (ddt, J=10.2, 1.9, 1.1 Hz, 1H), 4.92 (dd, J=2.4, 1.2 Hz,

1H), 4.36 (d, J=5.4 Hz, 1H), 4.25 (m, 1H), 3.87 (dd, J=10.6, 5.5 Hz,

1H), 3.85 (dd, J=5.3, 4.6 Hz, 1H), 3.83 (dd, J=10.6, 4.9 Hz, 1H), 2.91

(dd, J=7.5, 2.0 Hz, 1H), 2.90 (dd, J=17.4, 2.7 Hz, 1H), 2.87 (br. d, J=

3.2 Hz, 1H, OH), 2.73 (dd, J=17.4, 9.3 Hz, 1H), 2.68 (3d, J=6.3, 5.4,

2.0 Hz, 1H), 2.49 (sext., J=7.0 Hz, 1H), 2.13 (3d, J=14.2, 10.4, 2.8 Hz,

1H), 2.10–2.07 (m, 5H), 2.03 (m, 1H), 1.95 (s(d), J=1.3 Hz, 3H), 1.93

(dd, J=13.6, 7.6 Hz, 1H), 1.81 (m, 1H), 1.78 (3d, J=13.7, 8.5, 7.0 Hz,

1H), 1.76 (s(d), J=1.4 Hz, 3H), 1.60 (3d, J=14.1, 10.9, 2.6 Hz, 1H), 1.55

(3d, J=13.7, 6.4, 4.8 Hz, 1H), 1.38 (3d, J=13.7, 7.6, 4.5 Hz, 1H), 1.18 (s,

9H), 1.15 (3d, J=13.8, 8.8, 5.3 Hz, 1H), 1.15 (d, J=6.8 Hz, 3H), 1.03 (d,

J=6.9 Hz, 3H), 1.01 (s, 9H), 1.01 (t, J=7.9 Hz, 9H), 0.88 (d, J=6.7 Hz,

3H), 0.67 (q, J=8.0 Hz, 6H), 0.20 (s, 3H), 0.10 ppm (s, 3H); ¹³C NMR

(100 MHz, C₆D₆): d=211.3, 167.5, 144.7, 143.4, 141.5, 137.8, 136.8, 136.0,

135.9, 133.9, 133.8, 130.0, 128.7, 128.1, 128.0, 125.7, 118.0, 115.3, 115.0,

82.0, 79.0, 72.1, 66.5, 66.4, 59.0, 46.9, 46.2, 42.8, 40.2, 39.1, 33.7, 32.9, 32.6,

29.9, 28.5, 27.0, 26.4, 19.7, 19.5, 19.4, 18. 6, 17.3, 14.7, 12.8, 7.2, 5.3, ꢀ3.3,

ꢀ4.2 ppm; IR (film): n˜ =3370, 2950, 2872, 1705, 1610, 1514, 1462, 1423,

Compound 63: A precooled solution of TBSOTf (39.6 mg, 0.15 mmol)

and 2,6-lutidine (27.8 mg, 0.26 mmol) in CH₂Cl₂(0.5 mL) was added to a

solution of 62 (130 mg, 0.13 mmol) in CH₂Cl₂(0.8 mL) at 08C and the re-

sulting mixture was slowly warmed to ambient temperature. After stirring

for 1 h, the reaction was quenched with sat. aq. NH₄Cl (5 mL), the mix-

ture extracted with CH₂Cl₂(3ꢄ10 mL), and the combined organic phases

were dried over Na₂SO₄and evaporated. Purification of the residue by

flash chromatography (hexanes/tert-butyl methyl ether 11:1) gave product

63 as a pale yellow oil (112 mg, 79%). ¹H NMR (400 MHz, C₆D₆): d=

7.78 (m, 4H), 7.31 (d, J=8.2 Hz, 2H), 7.24 (m, 6H), 6.99 (tq, J=7.1,

1.4 Hz, 1H), 6.78 (d, J=8.5 Hz, 2H), 6.06 (s, 1H), 5.71 (ddt, J=17.0,

10.7, 6.2 Hz, 1H), 5.43 (m, 1H), 4.97 (m, 2H), 4.55 (d, J=11.1 Hz, 1H),

4.39 (m, 1H), 4.29 (d, J=10.9 Hz, 1H), 4.04 (dd, J=10.8, 3.3 Hz, 1H),

3.89 (d, J=5.8 Hz, 1H), 3.81 (dd, J=10.8, 5.5 Hz, 1H), 3.27 (s, 3H), 3.26

(m, 1H), 3.25 (m, 1H), 2.59 (dd, J=18.2, 7.7 Hz, 1H), 2.54 (ddq, J=9.8,

6.7, 5.5 Hz, 1H), 2.15 (m, 1H), 2.09 (m, 2H), 2.01 (m, 2H), 1.92 (s(d), J=

1.3 Hz, 3H), 1.76 (s(d), J=1.0 Hz, 3H), 1.74 (m, 1H), 1.68–1.65 (m, 2H),

1.17 (s, 9H), 1.08 (d, J=6.8 Hz, 3H), 1.0 (s, 9H), 0.99 (d, J=6.8 Hz, 3H),

0.93 (s, 9H), 0.15 (s, 3H), 0.12 (s, 3H), 0.11 (s, 3H), 0.05 ppm (s, 3H); IR

(film): n˜ =2926, 2855, 1713, 1613, 1515, 1462, 1462, 1428, 1361, 1250,

1112, 1084, 1039, 1005, 914, 834, 775, 701 cm^ꢀ1

.

Compound 77: Prepared analogously from alcohol 76 (146 mg,

0.186 mmol) as a colorless oil (136 mg, 81%). [a]²_D⁰= +42.5 (c=0.94,

CH₂Cl₂); ¹H NMR (400 MHz, C₆D₆): d=7.32 (d, J=8.6 Hz, 2H), 6.96–

6.92 (m, 1H), 6.82 (d, J=8.7 Hz, 2H), 6.05 (s, 1H), 5.68 (ddt, J=16.9,

10.4, 6.3 Hz, 1H), 5.32–5.24 (m, 1H), 5.01–4.92 (m, 2H), 4.57 (d, J=

10.9 Hz, 1H), 4.43–4.38 (m, 1H), 4.33 (d, J=10.9 Hz, 1H), 4.05 (dd, J=

6.1, 3.4 Hz, 1H), 3.90 (d, J=6.2 Hz, 1H), 3.29 (s, 3H), 3.26 (dd, J=18.2,

6.6 Hz, 1H), 2.59–2.53 (m, 2H), 2.07–1.98 (m, 5H), 1.90–1.83 (m, 2H),

1.88 (d, J=1.1 Hz, 3H), 1.77 (d, J=1.0 Hz, 3H), 1.68–1.61 (m, 2H), 1.58–

1.51 (m, 2H), 1.36–1.27 (m, 1H), 1.22 (d, J=6.2 Hz, 3H), 1.06 (d, J=

6.7 Hz, 3H), 1.03 (t, J=7.8 Hz, 9H), 0.95 (s, 9H), 0.75–0.66 (m, 6H), 0.15

(s, 3H), 0.13 ppm (s, 3H); ¹³C NMR (100 MHz, C₆D₆): d=210.1, 167.4,

160.0, 152.2, 141.1, 137.7, 129.9, 129.0, 128.8, 115.3, 114.2, 88.4, 76.9, 75.8,

72.9, 69.2, 66.5, 54.7, 47.2, 43.7, 40.7, 39.8, 33.7, 32.8, 28.3, 26.1, 21.3, 21.1,

19.3, 18.2, 14.5, 12.8, 7.3, 5.7, ꢀ4.0, ꢀ4.6 ppm; IR (film): n˜ =2956, 1709,

1515, 1251, 1079 cm^ꢀ1; MS (EI): m/z (%): 660 (3), 553 (19), 213 (79), 121

(100); HRMS (ESI): m/z: calcd for C₄₄H₇₅IO₇Si₂Na [M⁺+Na]: 921.39883,

found: 921.39895.

1381, 1252, 1125, 906, 699 cm^ꢀ1

; HRMS (ESI): m/z: calcd for

C₆₂H₁₀₀O₈Si₃+NH₄[M⁺+NH₄]: 1074.7049, found: 1074.7064.

Compounds 96: A solution of the ketone 30 (20 mg, 24.7 mmol) in Et₂O

(0.8 mL) was added to a pre-mixed (08C) solution containing dicyclohex-

ylborane (1m in hexane, 37 mL, 37.1 mmol) and Et₃N (55.5 mL, 0.4 mmol)

at 08C and the resulting mixture was stirred at this temperature for 1 h

before it was cooled to ꢀ788C. A solution of aldehyde ent-41 (6 mg,

25.2 mmol) in Et₂O (1 mL) was slowly introduced and stirring continued

for 15 min at ꢀ788C and for 13 h at ꢀ208C. For work up, the mixture

was partitioned between Et₂O (3ꢄ5 mL) and pH 7 buffer solution

(10 mL), and the combined organic extracts were dried (Na₂SO₄) and

evaporated. The residue was taken up in MeOH (3 mL) and pH 7 buffer

solution (3 mL) and stirred at 08C before aq. H₂O₂(30% w/w, 20 mL)

was added. After stirring for 1 h at room temperature, the mixture was

diluted with H₂O (5 mL) and extracted with CH₂Cl₂(2ꢄ10 mL). The

combined organic layers were washed with aq. sat. sodium thiosulfate so-

lution (3ꢄ10 mL), dried over Na₂SO₄and evaporated, and the residue

purified by flash chromatography (hexanes/tert-butyl methyl ether 25:1)

to give compound (R)-96 as a colorless oil (12 mg, 46%) and a second

fraction containing (S)-96 (3 mg, 12%). The major diastereomer (R)-96

analyzed as follows: ¹H NMR (400 MHz, C₆D₆): d=7.67 (m, 4H), 7.12

(m, 6H), 6.88 (t, J=7.0 Hz, 1H), 5.75 (s, 1H), 5.57 (ddt, J=16.9, 10.7,

5.6 Hz, 1H), 5.33 (m, 1H), 4.85 (ddt, J=17.2, 1.5, 1.3 Hz, 1H), 4.83 (ddt,

J=10.9, 1.5, 1.1 Hz, 1H), 4.17 (d, J=5.3 Hz, 1H), 3.96 (m, 1H), 3.74 (m,

2H), 3.60 (m, 1H), 2.90 (d, J=2.8 Hz, 1H), 2.80 (dd, J=17.9, 2.3 Hz,

1H), 2.45 (m, 1H), 2.37 (dd, J=17.7, 9.6 Hz, 1H), 1.99–1.87 (m, 5H),

1.79 (s, 3H), 1.66 (m, 1H), 1.53 (s(d), J=1.0 Hz, 3H), 1.16 (m, 3H), 1.04

(s, 9H), 0.91 (d, J=6.6 Hz, 3H), 0.84 (s, 9H), 0.72 (m, 9H), 0.66 (d, J=

6.8 Hz, 3H), 0.49 (q, J=7.8 Hz, 6H), 0.05 (s, 3H), ꢀ0.01 ppm (s, 3H);

¹³C NMR (100 MHz, C₆D₆): d=211.6, 167.5, 152.4, 141.6, 137.8, 136.0,

135.9, 135.2, 133.8, 133.7, 130.0, 129. 8, 128.7, 128.1, 128.0, 127.8, 127.6,

115.4, 82.0, 78.6, 75.7, 72.3, 66.2, 65.6, 47.3, 42.1, 39.7, 35.8, 32.9, 32.5,

32.3, 30.4, 30.2, 30.1, 29.6, 29.56, 29.55, 28.4, 27.0, 26.7, 26.3, 26.21, 26.18,

Compound 91: Prepared analogously from alcohol 90 (141 mg,

0.154 mmol) as a colorless oil (137 mg, 86%). [a]²_D⁰= +43.6 (c=1.4,

CH₂Cl₂); ¹H NMR (300 MHz, C₆D₆): d=7.36 (d, J=8.6 Hz, 2H), 6.95–

6.91 (m, 1H), 6.82 (d, J=8.6 Hz, 2H), 6.44 (s, 1H), 5.68 (qt, J=10.3,

6.3 Hz, 1H), 5.37–5.26 (m, 1H), 5.01–4.93 (m, 2H), 4.62 (d, J=10.8 Hz,

1H), 4.51–4.43 (m, 1H), 4.32 (d, J=10.8 Hz, 1H), 4.06 (dd, J=6.8,

2.9 Hz, 1H), 3.90 (d, J=6.8 Hz, 1H), 3.35 (dd, J=18.0, 8.1 Hz, 1H), 3.29

(s, 3H), 2.72 (dd, J=18.0, 4.0 Hz, 1H), 2.08–1.85 (m, 8H), 1.94 (s, 3H),

1.88 (s, 3H), 1.61 (ddd, J=13.8, 8.9, 4.9 Hz, 1H), 1.27 (d, J=6.9 Hz, 3H),

1.26 (s, 3H), 1.10 (d, J=6.6 Hz, 3H), 1.07–0.97 (m, 18H), 0.94 (s, 9H),

0.77–0.68 (m, 6H), 0.65–0.57 (m, 6H), 0.19 (s, 3H), 0.18 ppm (s, 3H);

¹³C NMR (75 MHz, C₆D₆): d=210.5, 167.4, 160.0, 151.8, 141.1, 137.8,

130.1, 129.9, 129.1, 115.4, 114.1, 88.6, 79.1, 79.0, 76.4, 72.7, 69.1, 65.9, 54.8,

50.2, 47.4, 40.6, 33.6, 32.9, 28.5, 28.4, 26.3, 22.3, 21.1, 18.3, 14.5, 12.9, 7.5,

7.4, 7.1, 5.8, ꢀ3.8, ꢀ4.1 ppm; IR (film): n˜ =2955, 2877, 1708, 1575, 1250,

1003 cm^ꢀ1; MS (EI): m/z (%): 790 (2), 683 (3), 551 (10), 325 (28), 213

Chem. Eur. J. 2009, 15, 3983 – 4010

ꢂ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

www.chemeurj.org

4001

A. Fꢀrstner et al.

(93), 121 (100); HRMS (ESI): m/z: calcd for C₅₀H₈₉IO₈Si₃Na [M⁺+Na]:

1051.48045, found: 1051.48022.

(s, 3H), 1.89–1.84 (m, 1H), 1.89 (s, 3H), 1.54–1.44 (m, 1H), 1.33 (s, 3H),

1.26 (d, J=6.1 Hz, 3H), 1.09–0.96 (m, 30H), 0.98 (s, 9H), 0.77–0.66 (m,

12H), 0.63–0.55 (m, 6H), 0.18 (s, 3H), 0.17 ppm (s, 3H); ¹³C NMR

(75 MHz, C₆D₆): d=207.9, 167.4, 152.1, 141.0, 137.8, 129.1, 115.4, 81.8,

79.3, 78.9, 78.2, 68.8, 65.7, 50.2, 49.4, 41.2, 33.0, 32.5, 28.5, 28.4, 26.4, 22.2,

21.0, 18.3, 15.7, 12.9, 7.5, 7.4, 7.3, 7.1, 5.7, 5.5, ꢀ3.7, ꢀ4.0 ppm; IR (film):

Compound 97: Prepared analogously from alcohol 96 (157 mg,

0.152 mmol) as a colorless oil (155 mg, 89%). [a]_D²⁰

=

ꢀ4.1 (c=1.0,

1

CH₂Cl₂); H NMR (400 MHz, C₆D₆): d=7.93–7.89 (m, 4H), 7.41–7.34 (m,

6H), 7.13–7.09 (m, 1H), 6.13 (s, 1H), 5.81 (ddt, J=16.9, 10.3, 6.3 Hz,

1H), 5.59 (sext., J=4.3 Hz, 1H), 5.13–5.05 (m, 2H), 4.45 (quint., J=

6.0 Hz, 1H), 4.40 (d, J=5.3 Hz, 1H), 4.05 (dd, J=5.0, 3.7 Hz, 1H), 4.00

(s, 1H), 3.98 (d, J=0.8 Hz, 1H), 3.20 (dd, J=18.8, 6.3 Hz, 1H), 2.91 (dd,

J=18.7, 5.3 Hz, 1H), 2.70 (q, J=6.9 Hz, 1H), 2.29 (brs, 1H), 2.22–2.11

(m, 5H), 2.03 (s, 3H), 1.88–1.82 (m, 1H), 1.85 (d, J=0.8 Hz, 3H), 1.77–

1.72 (m, 2H), 1.29 (s, 9H), 1.16–1.11 (m, 9H), 1.12 (s, 9H), 1.09 (s, 9H),

1.06 (d, J=6.8 Hz, 3H), 0.96 (d, J=6.5 Hz, 3H), 0.77 (q, J=3.7 Hz, 6H),

0.32 (s, 3H), 0.30 (s, 3H), 0.27 (s, 3H), 0.23 ppm (s, 3H); ¹³C NMR

(100 MHz, C₆D₆): d=207.6, 167.4, 152.4, 141.4, 137.8, 136.1, 136.0, 133.9,

133.8, 130.1, 115.4, 81.2, 78.7, 75.7, 72.5, 66.3, 66.2, 49.2, 43.9, 40.1, 36.5,

33.0, 31.8, 28.5, 27.1, 26.3, 26.2, 21.3, 19.6, 19.1, 18.5, 18.3, 15.4, 12.9, 7.2,

5.4, ꢀ3.6, ꢀ3.9, ꢀ4.3, ꢀ4.4 ppm; IR (film): n˜ =2955, 2930, 2857, 1710,

1255, 1111 cm^ꢀ1; MS (EI): m/z (%): 1089 (1) [M⁺ꢀtBu], 957 (3), 721 (3),

467 (46), 185 (100); HRMS (ESI): m/z: calcd for C₅₈H₉₉IO₇Si₄Na [M⁺

+Na]: 1169.540481, found: 1169.541301.

n˜ =2954, 2877, 1708, 1002 cm^ꢀ1

;

HRMS (ESI): m/z: calcd for

C₄₈H₉₅IO₇Si₄Na [M⁺+Na]: 1045.50918, found: 1045.50828.

Stille–Migita cross-coupling reactions

Compound 65: A degassed solution of stannane 55 (51 mg, 113 mmol)

and vinyl iodide 64 (65 mg, 57 mmol) in DMF (0.6 mL) was added to a

ꢀ

+

Schlenk tube containing flame-dried [Ph₂PO₂

230 mmol). Copper-thiophene carboxylate (CuTC, 33 mg, 170 mmol) was

then introduced followed by [Pd(PPh₃)₄] (46 mg, 40 mmol). The resulting

]

[NBu₄

]

(105 mg,

AHCTUNGTRENNUNG

mixture was stirred for 30 min before the reaction was quenched with

water (1 mL). The aqueous phase was extracted with Et₂O (2ꢄ2 mL),

the combined organic layers were dried over Na₂SO₄and evaporated,

and the residue was purified by flash chromatography (hexanes/tert-butyl

methyl ether 4:1) to afford product 65 as a pale yellow oil (58.6 mg,

89%). [a]²_D⁰= +12.3 (c=0.4, CHCl₃); ¹H NMR (400 MHz, C₆D₆): d=

7.81 (tt, J=1.8, 6.6 Hz, 4H), 7.26 (m, 6H), 7.01 (tq, J=7.4, 1.1 Hz, 1H),

5.78 (s, 1H), 5.70 (ddt, J=16.9, 10.3, 6.4 Hz, 1H), 5.53 (m, 1H), 5.02

(ddt, J=17.7, 1.7, 1.4 Hz, 1H), 4.98 (ddt, J=11.0, 1.8, 1.2 Hz, 1H), 4.96

(s, 1H), 4.94 (s, 1H), 4.42 (m, 1H), 4.34 (d, J=4.6 Hz, 1H), 3.96 (dd, J=

4.5, 4.3 Hz, 1H), 3.89 (dd, J=10.7, 5.5 Hz, 2H), 3.51 (ddd, J=12.1, 5.4,

2.9 Hz, 1H), 3.34 (ddd, J=12.3, 6.8, 4.7 Hz, 1H), 3.15 (dd, J=17.7,

5.2 Hz, 1H), 2.85 (dd, J=18.2, 7.2 Hz, 1H), 2.81 (ddd, J=7.2, 6.4, 2.1 Hz,

1H), 2.58 (ddd, J=7.2, 6.7, 2.7 Hz, 1H), 2.52 (dq, J=13.8, 6.7 Hz, 1H),

2.16 (m, 1H), 2.14 (m, 1H), 2.08 (m, 3H), 2.04 (m, 2H), 1.94 (s(d), J=

0.9 Hz, 3H), 1.94 (m, 1H), 1.84 (s(d), J=1.3 Hz, 3H), 1.81 (m, 1H), 1.78

(m, 1H), 1.71 (m, 1H), 1.55 (m, 1H), 1.36 (ddd, J=13.2, 8.4, 4.0 Hz, 1H),

1.18 (s, 9H), 1.10 (m, 1H), 1.08 (d, J=6.7 Hz, 3H), 1.06 (d, J=6.8 Hz,

3H), 1.03 (s, 9H), 1.02 (s, 9H), 0.89 (t, J=7.8 Hz, 9H), 0.86 (d, J=

6.7 Hz, 3H), 0.7 (q, J=7.8 Hz, 6H), 0.45 (s, 3H), 0.20 (s, 3H), 0.17 (s,

3H), 0.16 ppm (s, 3H); ¹³C NMR (100 MHz, C₆D₆): d=208.1, 167.5,

144.8, 143.2, 141.4, 137.8, 136.0, 135.9, 133.8, 129.9, 125.6, 115.3, 114.9,

81.8, 78.6, 72.5, 66.9, 66.3, 62.0, 58.8, 54.3, 48.7, 46.3, 39.8, 39.0, 35.8, 32.9,

32.4, 30.2, 30.0, 29.6, 28.4, 28.3, 28.2, 28.1, 26.0, 26.6, 26.3, 22.7, 19.7, 19.5,

19.4, 18.5, 18.4, 18.3, 18.2, 17.3, 16.3, 16.2, 16.1, 15.6, 15.0, 13.9, 13.7, 12.9,

10.0, 7.2, 5.4, ꢀ3.8, ꢀ4.1, ꢀ4.3, ꢀ4.5 ppm; IR (film): n˜ =3390, 2927, 2876,

Compound 64: DDQ (66 mg, 0.29 mmol) was added to a solution of 63

(110 mg, 97 mmol) in aq. CH₂Cl₂(2 mL). After stirring for 2 h, the reac-

tion was quenched with sat. aq. NaHCO₃(5 mL) and ice, the aqueous

phase was extracted with CH₂Cl₂(3ꢄ10 mL), and the combined organic

layers were dried over Na₂SO₄and evaporated. Purification of the resi-

due by flash chromatography (hexanes/tert-butyl methyl ether 9:1) gave

the corresponding alcohol as

a colorless oil (61 mg, 62%). DMAP

(13 mg, 0.10 mmol), imidazole (21.8 mg, 0.32 mmol) and TESCl (48.2 mg,

53 mL, 0.32 mmol) were added to a solution of this compound (100 mg,

96.8 mmol) in DMF (4 mL) and the resulting mixture was stirred at 458C

for 3 d. The reaction was quenched with sat. aq. NH₄Cl (20 mL), the

aqueous phase extracted with EtOAc (4ꢄ10 mL), the combined organic

layers were dried over Na₂SO₄and evaporated, and the residue was puri-

fied by flash chromatography (hexanes/tert-butyl methyl ether 20:1) to

give product 64 as a colorless oil (86 mg, 79%). ¹H NMR (400 MHz,

C₆D₆): d=7.81 (m, 4H), 7.26 (m, 6H), 7.01 (tq, J=7.1, 1.5 Hz, 1H), 6.01

(s, 1H), 5.71 (ddt, J=16.7, 10.8, 6.6 Hz, 1H), 5.50 (m, 1H), 4.97 (m, 2H),

4.36 (m, 1H), 4.30 (d, J=4.6 Hz, 1H), 3.89 (m, 3H), 3.09 (dd, J=18.4,

4.5 Hz, 1H), 2.74 (dd, J=18.4, 7.6 Hz, 1H), 2.64 (m, 1H), 2.12–2.06 (m,

5H), 1.94 (s, 3H), 1.76 (s(d), J=1.0 Hz, 3H), 1.67 (m, 1H), 1.57 (m, 2H),

1.19 (s, 9H), 1.0 (s, 9H), 0.99 (d, J=6.8 Hz, 3H), 0.97 (d, J=6.8 Hz, 3H),

0.93 (s, 9H), 0.89 (t, J=7.8 Hz, 9H), 0.56 (q, J=7.8 Hz, 6H), 0.19 (s,

3H), 0.15 (s, 3H), 0.14 (s, 3H), 0.09 ppm (s, 3H).

1711, 1608, 1514, 1462, 1425, 1390, 1252, 11125, 834, 702, 691 cm^ꢀ1

;

HRMS (ESI): m/z: calcd for C₆₇H₁₁₄O₉Si₄Na [M⁺+Na]: 1197.74376,

found: 1197.74369.

Compound 56: Prepared analogously as a yellow oil (390 mg, 83%). [a]_D²⁰

= ꢀ3.6 (c=0.95, CH₂Cl₂); ¹H NMR (400 MHz, C₆D₆): d=7.80–7.77 (m,

4H), 7.25–7.22 (m, 6H), 5.65 (brs, 1H), 5.00–4.99 (m, 1H), 4.88 (brs,

1H), 3.71–3.62 (m, 2H), 3.46 (brd, J=12.0 Hz, 1H), 3.28 (brd, J=

12.0 Hz, 1H), 2.70 (ddd, J=7.5, 5.6, 2.2 Hz, 1H), 2.51 (ddd, J=4.9, 4.2,

2.8 Hz, 1H), 2.39 (qd, J=13.4, 6.6 Hz, 1H), 2.08 (dd, J=13.4, 6.6 Hz,

1H), 1.87 (dd, J=13.4, 7.8 Hz, 1H), 1.75–1.66 (m, 2H), 1.62 (d, J=

1.2 Hz, 3H), 1.62–1.55 (m, 2H), 1.47 (ddd, J=11.4, 6.6, 5.0 Hz, 1H), 1.19

(s, 9H), 1.09 (ddd, J=13.9, 8.6, 5.4 Hz, 1H), 1.02 (d, J=6.6 Hz, 3H), 0.97

(d, J=6.9 Hz, 3H); ¹H NMR (400 MHz, CD₂Cl₂): d=7.67–7.65 (m, 4H),

7.44–7.36 (m, 6H), 5.67 (brs, 1H), 4.95–4.94 (m, 1H), 4.76 (brs, 1H),

3.83 (ddd, J=12.5, 5.4, 2.6 Hz, 1H), 3.67–3.69 (m, 2H), 3.53 (ddd, J=

11.8, 7.5, 4.7 Hz, 1H), 2.84–2.77 (m, 2H), 2.38 (qd, J=13.4, 6.6 Hz, 1H),

2.09 (dd, J=13.4, 6.4 Hz, 1H), 1.91 (dd, J=13.5, 7.8 Hz, 1H), 1.75–1.66

(m, 2H), 1.64 (d, J=1.3 Hz, 3H), 1.61–1.56 (m, 3H), 1.22 (ddd, J=13.9,

8.6, 5.5 Hz, 1H), 1.03 (s, 9H), 1.00 (d, J=6.8 Hz, 3H), 0.85 ppm (d, J=

6.6 Hz, 3H); ¹³C NMR (100 MHz, C₆D₆): d=145.4, 142.9, 136.5, 135.1,

129.2, 128.5, 126.5, 115.4, 63.3, 62.4, 59.2, 54.9, 46.8, 40.7, 39.5, 38.6, 30.6,

27.7, 20.5, 20.2, 20.1, 14.7 ppm; ¹³C NMR (100 MHz, CD₂Cl₂): d=144.6,

142.5, 135.6, 134.2, 129.6, 129.5, 127.7; 125.4, 114.2, 62.5, 62.0, 58.0, 54.5,

45.9, 39.8, 38.6, 37.7, 29.7, 26.7, 19.5, 19.3, 19.1, 13.9 ppm; IR (film): n˜ =

2956, 2921, 2855, 1428, 1110, 705 cm^ꢀ1; HRMS (ESI): m/z: calcd for

C₃₂H₄₆NaO₃SiNa [M⁺+Na]: 529.3106, found: 529.3106.

Compound 78: Prepared analogously from compound 77 by DDQ cleav-

age of the PMB ether (73%) followed by TES protection (81%). Color-

less oil (122 mg); [a]_D²⁰= ꢀ15.1 (c=1.2, CH₂Cl₂); ¹H NMR (400 MHz,

C₆D₆): d=6.98–6.95 (m, 1H), 6.03 (s, 1H), 5.69 (qt, J=10.3, 6.3 Hz, 1H),

5.36–5.30 (m, 1H), 5.00–4.94 (m, 2H), 4.40–4.35 (m, 1H), 4.29 (d, J=

5.0 Hz, 1H), 3.91 (dd, J=4.6, 4.3 Hz, 1H), 3.13 (dd, J=18.3, 4.3 Hz, 1H),

2.76 (dd, J=18.3, 8.1 Hz, 1H), 2.66 (q, J=6.8 Hz, 1H), 2.09–2.00 (m,

6H), 1.91 (s, 3H), 1.78 (d, J=0.7 Hz, 3H), 1.61 (dd, J=6.7, 6.0 Hz, 1H),

1.46–1.36 (m, 2H), 1.27 (d, J=6.1 Hz, 3H), 1.06 (t, J=7.9 Hz, 18H), 1.03

(d, J=6.9 Hz, 3H), 1.00 (d, J=6.8 Hz, 3H), 0.98 (s, 9H), 0.76–0.66 (m,

12H), 0.16 (s, 3H), 0.11 ppm (s, 3H); ¹³C NMR (100 MHz, C₆D₆): d=

208.1, 167.3, 152.7, 141.0, 137.7, 129.0, 115.2, 81.9, 78.3, 75.5, 68.7, 66.5,

48.8, 43.6, 41.3, 39.7, 32.9, 32.4, 28.3, 26.1, 21.4, 20.9, 18.8, 18.2, 15.3, 12.7,

7.3, 7.2, 5.6, 5.5, ꢀ4.1, ꢀ4.6 ppm; IR (film): n˜ =2955, 2877, 1708, 1258,

1075, 1004 cm^ꢀ1; MS (EI): m/z (%): 654 (10), 540 (2), 453 (2), 353 (6),

213 (100); HRMS (ESI): m/z: calcd for C₄₂H₈₁IO₆Si₃Na [M⁺+Na]:

915.42780, found: 915.42680.

Compound 92: Prepared analogously from compound 91 by DDQ cleav-

age of the PMB ether (92%) followed by TES protection (75%). Color-

less oil (77 mg); [a]_D²⁰

=

ꢀ5.2 (c=0.8, CH₂Cl₂); ¹H NMR (300 MHz,

C₆D₆): d=6.97–6.92 (m, 1H), 6.36 (d, J=0.8 Hz, 1H), 5.67 (qt, J=10.2,

6.4 Hz, 1H), 5.38–5.28 (m, 1H), 5.00–4.91 (m, 2H), 4.35 (t, J=5.8 Hz,

1H), 4.28 (d, J=5.3 Hz, 1H), 3.91 (dd, J=5.1, 4.2 Hz, 1H), 3.10 (dd, J=

18.4, 5.9 Hz, 1H), 2.82 (dd, J=18.4, 6.1 Hz, 1H), 2.10–1.95 (m, 7H), 2.02

Compound 79: Prepared analogously from vinyl iodide 78 (122 mg,

0.137 mmol) as a pale yellow oil (107 mg, 85%). [a]²_D⁰= ꢀ28.4 (c=1.1,

4002

www.chemeurj.org

ꢂ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Chem. Eur. J. 2009, 15, 3983 – 4010

Total Syntheses of Amphidinolides

FULL PAPER

CH₂Cl₂); ¹H NMR (300 MHz, C₆D₆): d=6.99–6.96 (m, 1H), 5.81 (s, 1H),

5.74–5.64 (m, 1H), 5.39–5.33 (m, 1H), 5.05–4.94 (m, 4H), 4.49–4.43 (m,

1H), 4.34 (d, J=4.9 Hz, 1H), 3.95 (t, J=4.4 Hz, 1H), 3.54 (ddd, J=12.4,

5.4, 3.1 Hz, 1H), 3.37 (ddd, J=11.5, 7.0, 4.3 Hz, 1H), 3.19 (dd, J=18.0,

4.8 Hz, 1H), 2.86 (dd, J=18.0, 7.0 Hz, 1H), 2.82 (td, J=5.8, 2.1 Hz, 1H),

2.61–2.59 (m, 1H), 2.58–2.53 (m, 1H), 2.17–2.12 (m, 2H), 2.08–2.00 (m,

5H), 1.98–1.94 (m, 1H), 1.91 (s, 3H), 1.86 (d, J=1.2 Hz, 3H), 1.84–1.70

(m, 4H), 1.60–1.54 (m, 1H), 1.51–1.45 (m, 1H), 1.36 (t, J=6.7 Hz, 1H),

1.28 (d, J=6.2 Hz, 3H), 1.19 (d, J=6.8 Hz, 3H), 1.09 (d, J=5.3 Hz, 3H),

1.08–1.05 (m, 18H), 1.02 (s, 9H), 0.91 (d, J=6.6 Hz, 3H), 0.76–0.70 (m,

12H), 0.20 (s, 3H), 0.19 ppm (s, 3H); ¹³C NMR (75 MHz, C₆D₆): d=

208.5, 167.5, 144.9, 143.3, 141.1, 137.8, 129.1, 125.7, 115.4, 115.0, 82.0,

78.3, 68.8, 67.0, 62.0, 58.8, 54.4, 48.6, 46.3, 44.1, 41.2, 39.9, 39.1, 32.9, 32.6,

30.1, 28.4, 26.2, 21.0, 19.8, 19.3, 18.3, 15.5, 15.2, 12.8, 7.4, 7.3, 5.7, 5.6,

ꢀ4.0, ꢀ4.4 ppm; IR (film): n˜ =2956, 2876, 1708, 1257, 1075 cm^ꢀ1; MS

(EI): m/z (%): 788 (1), 682 (4), 550 (1), 419 (1), 353 (8), 213 (100);

HRMS (ESI): m/z: calcd for C₅₁H₉₆O₈Si₃Na [M⁺+Na]: 943.63052, found:

943.63086.

Compound 93: Prepared analogously as a pale yellow oil (85 mg, 87%)

which was immediately used in the next step without further characteri-

zation.

Compound 98: Prepared analogously as a pale yellow oil (17 mg, 87%).

1

[a]²_D⁰= ꢀ13.3 (c=0.8, CH₂Cl₂); H NMR (600 MHz, C₆D₆): d=7.81–7.79

(m, 4H), 7.29–7.22 (m, 6H), 7.04–6.99 (m, 1H), 5.76 (s, 1H), 5.70 (ddt,

J=17.0, 10.3, 6.5 Hz, 1H), 5.51 (sext., J=4.8 Hz, 1H), 5.03–5.02 (m, 1H),

5.00 (dq, J=17.1, 1.6 Hz, 1H), 4.97–4.95 (m, 2H), 4.46–4.42 (m, 1H),

4.31 (d, J=5.2 Hz, 1H), 3.97 (dd, J=5.2, 3.0 Hz, 1H), 3.91–3.85 (m, 2H),

3.62–3.59 (m, 1H), 3.48–3.44 (m, 1H), 3.16 (dd, J=18.9, 4.5 Hz, 1H),

2.90 (td, J=6.0, 2.2 Hz, 1H), 2.67–2.65 (m, 1H), 2.40 (sext., J=6.6 Hz,

1H), 2.29–2.25 (m, 1H), 2.14 (dd, J=13.2, 6.5 Hz, 1H), 2.10–2.02 (m,

4H), 2.01–1.98 (m, 1H), 1.96–1.92 (m, 1H), 1.93 (d, J=0.8 Hz, 3H),

1.87–1.76 (m, 3H), 1.81 (d, J=1.2 Hz, 3H), 1.68–1.63 (m, 2H), 1.19 (s,

9H), 1.16–1.13 (m, 1H), 1.11 (d, J=6.9 Hz, 3H), 1.10–1.07 (m, 2H), 1.05

(d, J=6.5 Hz, 3H), 1.04 (t, J=8.1 Hz, 9H), 1.02 (s, 9H), 1.01 (s, 9H),

0.92 (d, J=6.6 Hz, 3H), 0.71–0.66 (m, 6H), 0.25 (s, 3H), 0.22 (s, 3H),

0.21 (s, 3H), 0.17 ppm (s, 3H); ¹³C NMR (150 MHz, C₆D₆): d=207.7,

167.5, 144.6, 142.2, 141.5, 137.8, 136.0, 133.8, 133.7, 129.7, 128.8, 126.1,

115.4, 115.2, 80.9, 78.8, 72.3, 66.1, 62.3, 58.9, 54.6, 49.2, 46.3, 43.8, 40.4,

38.9, 36.8, 32.9, 31.0, 29.8, 28.4, 27.0, 26.3, 26.2, 20.0, 19.8, 19.5, 18.4, 18.2,

14.8, 14.6, 12.8, 7.2, 5.3, ꢀ3.6, ꢀ3.9, ꢀ4.3, ꢀ4.5 ppm; IR (film): n˜ =3483,

2955, 2929, 2857, 1710, 1255, 1112 cm^ꢀ1; MS (EI): m/z (%): 607 (7), 467

(49), 295 (27), 185 (100); HRMS (ESI): m/z: calcd for C₆₇H₁₁₄O₉Si₄Na

[M⁺+Na]: 1197.74322, found: 1197.74356.

Table 1. Compilation of the NMR data of synthetic 9 in C₆D₆; number-

ing scheme as shown in the insert.

Alkenyl epoxide formation

Compound 66: A mixture containing compound 65 (45 mg, 38 mmol) and

NaHCO₃(32 mg, 380 mmol) in CH₂Cl₂(0.5 mL) was stirred at 08C for

0.5 h before Dess–Martin periodinane (21 mg, 49 mmol) was introduced.

Stirring was continued for 1.5 h at 08C before the solvent was removed

Position

¹³C NMR (150MHz)

¹H NMR (600MHz)^[a]

Table 2. Comparison between reported ¹³C NMR data (CDCl₃) of amphi-

1

2

3

4

5

6

7

8

168.3 (s)

128.6 (s)

140.5 (d)

27.7 (t)

dinolide H1 and the data recorded for synthetic 9.

Position

Synthetic 9

Lit.^[10]

6.98 (t, J=7 Hz)

2.07 (m)/1.82 (m)

1.93 (m)/1.77 (m)

5.49 (m)

5.02 (dd, J=15.4, 8.4 Hz)

2.83 (dd, J=8.4, 2.2 Hz)

2.78 (dt, J=9.6, 2.2 Hz)

1.20 (m)/0.97 (m)

1.76 (m)

1

2

3

4

5

6

7

8

168.7

127.9

141.0

30.9

27.0

135.7

128.6

60.4

59.5

39.8

29.1

47.2

144.2

126.1

141.7

40.8

40.9

67.6

45.2

212.2

77.7

75.4

33.0

33.4

73.4

66.2

12.6

18.0

114.7

13.1

20.3

15.6

168.7

127.9

141

31.1 (t)

130.1 (d)

129.1 (d)

60.8 (d)

59.4 (d)

39.9 (t)

30.9

26.9

135.7

128.6

60.3

59.5

39.8

29.1

47.1

144.1

126.1

141.7

40.7

40.9

67.5

45.2

212.2

77.7

75.4

33

33.5

73.4

66.1

12.5

18.0

114.7

13.1

20.3

15.6

9

10

11

12

13

14

15

16

17

18

19

29.4 (d)

47.4 (t)

9

2.03 (m)/1.81 (m)

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

144.8 (s)

127.2 (d)

141.4 (s)

40.2 (d)

41.9 (t)

5.80 (s)

2.77 (m)

1.41 (m)/1.33 (m)

4.05 (dd, J=9.4, 2.4 Hz)

2.69 (dd, J=14.1, 9.4 Hz),

2.26 (dd, J=14.1, 2.4 Hz)

67.8 (d)

46.7 (t)

20

21

22

23

24

25

26

27

28

29

30

31

32

212.5 (s)

78.5 (d)

76.1 (d)

33.4 (d)

34.1 (t)

73.4 (d)

65.9 (t)

12.8 (q)

17.8 (q)

114.5 (t)

13.1 (q)

20.1 (q)

16.0 (q)

4.21 (d, J=3 Hz)

3.62 (t, J=9 Hz)

2.00 (m)

1.95 (m)/1.11 (m)

5.19 (m)

3.45 (m)

1.86 (s)

0.98 (d, J=5.8 Hz)

5.05 (s)/4.96 (d, J=1 Hz)

1.68 (d, J=1.1 Hz)

0.98 (d, J=6.8 Hz)

1.02 (d, J=6.5 Hz)

[a] The -OH protons were found to resonate at: d=1.57 (brs, 26-OH),

2.99 (d, J=9.7 Hz, 22-OH), 3.39 (s, 18-OH), 4.02 (brs, 21-OH).

Chem. Eur. J. 2009, 15, 3983 – 4010

ꢂ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

www.chemeurj.org

4003

A. Fꢀrstner et al.

1

1258, 1078 cm^ꢀ1; MS (EI): m/z (%):

678 (3), 353 (6), 213 (100), 115 (14);

HRMS (ESI): m/z: calcd for

C₅₂H₉₆O₇Si₃Na [M⁺+Na]: 939.63561,

found: 939.63597.

Table 3. Comparison between the well resolved H NMR signals (CDCl₃) of amphidinolide H1 reported in the

literature and the data recorded for synthetic 9.

Position

Lit.^[10](MHz not specified)

J [Hz]

Synthetic 9^[a](600MHz)

J [Hz]

3

6

7

8

6.81 (t)

7.2

6.78 (ddq)

5.87 (ddd)

5.14 (dd)

3.13 (dd)

2.97 (dt)

5.58 (s)

3.85 (m)

2.88 (dd)

2.34 (dd)

4.23 (dd)

5.07 (dddd)

1.82 (s)

0.89 (d)

4.96 (s), 4.79 (s)

1.66 (d)

1.06 (d)

1.01 (d)

8.4, 5.6, 1.6

15.4, 9.2, 4.6

15.4, 8.4

8.6, 2.2

9.7, 2.2

5.88 (ddd)

5.13 (dd)

3.12 (dd)

2.94 (dt)

5.57 (s)

3.92 (m)

2.73 (dd)

2.61 (dd)

4.30 (m)

5.07 (ddd)

1.82 (s)

0.84 (d)

4.97 (s), 4.80 (s)

1.71 (s)

1.05 (d)

1.00 (d)

15.5, 9.0, 4.7

15.5, 8.2

8.2, 2.3

9.7, 2.3

Compound 94: Prepared analogously

from

compound

93

(41 mg,

0.039 mmol), using preformed Ph₃P=

CH₂(11 mg, 0.05 mmol) in the olefi-

nation step. Flash chromatography

(1% v/v EtOAc in hexanes) of the

crude material gave compound 94 as

9

14

18

19

15.8, 8.6

15.8, 1.6

13.7, 9.9

13.8, 1.6

5.8, 1.4

11.5, 5.7, 2.9, 1

a colorless oil (13 mg, 32%). [a]_D²⁰

=

21

25

27

28

29

30

31

32

ꢀ21.2 (c=0.6, CH₂Cl₂); ¹H NMR

(600 MHz, C₆D₆): d 6.97 (tq, J=5.8,

1.4 Hz, 1H), 6.02 (s, 1H), 5.66 (qt,

J=10.3, 6.6 Hz, 1H), 5.58 (ddd, J=

17.3, 10.5, 7.6 Hz, 1H), 5.43–5.37 (m,

1H), 5.33 (ddd, J=17.2, 1.4, 0.4 Hz,

1H), 5.09–5.06 (m, 2H), 5.05 (dd, J=

10.5, 1.5 Hz, 1H), 4.97 (dq, J=17.3,

1.7, 1H), 4.96–4.93 (m, 1H), 4.47

(quint, J=1.6 Hz, 1H), 4.31 (d, J=

5.2 Hz, 1H), 3.99 (dd, J=5.2, 4.0 Hz,

1H), 3.22 (dd, J=18.4, 7.1 Hz, 1H),

3.02 (dd, J=18.4, 5.0 Hz, 1H), 2.97

11.4, 5.7, 3.0

6.4

6.5

1.2

6.7

[a] The OH protons were found to resonate at: d=3.10 (d, J=9.1 Hz, 22-OH), 3.47 (d, J=3.6 Hz, 18-OH),

3.92 (d, J=5.8 Hz, 21-OH).

under reduced pressure and the residue was suspended in pentane

(3 mL). The precipitates were filtered off through a pad of Florisil which

(dd, J=7.6, 1.9 Hz, 1H), 2.88 (td, J=6.0, 2.0 Hz, 1H), 2.20 (dd, J=12.8,

7.4 Hz, 1H), 2.18–2.14 (m, 1H), 2.05–2.04 (m, 5H), 1.99–1.96 (m, 4H),

1.99 (s, 3H), 1.90 (s, 3H), 1.71 (ddd, J=14.0, 6.5, 4.5 Hz, 1H), 1.60 (ddd,

J=13.7, 8.8, 4.5 Hz, 1H), 1.46 (s, 3H), 1.31 (d, J=6.4 Hz, 3H), 1.22–1.17

was carefully rinsed with Et₂O (5ꢄ5 mL). Evaporation of the combined

filtrates gave the corresponding epoxy-aldehyde as a pale yellow oil,

which was immediately used in the next step.

A solution of NaHMDS in THF (1m, 95 mL, 0.40 mmol) was added drop-

wise to a suspension of (methyl) triphenylphosphonium bromide (53 mg,

95 mmol) in THF (0.5 mL) at 08C. The resulting yellow suspension was

stirred for 45 min at this temperature before a solution of the crude alde-

hyde prepared above in THF (0.2 mL) was slowly added. After stirring

for 1 h, the reaction was quenched with sat. aq. NH₄Cl, the aqueous

phase was extracted with EtOAc (2ꢄ3 mL), the combined extracts were

dried over Na₂SO₄and evaporated, and the residue was purified by flash

chromatography (hexanes/tert-butyl methyl ether 15:1) to afford product

66 as a colorless oil (28 mg, 65% over two steps). ¹H NMR (400 MHz,

C₆D₆): d=7.67 (m, 4H), 7.13 (m, 6H), 6.89 (tq, J=7.4, 1.1 Hz, 1H), 5.65

(s, 1H), 5.57 (ddt, J=16.9, 10.3, 6.4 Hz, 1H), 5.39 (m, 3H), 5.15 (3d, J=

17.5, 1.7, 0.5 Hz, 1H), 4.86 (m, 4H), 4.30 (m, 1H), 4.21 (d, J=6.3 Hz,

1H), 3.82 (dd, J=4.5, 4.3 Hz, 1H), 3.76 (dd, J=10.7, 5.5 Hz, 2H), 3.0

(dd, J=14.4, 4.8 Hz, 1H), 2.76 (dd, J=13.2, 2.4 Hz, 1H), 2.69 (dd, J=7.8,

2.2 Hz, 1H), 2.58 (ddd, J=6.8, 5.7, 2.2 Hz, 1H), 2.39 (m, 1H), 2.16–1.98

(m, 7H), 1.94 (m, 1H), 1.91 (s(d), J=0.9 Hz, 3H), 1.81 (s, 3H), 1.80 (m,

1H), 1.79 (m, 2H), 1.71 (m, 1H), 1.55 (m, 1H), 1.18 (s, 9H), 1.13 (m,

1H), 1.08 (d, J=6.8 Hz, 3H), 1.06 (d, J=6.8 Hz, 3H), 1.03 (s, 9H), 1.0 (s,

9H), 0.98 (d, J=6.7 Hz, 3H), 0.87 (t, J=7.8 Hz, 9H), 0.8 (q, J=7.8 Hz,

6H), 0.45 (s, 3H), 0.20 (s, 3H), 0.17 (s, 3H), 0.16 ppm (s, 3H).

Table 4. Comparison between reported ¹³C NMR data (CDCl₃) of amphi-

dinolide B1 and the data recorded for synthetic 1. The assignments of the

signals follow the original literature, cf. ref. [14].

Position

Lit.^[14](125MHz)

Synthetic 1 (150MHz)

1

2

3

4

5

6

7

8

167.7

128.3

139.9

26.8

30.8

135.4

128.5

60.0

59.3

39.4

29.1

46.7

144.4

124.3

143.1

75.9

45.2

66.5

45.9

212.4

77.7

75.5

33.2

39.3

68.3

28.3

12.4

18.2

114.8

15.0

21.0

15.6

167.7

128.3

139.9

26.7

30.8

135.5

128.4

60.1

59.3

39.4

29.1

46.9

144.3

124.2

143.0

76.0

45.1

66.6

45.9

212.4

77.7

75.6

33.1

39.2

68.3

28.3

12.4

18.0

114.8

15.1

20.9

15.6

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

Compound 80: Prepared analogously from compound 79 (74 mg,

0.08 mmol) as a colorless oil (32 mg, 44% over two steps). [a]²_D⁰= ꢀ17.1

(c=0.7, CH₂Cl₂); ¹H NMR (600 MHz, C₆D₆): d=6.98 (td, J=7.3, 1.4 Hz,

1H), 5.80 (s, 1H), 5.71–5.65 (m, 1H), 5.52 (ddd, J=17.3, 10.4, 7.6 Hz,

1H), 5.37–5.34 (m, 1H), 5.30 (ddd, J=17.2, 1.5, 0.5 Hz, 1H), 5.04 (d, J=

1.4, 0.4 Hz, 1H), 5.02–4.93 (m, 2H), 4.46–4.43 (m, 1H), 4.34 (d, J=

4.8 Hz, 1H), 3.95 (t, J=4.5 Hz, 1H), 3.17 (dd, J=17.9, 4.9 Hz, 1H), 2.91

(dd, J=7.6, 2.0 Hz, 1H), 2.87 (dd, J=18.0, 7.1 Hz, 1H), 2.72 (td, J=5.9,

2.0 Hz, 1H), 2.56 (sext, J=6.8 Hz, 1H), 2.14–2.10 (m, 2H), 2.07–1.98 (m,

7H), 1.96–1.92 (m, 1H), 1.91 (d, J=1.3 Hz, 3H), 1.88–1.82 (m, 1H), 1.85

(d, J=1.3 Hz, 3H), 1.79–1.72 (m, 2H), 1.62–1.56 (m, 1H), 1.49–1.44 (m,

1H), 1.27 (d, J=6.2 Hz, 3H), 1.19 (d, J=6.8 Hz, 3H), 1.18–1.11 (m, 1H),

1.09–1.04 (m, 18H), 1.04 (d, J=6.7 Hz, 3H), 1.02 (s, 9H), 0.90 (d, J=

6.6 Hz, 3H), 0.77–0.68 (m, 12H), 0.19 (s, 3H), 0.17 ppm (s, 3H);

¹³C NMR (150 MHz, C₆D₆): d=208.4, 167.3, 144.7, 143.3, 141.1, 137.7,

136.9, 128.9, 125.5, 118.0, 115.3, 115.0, 81.9, 78.1, 68.7, 66.9, 59.0, 58.9,

48.3, 46.3, 43.8, 41.0, 39.8, 32.9, 32.5, 29.9, 28.3, 26.1, 21.0, 19.6, 19.2, 18.3,

15.4, 15.0, 12.8, 7.3, 5.5, ꢀ4.1, ꢀ4.5 ppm; IR (film): n˜ =2956, 1710, 1460,

4004

www.chemeurj.org

ꢂ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Chem. Eur. J. 2009, 15, 3983 – 4010

Total Syntheses of Amphidinolides

FULL PAPER

(m, 1H), 1.11 (t, J=7.9 Hz, 9H), 1.09 (d, J=8.1 Hz, 3H), 1.09 (t, J=

7.9 Hz, 9H), 1.07 (t, J=7.9 Hz, 9H), 1.03 (s, 9H), 0.97 (d, J=6.6 Hz,

3H), 0.81–0.73 (m, 12H), 0.72–0.67 (m, 6H), 0.25 (s, 3H), 0.24 ppm (s,

3H); ¹³C NMR (150 MHz, C₆D₆): d=208.4, 167.3, 144.9, 142.6, 140.9,

137.8, 136.9, 129.0, 126.0, 118.1, 115.5, 115.3, 81.5, 78.1, 78.0, 68.8, 66.0,

59.2, 58.9, 50.2, 49.2, 46.5, 41.0, 39.6, 32.9, 32.3, 29.7, 28.6, 28.3, 26.3, 21.0,

19.6, 18.2, 15.8, 15.2, 12.8, 7.6, 7.4, 7.3, 7.2, 5.6, 5.4, ꢀ3.8, ꢀ4.2 ppm; IR

(film): n˜ =2954, 2877, 1709, 1257, 1128, 1005 cm^ꢀ1; MS (EI): m/z (%):

1046 (1) [M⁺], 653 (1), 444 (5), 349 (28), 213 (100); HRMS (ESI): m/z:

calcd for C₅₈H₁₁₀O₈Si₄Na [M⁺+Na]: 1069.71700, found: 1069.71705.

1H), 5.57 (ddd, J=17.3, 10.6, 7.8 Hz, 1H), 5.54–5.49 (m, 1H), 5.32 (dd,

J=17.3, 1.4 Hz, 1H), 5.05 (dd, J=10.4, 1.5 Hz, 1H), 5.03 (s, 1H), 4.99–

4.95 (m, 3H), 4.45 (quint., J=5.7 Hz, 1H), 4.32 (d, J=5.2 Hz, 1H), 3.98

(dd, J=5.1, 3.2 Hz, 1H), 3.90–3.89 (m, 1H), 3.17 (dd, J=18.9, 5.0 Hz,

1H), 2.94 (dd, J=7.4, 1.8 Hz, 1H), 2.85 (dd, J=18.7, 6.6 Hz, 1H), 2.77

(td, J=5.7, 1.9 Hz, 1H), 2.44 (q, J=6.9 Hz, 1H), 2.25 (brs, 1H), 2.16–

2.01 (m, 7H), 1.98 (d, J=8.0 Hz, 2H), 1.94 (s, 3H), 1.88–1.75 (m, 3H),

1.83 (d, J=1.0 Hz, 3H), 1.72–1.62 (m, 2H), 1.19 (s, 9H), 1.13 (d, J=

6.6 Hz, 3H), 1.07 (d, J=5.4 Hz, 3H), 1.05 (t, J=8.0 Hz, 9H), 1.03 (s,

18H), 0.93 (d, J=6.5 Hz, 3H), 0.68 (q, J=7.8 Hz, 6H), 0.26 (s, 3H), 0.23

(s, 6H), 0.18 ppm (s, 3H); ¹³C NMR (100 MHz, C₆D₆): d=207.5, 167.4,

144.6, 142.7, 141.4, 137.8, 137.0, 136.1, 132.7, 132.6, 131.3, 130.1, 128.9,

126.1, 118.0, 115.4, 115.1, 81.1, 78.7, 72.5, 66.3, 66.2, 59.1, 59.0, 49.1, 46.3,

44.1, 40.4, 39.4, 39.3, 36.7, 33.0, 31.5, 30.0, 28.5, 27.1, 26.4, 26.3, 19.9, 19.8,

19.6, 18.5, 18.3, 15.2, 14.8, 12.9, 7.3, 5.4, ꢀ3.5, ꢀ3.8, ꢀ4.2, ꢀ4.3 ppm; IR

(film): n˜ =2956, 2926, 2860, 1711, 1256, 1105 cm^ꢀ1; HRMS (ESI): m/z:

calcd for C₆₈H₁₁₄O₈Si₄Na [M⁺+Na]: 1193.74830, found: 1193.74933.

Compound 99: Prepared analogously from compound 98 (35 mg,

0.03 mmol), using preformed Ph₃P=CH₂(8 mg, 0.06 mmol) in the olefina-

tion step. Flash chromatography (1% v/v EtOAc in hexanes) of the

crude material gave compound 99 as a colorless oil (20 mg, 57%). [a]_D²⁰

= ꢀ12.2 (c=1.0, CH₂Cl₂); ¹H NMR (400 MHz, C₆D₆): d=7.83–7.79 (m,

4H), 7.29–7.25 (m, 6H), 6.99–6.96 (m, 1H), 5.79 (s, 1H), 5.77–5.67 (m,

Macrocyclization and deprotection

1

Table 5. Comparison between reported H NMR data (CDCl₃) of amphi-

Compound 67: Ruthenium complex 60 (1.0 mg, 1.6 mmol) was added to a

solution of compound 66 (19 mg, 16 mmol) in C₆H₆(20 mL) and the re-

sulting mixture was stirred at 208C for 2 h. The reaction was quenched

with ethyl vinyl ether (20 mL, 216 mmol) and stirring was continued for

10 min before all volatile materials were evaporated under reduced pres-

sure at 208C. The crude product was then adsorbed onto Celite and puri-

fied by flash chromatography (hexanes/tert-butyl methyl ether 15:1) to

afford 67 as a yellow oil (12 mg, 68%). ¹H NMR (400 MHz, C₆D₆): d=

7.80 (m, 4H), 7.24 (m, 6H), 6.92 (tq, J=7.2, 1.1 Hz, 1H), 5.68 (s, 1H),

5.77 (m, 1H), 5.51 (m, 1H), 5.17 (dd, J=16.7, 8.3 Hz, 1H), 5.06 (d, J=

1.6 Hz, 1H), 5.06 (d, J=1.6 Hz, 1H), 4.92 (d, J=1.7 Hz, 1H), 4.50 (d, J=

3.1 Hz, 1H), 4.22 (m, 1H), 3.96 (dd, J=9.8, 4.1 Hz, 1H), 3.88 (m, 3H),

3.0 (m, 2H), 2.92 (dd, J=16.1, 2.8 Hz, 1H), 2.86 (dd, J=16.8, 4.6 Hz,

dinolide B1 and the data recorded for synthetic 1.

Position Lit.^[14]

Lit.^[9]

J [Hz]

Synthetic 1

(600MHz)

J [Hz]

(500MHz)^[a](400MHz)

3

4

6.77 (td)

2.42 (m),

2.20 (m)

2.40 (m),

2.15 (m)

5.92 (ddd)

6.78 (t)

7.8

6.76 (td)

2.43 (m),

2.23 (m)

2.37 (m),

2.12 (m)

7.3

2.43 (m),

2.25 (m)

2.38 (m),

2.17 (m)

5.93 (ddd) 4.8, 8.5, 5.92 (ddd)

15.2

5

6

7

4.9, 8.7,

15.4

8.7, 15.6

5.16 (dd)

5.18 (dd)

8.6,

5.15 (dd)

15.8

8

9

3.14 (dd)

2.93 (dt)

3.16 (dd)

2.0, 8.3 3.14 (dd)

2.2, 8.5

2.4, 9.0

Table 6. Comparison between reported ¹³C NMR data (CDCl₃) of amphi-

dinolide B4 and the data recorded for synthetic 4.

2.94 (ddd) 2.2, 2.6, 2.93 (dt)

8.9

[b]

10

1.49 (ddd),

1.27 (m)

1.65 (m)

2.19 (m)

1.95 (m)

5.97 (s)

1.49 (ddd),

1.26 (m)

1.63 (m)

2.18 (m)

1.93 (m)

5.97 (s)

2.8, 10.8,

13.6

Position

Lit.^[15](150MHz)

Synthetic 4 (150MHz)

[b]

1

2

3

4

5

6

7

8

167.8

128.5

139.8

26.8

31.2

135.9

128.7

60.6

59.5

39.8

29.4

47.1

144.2

126.5

141.7

40.9

40.8

67.4

45.1

212.9

77.9

75.8

33.2

39.2

68.3

21.2

12.4

18.0

114.8

13.1

20.5

15.8

167.8

128.3

139.7

26.9

31.0

136.0

128.5

60.5

59.4

39.8

29.2

47.1

144.1

126.1

141.7

40.8

40.7

67.6

45.2

212.3

77.7

75.6

33.3

39.0

68.2

21.2

12.5

17.8

114.7

13.1

20.3

15.6

11

12

13

14

2.20 (m)

[b]

5.99 (s)

[b]

16-OH 1.42 (s)

1.44 (s)

[b]

17

18

1.95 (m),

1.78 (dd)

4.19 (m)

1.93 (m),

1.76 (dd)

4.18 (m)

3.95 (d)

2.87 (dd),

2.79 (dd)

5.3, 14.6

4.20 (m)

3.92 (d)

2.86 (d),

2.80 (dd)

9

18-OH 3.91 (d)

19

3.3

3.1

7.5, 15.9,

3.1, 16.2

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

2.87 (dd),

2.79 (dd)

7.3,

3.2,

15.9

21

4.33 (dd)

4.34 (dd)

3.88 (d)

3.73 (ddd) 1.5, 8.8, 3.71 (td)

10.3

1.4, 4.8 4.33 (dd)

5.0 3.89 (d)

1.9, 5.0

5.0

10.2, 10.2

21-OH 3.87 (d)

22 3.71 (td)

22-OH 3.16 (d)

23

24

3.19 (d)

10.0

3.23 (s)

1.87 (m)

1.93 (m),

1.28 (m)

5.05 (m)

1.27 (d)

1.82 (s)

0.87 (d)

5.03 (s),

4.82 (s)

1.83 (s)

1.38 (s)

1.00 (d)

[b]

1.85 (m)

1.95 (m),

1.28 (m)

5.06 (ddd)

1.26 (d)

1.82 (brs)

0.89 (d)

5.03 (s),

4.83 (s)

[b]

25

26

27

28

29

5.06 (m)

1.30 (d)

1.80 (s)

0.90 (d)

5.05 (s),

4.84 (s)

1.80 (s)

1.44 (s)

1.03 (d)

6.1

6.4

6.1

6.5

30

31

32

1.83 (brs)

1.42 (s)

1.01 (d)

6.6

6.7

[a] No coupling constants (J) reported. [b] The remaining signals were

tabulated as follows: d = 1.98–1.91 (m, 4H), 1.76 (dd, J=14.5, 5.2 Hz),

1.64 (m, 1H), 1.49 (ddd, J=13.6, 10.9, 3.0 Hz), 1.31 (m, 1H), 1.26 ppm

(m, 1H).

Chem. Eur. J. 2009, 15, 3983 – 4010

ꢂ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

www.chemeurj.org

4005

A. Fꢀrstner et al.

1

Table 7. Comparison between reported H NMR data (CDCl₃) of amphi-

5.2 Hz, 1H), 4.31–4.27 (m, 1H), 4.00 (brs, 1H), 3.17–3.08 (m, 2H), 3.05–

3.03 (m, 1H), 2.33–2.29 (m, 1H), 2.24–2.19 (m, 1H), 2.11–2.05 (m, 1H),

2.04–1.90 (m, 8H), 1.89 (s, 3H), 1.88 (s, 3H), 1.78–1.66 (m, 2H), 1.38 (s,

3H), 1.35–1.29 (m, 2H), 1.28 (d, J=6.1 Hz, 3H), 1.14–1.07 (m, 27H),

1.03 (d, J=6.9 Hz, 3H), 1.02 (s, 9H), 1.00 (d, J=6.0 Hz, 3H), 0.84–0.67

(m, 18H), 0.23 (s, 3H), 0.19 ppm (s, 3H); ¹³C NMR (150 MHz, C₆D₆): d=

208.0, 167.4, 145.0, 142.3, 140.1, 133.8, 130.4, 129.2, 125.8, 115.6, 82.0,

78.1, 68.5, 66.4, 58.9, 58.8, 47.0, 40.2, 31.5, 29.8, 28.8, 27.6, 26.2, 21.2, 19.6,

18.2, 15.8, 14.8, 12.8, 7.6, 7.5, 7.4, 7.3, 5.8, 5.6, ꢀ3.8, ꢀ4.4 ppm; IR (film):

n˜ =2954, 2876, 1708, 1123, 1016 cm^ꢀ1; MS (EI): m/z (%): 1018 (2) [M⁺],

886 (2), 754 (2), 558 (1), 444 (11), 213 (100); HRMS (ESI): m/z: calcd for

C₅₆H₁₀₆O₈Si₄Na [M⁺+Na]: 1041.68571, found: 1041.68577.

dinolide B4 and the data recorded for synthetic 4.

Position

Lit.^[15]

J [Hz]

Synthetic 4

J [Hz]

(600MHz)

3

6.73 (m)

2.42 (m)

2.34 (m)

5.89 (m)

5.16 (dd)

6.73 (m)

2.43 (m)

2.35 (m)

5.89 (m)

5.12 (dd)

4a

5a

6

7

15.6,

8.2

15.6,

8.4

8

9

10

3.14 (brd)

2.94 (brd)

1.15 (m),

1.48 (m)

1.56 (m)

5.56 (s)

8.0

9.7

3.13 (dd)

2.94 (brd)

1.14 (m),

1.50 (m)

1.56 (m)

5.56 (s)

8.7, 2.4

9.6

Compound 100: Prepared analogously as an E/Z 5.2:1 mixture of iso-

mers. The major E isomer could be obtained in pure form by flash chro-

matography (hexanes/tert-butyl methyl ether 15:1) as a colorless oil

11

14

(11 mg, 56%). [a]_D²⁰

=

ꢀ8.7 (c=0.55, CH₂Cl₂); ¹H NMR (600 MHz,

C₆D₆): d= 7.78–7.76 (m, 4H), 7.24–7.21 (m, 6H), 6.87–6.84 (m, 1H), 5.71

(s, 1H), 5.59 (ddd, J=15.4, 8.0, 5.2 Hz, 1H), 5.54–5.50 (m, 1H), 5.49 (dd,

J=15.2, 8.0 Hz, 1H), 5.05 (d, J=2.2 Hz, 1H), 4.94 (s, 1H), 4.46–4.42 (m,

1H), 4.26 (d, J=5.5 Hz, 1H), 3.82–3.80 (m, 3H), 3.42 (ddd, J=8.6, 3.4,

2.4 Hz, 1H), 3.13 (dd, J=19.0, 2.3 Hz, 1H), 3.02 (dd, J=8.2, 1.8 Hz, 1H),

2.72 (dd, J=18.7, 8.9 Hz, 1H), 2.33–2.24 (m, 2H), 2.20–2.16 (m, 2H),

2.14–2.11 (m, 2H), 2.06–1.98 (m, 4H), 1.91–1.85 (m, 4H), 1.87 (s, 3H),

1.84–1.79 (m, 3H), 1.77 (d, J=1.0 Hz, 3H), 1.17 (s, 3H), 1.17–1.16 (m,

1H), 1.07 (t, J=8.0 Hz, 9H), 1.06 (d, J=8.7 Hz, 3H), 1.03–1.02 (m, 3H),

1.02 (s, 9H), 0.98 (s, 9H), 0.92 (d, J=6.5 Hz, 3H), 0.91 (d, J=6.8 Hz,

3H), 0.69–0.64 (m, 6H), 0.28 (s, 3H), 0.25 (s, 3H), 0.15 (s, 3H), 0.12 ppm

(s, 3H); ¹³C NMR (150 MHz, C₆D₆): d=206.4, 167.0, 144.8, 141.1, 140.6,

136.0, 133.8, 133.7, 133.6, 131.1, 130.0, 129.9, 129.0, 126.3, 115.2, 80.4,

79.1, 71.2, 66.6, 65.6, 59.8, 59.5, 49.7, 47.4, 43.1, 41.2, 39.6, 37.5, 31.7, 30.2,

29.8, 29.6, 27.7, 27.1, 26.9, 26.2, 26.1, 13.7, 13.0, 12.9, 7.3, 5.2, 1.4, ꢀ3.5,

ꢀ3.9, ꢀ4.3, ꢀ4.7 ppm; IR (film): n˜ =2955, 2930, 2857, 1721, 1707, 1254,

1112 cm^ꢀ1; MS (EI): m/z (%): 1142 (3) [M⁺], 1085 (2), 1010 (3), 953 (2),

467 (27), 295 (27), 185 (100); HRMS (ESI): m/z: calcd for

C₆₆H₁₁₀O₈Si₄Na [M⁺+Na]: 1165.71700, found: 1165.71685.

17a

18

19

1.42 (m)

3.92 (m)

2.61 (brd),

2.74 (dd)

1.41 (m)

3.91 (m)

2.60 (brd),

2.74 (dd)

16.0,

8.9

16.0,

8.9

21

22

24a

25

26

27

28

29

4.31 (brs)

3.71 (m)

1.20 (m)

5.08 (m)

1.24 (d)

1.82 (s)

0.85 (d)

4.81 (s),

4.97 (s)

1.71 (s)

1.06 (d)

0.98 (d)

4.31 (s)

3.70 (m)

1.20 (m)

5.04 (m)

1.25 (d)

1.80 (s)

0.83 (d)

4.79 (s),

4.96 (s)

1.71 (d)

1.04 (d)

0.97 (d)

6.7

6.5

6.3

6.5

30

31

32

1.4

6.8

6.7

12a, 17b, 23 1.84–1.92 (m)

5b, 12b,

24b

1.83–1.96 (m)

2.03–2.20 (m)

2.05–2.16 (m)

Compound 110: Prepared analogously as a pale yellow oil (10.5 mg,

54%). [a]²_D⁰= +35.6 (c=0.1, CHCl₃); ¹H NMR (600 MHz, C₆D₆): d=

7.78 (m, 4H), 7.26–7.22 (m, 6H), 7.00 (m, 1H), 5.89 (dm, J=15.4 Hz,

1H), 5.71 (s 1H), 5.43 (ddt, J=10.1, 2.7, 5.2 Hz, 1H), 5.29 (dd, J=15.5,

7.7 Hz, 1H), 5.02 (m, 1H), 4.91 (dd, J=2.4, 1.0 Hz, 1H), 4.34 (d, J=

6.2 Hz, 1H), 4.20 (m, 1H), 3.86 (dd, J=10.6, 5.3 Hz, 1H), 3.86 (dd, J=

6.2, 3.3 Hz, 1H), 3.82 (dd, J=10.6, 5.0 Hz, 1H), 3.03 (dd, J=7.7, 2.0 Hz,

1H), 2.94 (br. d, J=3.6 Hz, 1H, OH), 2.91 (dd, J=17.2, 2.7 Hz, 1H), 2.88

(3d, J=6.6, 5.2, 2.1 Hz, 1H), 2.76 (dd, J=17.2, 9.5 Hz, 1H), 2.61 (m,

1H), 2.17 (dd, J=13.2, 5.6 Hz, 1H), 2.09 (3d, J=14.0, 10.2, 2.6 Hz, 1H),

2.01–2.00 (m, 5H), 1.91 (dd, J=13.2, 8.8 Hz, 1H), 1.91 (s(d), J=1.2 Hz,

3H), 1.81 (dt, J=13.7, 7.9 Hz, 1H), 1.80 (m, 1H), 1.74 (s(d), J=1.3 Hz,

3H), 1.70 (3d, J=14.0, 10.8, 2.6 Hz, 1H), 1.67 (3d, J=13.8, 6.3, 5.5 Hz,

1H), 1.39 (dt, J=13.7, 5.9 Hz, 1H), 1.19 (m, 1H), 1.17 (s, 9H), 1.13 (d,

J=6.8 Hz, 3H), 1.01 (t, J=8.0 Hz, 9H), 1.01 (s, 9H), 0.98 (d, J=6.9 Hz,

3H), 0.90 (d, J=6.5 Hz, 3H), 0.66 (q, J=8.0 Hz, 6H), 0.20 (s, 3H),

0.08 ppm (s, 3H); ¹³C NMR (100 MHz, C₆D₆): d=210.8, 167.5, 144.9,

144.7, 141.4, 136.0, 135.9, 133.9, 133.8, 133.5, 130.2, 130.0, 129.0, 128.1,

125.9, 115.0, 82.2, 78.6, 72.3, 66.6, 66.5, 59.0, 58.5, 46.7, 46.2, 42.9, 40.8,

39.7, 33.1, 32.5, 31.1, 30.3, 28.3, 27.0, 26.4, 20.2, 20.0, 19.5, 18.5, 17.9, 14.5,

12.9, 7.2, 5.3, ꢀ3.2, ꢀ4.3 ppm; HRMS (ESI): m/z: calcd for

C₆₀H₉₆O₈Si₃Na [M⁺+Na]: 1051.62998, found: 1051.63022.

4b, 16

3ꢂ-OH

2.18–2.28 (m)

3.27, 3.55,

3.86 (brs)

2.21–2.25 (m)

3.30 (s),

3.61 (s), 3.87 (d)

5.5

1H), 2.58 (3d, J=16.8, 6.7, 3.2 Hz, 1H), 2.39 (m, 1H), 2.22 (m, 2H), 2.18

(m, 1H), 1.92 (m, 2H), 1.90 (s, 3H), 1.81 (m, 1H), 1.79 (m, 2H), 1.76 (s,

3H), 1.71 (m, 1H), 1.60 (m, 1H), 1.21 (s, 9H), 1.07 (m, 1H), 1.06 (d, J=

6.8 Hz, 3H), 1.04 (d, J=6.8 Hz, 3H), 1.01 (s, 9H), 1.0 (s, 9H), 0.98 (d,

J=6.7 Hz, 3H), 0.89 (t, J=7.8 Hz, 9H), 0.81 (q, J=7.6 Hz, 6H), 0.3 (s,

3H), 0.16 (s, 3H), 0.14 (s, 3H), 0.10 ppm (s, 3H).

Compound 81: Prepared analogously as a colorless oil (7.6 mg, 84%).

[a]²_D⁰= ꢀ35.9 (c=0.95, CH₂Cl₂); ¹H NMR (600 MHz, C₆D₆): d=6.84–

6.82 (m, 1H), 5.71 (s, 1H), 5.64–5.60 (m, 1H), 5.30–5.24 (m, 1H), 5.08–

5.02 (m, 1H), 5.06 (s, 1H), 4.93 (s, 1H), 4.56 (d, J=2.9 Hz, 1H), 4.33

(brs, 1H), 4.08–4.04 (m, 1H), 3.10 (dd, J=15.6, 6.5 Hz, 1H), 2.94 (dd, J=

8.6, 2.0 Hz, 1H), 2.87–2.84 (m, 1H), 2.79–2.77 (m, 1H), 2.66–2.60 (m,

1H), 2.25–2.16 (m, 3H), 2.12 (dd, J=12.1, 3.2 Hz, 1H), 2.09–1.96 (m,

4H), 1.90–1.81 (m, 3H), 1.88 (s, 3H), 1.75 (s, 3H), 1.71–1.66 (m, 1H),

1.35–1.30 (m, 2H), 1.33 (d, J=6.0 Hz, 1H), 1.27–1.21 (m, 2H), 1.13 (t,

J=8.0 Hz, 9H), 1.09 (d, J=7.0 Hz, 3H), 1.06 (t, J=8.0 Hz, 9H), 1.05 (d,

J=7.9 Hz, 3H), 0.99 (s, 9H), 0.87 (d, J=6.4 Hz, 3H), 0.86–0.79 (m, 6H),

0.72 (q, J=8.2 Hz, 6H), 0.15 (s, 3H), 0.12 ppm (s, 3H); ¹³C NMR

(150 MHz, C₆D₆): d=208.5, 167.7, 144.3, 142.6, 139.6, 134.7, 130.0, 129.7,

125.9, 115.0, 82.2, 68.8, 68.7, 59.8, 58.4, 47.3, 40.7, 40.4, 33.9, 31.8, 29.8,

27.5, 26.0, 21.3, 19.8, 18.6, 18.2, 15.4, 14.1, 12.7, 7.5, 7.4, 6.1, 5.4, 1.4, ꢀ4.5,

ꢀ4.7 ppm; IR (film): n˜ =2955, 2930, 2876, 1706, 1085 cm^ꢀ1; MS (EI): m/z

(%): 888 (2) [M⁺], 756 (2), 437 (1), 371 (3), 213 (100); HRMS (ESI):

m/z: calcd for C₅₀H₉₂O₇Si₃Na [M⁺+Na]: 911.60431, found: 911.60457.

Amphidinolides H1 (9) and G1 (14): A solution of TASF (16.4 mg,

59.3 mmol) in aq. DMF (0.2 mL + 4 mL H₂O) was added to a solution of

compound 67 (12 mg, 9.9 mmol) in THF (2 mL) at 08C. The mixture was

slowly warmed to ambient temperature over a period of 30 min and stir-

ring was continued for 2 h. For work up, the mixture was extracted with

cold (58C) phosphate buffer solution (pH 7, 3ꢄ2 mL), the aqueous

phases were extracted with EtOAc (2ꢄ1 mL), the combined organic

layers were dried over Na₂SO₄and evaporated, and the residue was puri-

fied by flash chromatography (EtOAc/hexane 9:1) to afford compound 9

as a white solid (3 mg, 55%). HRMS (ESI): m/z: calcd for C₃₂H₅₀O₈Na

[M⁺+Na]: 585.33979, found: 585.33996. A solution of 9 in acidic CDCl₃

Compound 95: Prepared analogously as a colorless oil (6 mg, 91%). [a]_D²⁰

= ꢀ26.0 (c=0.3, CH₂Cl₂); ¹H NMR (600 MHz, C₆D₆): d=6.89–6.87 (m,

1H), 6.06 (s, 1H), 5.76–5.72 (m, 1H), 5.35–5.30 (m, 1H), 5.24 (dd, J=

15.4, 8.3 Hz, 1H), 5.07 (d, J=2.3 Hz, 1H), 4.96 (s, 1H), 4.38 (d, J=

4006

www.chemeurj.org

ꢂ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Chem. Eur. J. 2009, 15, 3983 – 4010

Total Syntheses of Amphidinolides

FULL PAPER

equilibrates with amphidinolide G1 (14) by transesterification as previ-

ously reported in the literature.^[11,56]The two isomers can be separated by

preparative HPLC. For a compilation of the NMR data and a compari-

son with the reported spectra, see Tables 1–3.

6.7 Hz, 3H), 0.93 (d, J=6.5 Hz, 3H), 0.91 (m, 1H), 0.86 ppm (d, J=

6.4 Hz, 3H); ¹H NMR (600 MHz, C₆D₆): d=6.93 (ddq, J=9.6, 4.8,

1.6 Hz, 1H, H3), 5.67 (s, 1H, H14), 5.43 (3d, J=15.2, 9.8, 4.6 Hz, 1H,

H6), 5.26 (4d, J=12.4, 5.8, 4.6, 2.8 Hz, 1H, H25), 5.26 (dd, J=15.2,

9.2 Hz, 1H, H7), 5.02 (s, 1H, H29a), 4.92 (s(d), J=2.4 Hz, 1H, H29b),

4.15 (m, 1H, H18), 3.85 (t, J=2.5 Hz, 1H, H21), 3.82 (d, J=12.1, 1H,

OH-22), 3.68 (d, J=2.6 Hz, 1H, OH-21), 3.51 (dt, J=11.6, 5.8 Hz, 1H,

H26a), 3.46 (3d, J=11.6, 5.6, 4.4 Hz, 1H, H26b), 3.40 (3d, J=12.0, 11.0,

2.4 Hz, 1H, H22), 2.96 (dt, J=9.9, 2.0 Hz, 1H, H9), 2.94 (dd, J=17.6,

1.8 Hz, 1H, H19a), 2.78 (dd, J=9.0, 2.3 Hz, 1H, H8), 2.51 (ddm, J=12.4,

3.6 Hz, 1H, H12a), 2.50 (3d, J=14.0, 12.4, 3.0 Hz, 1H, H24a), 2.17 (dd,

J=17.6, 9.7 Hz, 1H, H19b), 2.13 (br. s, 1H, OH-18), 2.13 (m, 1H, H16),

2.11 (m, 1H, H23), 2.02 (m, 1H, H4a), 1.93 (m, 1H, H5a), 1.83 (s, 3H,

Me-27), 1.82 (m, 1H, H17a), 1.79 (m, 1H, OH-26), 1.73 (m, 1H, H11),

1.71 (s(d), J=1.4 Hz, 3H, Me-30), 1.70 (m, 1H, H5b), 1.69 (m, 1H, H4b),

1.68 (m, 1H, H12b), 1.54 (3d, J=14.2, 5.9, 1.7 Hz, 1H, H10a), 1.35 (3d,

J=14.0, 10.4, 4.0 Hz, 1H, H17b), 1.05 (3d, J=14.0, 12.0, 2.8 Hz, 1H,

H24b), 0.96 (d, J=6.8 Hz, 3H, Me-31), 0.95 (d, J=6.2 Hz, 3H, Me-28),

0.87 (d, J=6.6 Hz, 3H, Me-32), 0.79 ppm (3d, J=14.1, 9.9, 5.8 Hz, 1H,

H10b); for the ¹³C NMR data in CDCl₃and a comparison with natural

amphidinolide H2, see Table 8; ¹³C NMR (100 MHz, C₆D₆): d=211.6,

168.5, 145.0, 140.7, 140.3, 135.8, 130.4, 128.1, 127.4, 115.2, 78.7, 76.7, 73.1,

66.2, 65.7, 60.2, 59.7, 46.8, 43.9, 41.1, 40.7, 40.7, 34.3, 32.7, 31.2, 30.2, 26.8,

Amphidinolide B1 (1): Prepared analogously as a colorless solid (3.6 mg,

93%). For a compilation of the NMR data, see Tables 4 and 5.

Amphidinolide B4 (4): Prepared analogously as a colorless oil (7.6 mg,

58%). For a compilation of the NMR data, see Tables 6 and 7.

Compound 10: Prepared analogously as a colorless oil (3.1 mg, 46%).

For a compilation of the NMR data, see Tables 8 and 9.

Compound 102: Prepared analogously as a white solid (4 mg, 80%). [a]_D²⁰

= ꢀ79.8 (c=0.1, CHCl₃); ¹H NMR (600 MHz, CDCl₃): d=6.77 (dd, J=

9.2, 4.8 Hz, 1H), 5.84 (3d, J=15.4, 10.0, 4.4 Hz, 1H), 5.50 (s, 1H), 5.21

(dd, J=15.4, 9.0 Hz, 1H), 5.10 (m, 1H), 4.93 (s, 1H), 4.78 (s, 1H), 4.21

(d, J=1.2 Hz, 1H), 4.05 (t, J=9.2 Hz, 1H), 3.69 (m, 2H), 3.59 (m, 1H),

3.06 (dd, J=8.8, 2.2 Hz, 1H), 3.03 (dd, J=18.0, 2.3 Hz, 1H), 2.94 (dt, J=

9.6, 2.2 Hz, 1H), 2.51 (dd, J=18.0, 9.8 Hz, 1H), 2.46 (m, 1H), 2.38 (m,

1H), 2.36 (m, 1H), 2.26 (m, 1H), 2.21 (m, 1H), 2.20 (m, 1H), 2.12 (m,

1H), 1.88 (m, 1H), 1.81 (s, 3H), 1.80 (m, 1H), 1.70 (s, 3H), 1.70 (m, 1H),

1.64 (m, 1H), 1.59 (m, 1H), 1.41 (m, 1H), 1.23 (m, 1H), 1.04 (d, J=

Table 8. Comparison of the ¹³C NMR data (CDCl₃) of amphidinolide H2

reported by Kobayashi et al.^[12]with those of synthetic 10 and synthetic

102.

Table 9. Compilation of the NMR data of synthetic 10 in C₆D₆; number-

ing Scheme analogous to that shown in the Insert of the previous Table.

Position

¹³C NMR (150MHz)

¹H NMR (600MHz)^[a]

1

2

3

4

168.3 (s)

129.2 (s)

141.0 (d)

27.0 (t)

6.99 (ddq, J=8.3, 7.5, 1.4 Hz)

2.00 (m)/1.87 (m)

5

31.2 (t)

1.93 (m)/1.73 (m)

6

7

8

9

10

11

12

13

14

15

16

17

134.9 (d)

129.2 (d)

60.8 (d)

59.2 (d)

39.5 (t)

5.50 (ddd, J=15.4, 9.4, 4.5 Hz)

4.86 (dd, J=15.5, 8.4 Hz)

2.93 (dd, J=8.4, 2.2 Hz)

2.70 (dd, J=9.2, 5.2 Hz)

1.10 (m)

Position

Amphidinolide H2

102

dD

10

dD

1

2

3

4

5

6

7

8

168.7

127.6

140.8

26.9

31.0

136.1

129.7

59.8

60.1

40.4

29.8

46.6

144.3

126.7

140.6

40.8

40.2

65.9

43.8

211.3

78.4

76.2

32.3

33.9

73.3

66.6

12.7

19.5

115.0

12.3

20.4

15.1

168.8

127.5

140.8

26.8

31.0

136.1

129.7

59.8

60.2

40.4

29.8

46.5

144.2

126.7

140.5

40.8

40.0

65.8

43.7

211.3

78.4

76.2

32.2

33.8

73.3

66.7

12.7

19.5

115.0

12.2

20.4

15.1

ꢀ0.1

0.1

0

0.1

0

168.7

127.9

141.4

27.0

30.8

135.2

128.7

60.6

59.4

38.8

28.3

47.4

143.5

125.6

140.8

41.3

40.8

66.9

44.8

211.6

78.2

76.1

32.5

33.6

73.4

66.2

12.5

18.6

114.8

12.8

20.0

15.6

0

ꢀ0.3

ꢀ0.6

ꢀ0.1

0.2

0.9

1.0

28.3 (d)

47.7 (t)

1.87 (m)

1.98 (m)/1.87 (m)

144.2 (s)

126.2 (d)

140.5 (s)

41.3 (d)

41.2 (t)

5.77 (s)

ꢀ0.8

9

ꢀ0.1

0.7

2.15 (ddq, J=11.4, 6.8, 4.4 Hz)

1.72 (m),

1.37 (ddd, J=13.6, 9.6, 4.3 Hz)

4.23 (m)

2.85 (dd, J=16.9, 1.0 Hz),

2.37 (dd, J=17.0, 9.2 Hz)

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

0

1.6

1.5

0

0.1

0

0.1

0

0.2

0.1

0

0.1

0

ꢀ0.8

18

19

66.1 (d)

44.6 (t)

0.8

1.1

ꢀ0.2

ꢀ0.5

ꢀ0.6

ꢀ1.0

ꢀ0.3

0.2

20

21

22

23

24

211.1 (s)

78.4 (d)

76.7 (d)

32.8 (d)

34.0 (t)

3.97 (dd, J=4.4, 1.9 Hz)

3.49 (ddd, J=11.0, 9.0, 1.9 Hz)

2.10 (m)

2.02 (m),

0.99 (ddd, J=13.4, 11.8, 2.3 Hz)

5.25 (m)

25

26

27

28

29

73.1 (d)

65.9 (t)

12.7 (q)

18.3 (q)

115.0 (t)

0.1

3.58 (m)

ꢀ0.2

1.88 (d, J=1.3 Hz)

0.86 (d, J=6.0 Hz)

5.00 (d, J=2.7 Hz),

4.92 (dd, J=2.6, 1.1 Hz)

1.70 (d, J=1.3 Hz)

0.95 (d, J=6.8 Hz)

1.17 (d, J=6.6 Hz)

0.3

ꢀ0.1

0.4

0.2

0.9

0.2

ꢀ0.1

0

30

31

32

12.7 (q)

20.1 (q)

15.9 (q)

0

0.1

0

ꢀ0.5

[a] The -OH protons were found to resonate at: d=2.46 (brs, 18-OH),

1.95 (brs, 26-OH), 3.95 (d, J=4.4 Hz, 21-OH), 4.05 (d, J=11.1 Hz, 22-

OH).

0.4

ꢀ0.5

Chem. Eur. J. 2009, 15, 3983 – 4010

ꢂ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

www.chemeurj.org

4007

A. Fꢀrstner et al.

20.5, 20.1, 15.2, 12.9, 12.3 ppm; HRMS (ESI): m/z: calcd for C₃₂H₅₀O₈Na

[M⁺+Na]: 585.33979, found: 585.33996.

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Generous financial support by the MPG, the Chemical Genomics Center

(CGC Initiative of the MPG), the Fonds der Chemischen Industrie, the

Swiss National Foundation (stipends to L.C.B. and F.B.), the NSERC (sti-

pend to L. M.), the Swedish Research Council (to V.L.), the Roche Foun-

dation (stipend to L.C.B.), and the JSPS (to M.T.) is gratefully acknowl-

edged. We thank S. Schulthoff, K. Tꢀcking, and S. Marcus for technical

assistance, Dr. J. Ruiz-Caro for exploratory studies, Dr. R. Mynott, B.

Gabor and C. Wirtz for superb NMR support, and A. Deege, H. Hin-

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Received: October 7, 2008

Published online: February 24, 2009

4010

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Chem. Eur. J. 2009, 15, 3983 – 4010

Article Doi

Total syntheses of amphidinolides B1, B4, G1, H1 and structure revision of amphidinolide H2

DOI: 10.1002/chem.200802067

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