A fully stereocontrolled total synthesis of (+)-leucascandrolide A

Tetrahedron 59 (2003) 6833–6849

A fully stereocontrolled total synthesis of (1)-leucascandrolide A

*

Ian Paterson and Matthew Tudge

Department of Chemistry, University Chemical Laboratory, Lensﬁeld Road, Cambridge CB2 1EW, UK

Received 28 April 2003; revised 16 May 2003; accepted 16 May 2003

Abstract—A highly stereocontrolled total synthesis of leucascandrolide A, a cytotoxic 18-membered macrolide from the calcareous sponge

Leucascandra caveolata, starts out with a Jacobsen asymmetric hetero Diels–Alder reaction to conﬁgure the 2,6-cis-tetrahydropyran ring.

All the remaining oxygenated stereocentres are introduced with high selectivity by relying on substrate-based control. An efﬁcient endgame

depends on two Mitsunobu reactions, the ﬁrst to close the macrolactone with inversion at C17 and the second to attach the oxazole-containing

side chain at C5, followed by Lindlar hydrogenation of the two alkynes to provide (þ)-leucascandrolide A.

1. Introduction

genera. While the true biosynthetic origin of this archi-

tecturally unique polyketide is unknown, it has been

proposed that leucascandrolide A and its co-metabolite

leucascandrolide B are products of opportunistic microbial

colonization of the sponge, as a further collection of

L. caveolata by the Pietra group did not yield any traces of

either compound.⁴

Marine organisms produce a fascinating range of structu-

rally diverse secondary metabolites, which often possess

signiﬁcant biological activities and have great potential as

molecular probes for investigating biochemical pathways.¹

Marine-derived macrolides have attracted prominent atten-

tion in this regard.²Leucascandrolide A (1, Fig. 1) was

isolated in 1996 from the New Caledonian calcareous

sponge Leucascandra caveolata by Pietra and co-workers.³

This highly oxygenated 18-membered macrolide has eight

stereogenic centres and three alkenes, and also features two

trisubstituted tetrahydropyran rings, one of these having an

unusual oxazole-containing side chain axially appended at

C5. At the time, this represented a breakthrough in the

search for molecular diversity from the biodiversity of

calcareous sponges, which have been much less investigated

by marine natural products chemists than other sponge

In preliminary biological studies, leucascandrolide A

exhibited potent cytotoxic activity in vitro against KB oral

epidermoid carcinoma and P388 leukemia cell lines

(IC₅₀¼0.05 and 0.25 mg/mL, respectively), as well as

signiﬁcant inhibition of the pathogenic fungus Candida

albicans.³Additionally, following hydrolysis of the C5 ester

linkage, biological testing of the 18-membered macrocyclic

core and the separated side chain demonstrated that the

macrocyclic domain is solely responsible for the cyto-

toxicity, while the oxazole-containing unsaturated side

chain appears to be responsible for the antifungal activity.

As a consequence of the natural supply of leucascandrolide

A (1) being extremely limited, if not entirely exhausted due

to the failure to reisolate it, a ﬂexible and efﬁcient synthesis

is essential for further biological studies, while also opening

access to de novo analogues. Due to its challenging and

unusual polyketide structure and interesting biological

proﬁle, leucascandrolide A has attracted considerable

synthetic attention from several groups,^5–8with the ﬁrst

total synthesis reported by Leighton and co-workers.^6a

Recently, we disclosed our successful route to (þ)-

leucascandrolide A,⁵and we now report full details of the

evolution of our initial formal synthesis and the steps

leading to the completion of a total synthesis by the

preparation and attachment of the oxazole-containing side

chain.

Figure 1. Structure of leucascandrolide A.

Keywords: macrolides; hetero Diels–Alder reaction; aldol reaction;

Mitsunobu reaction; cytotoxic; antifungal.

*

Corresponding author. Tel.: þ44-1223-336407; fax: þ44-1223-336362;

e-mail: ip100@cam.ac.uk

doi:10.1016/S0040-4020(03)00814-7

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2. Retrosynthetic analysis and general synthetic strategy

characteristic polyketide biosynthetic pathway, we planned

to introduce the oxygenated stereocentres at C9, C11 and

C15 using suitable substrate-controlled reactions. Recog-

nising the 1,5-anti relationship between the C7 and C11

stereocentres, the seco-acid 2 (with either (R)- or (S)-

conﬁguration at C5 and C17) should be accessible by a

strategic aldol coupling step performed between the methyl

ketone 4 (with either (R)- or (S)-conﬁguration at C5) and

aldehyde 5, as a suitable C11–C15 subunit, using

methodology developed in our laboratory.^9,10Furthermore,

the newly created C11 stereocentre could, in turn, direct an

anomeric alkylation with silyl enol ether 6, as a suitable

C16–C23 subunit, thus conﬁguring the C15 centre in 2 and

installing C17 initially as a ketone. However, two additional

considerations were identifying a reliable method for the

asymmetric synthesis of the 2,6-cis-tetrahydropyran with

introduction of the C3 and C7 stereocentres, as required for

the generalised C1–C10 subunit 4, and a workable ro₀ute to

preparing the proposed oxazole-containing C1⁰–C11 sub-

unit 3. As indicated in the following account, this general

plan, with the selection of suitable protecting groups, served

us well and provided sufﬁcient ﬂexibility in deﬁning the

optimum ordering of the steps.

As outlined in Scheme 1, two late-stage esteriﬁcation steps

were envisaged as part of an appropriate endgame to access

leucascandrolide A (1). The ﬁrst would involve the

macrolactonisation of seco-acid 2, while the second would

be employed to append the unsaturated side chain using the

oxazole containing acid 3, which contains two alkyne

groups. In the ﬁnal step, a double Lindlar hydrogenation was

anticipated to reduce these alkynes to install the two (Z)-

conﬁgured alkenes stereospeciﬁcally to provide 1 directly.

In order to have the option of performing a conventional

acylation or a Mitsunobu-type inversion protocol, we

planned to control the C5 and C17 stereocentres in either

sense by appropriate ketone reductions. Importantly, we

envisaged that the conﬁguration of these two hydroxyl-

bearing stereocentres could be inverted as required,

providing considerable ﬂexibility in the synthetic route.

By exploiting the 1,3-dioxygenation pattern, arising from a

3. Results and discussion

In initiating our synthetic efforts, we turned to exploring the

use of the recently reported Jacobsen hetero Diels–Alder

reaction¹¹for constructing the right-hand tetrahydropyran

ring of leucascandrolide A, simultaneously conﬁguring the

C3 and C7 stereocentres (Scheme 2). For access to the

proposed C1–C10 subunit 4, this involved starting out from

the readily available 2-silyloxydiene 7 (obtained by silyl

enol ether formation from the corresponding enone¹²) and

aldehyde 8. Thus, treatment of a neat mixture of diene 7 and

aldehyde 8 with the chiral tridentate chromium-(III) catalyst

˚

9 (10 mol%, 4 A molecular sieves) for 20 h afforded, after

mild acidic work-up to hydrolyse the initially formed

[4þ2]-cycloadduct, the required 2,6-cis-tetrahydropyran 10

in 80% yield. After optimisation, this hetero Diels–Alder

reaction¹³proved reasonably scaleable and proceeded

with (.20:1 dr and, importantly, delivered the desired

(3S,7S)-conﬁguration with (.95% ee (as determined by

later Mosher ester analysis).

Although we assumed the C5 conﬁguration could be

inverted if required at the macrocycle stage, to cover

every eventuality both alcohols 11 and 12 were prepared. To

this end, reduction of ketone 10 with NaBH₄in MeOH

afforded the C5-equatorial alcohol 11 (99%, 13:1 dr), while

treatment of 10 with ^L-Selectride^win THF provided the

axial epimer 12 with high selectivity (88%, 32:1 dr).

The C5-equatorial isomer 11 was initially selected to

progress through the synthesis in order to evaluate the

later chemistry. As shown in Scheme 3, the alcohol 11 was

ﬁrst converted into its TIPS derivative and the TBS ether

was cleaved selectively under acidic methanolysis con-

ditions to afford alcohol 13. In order to homologate the C7

substituent on the tetrahydropyran ring, alcohol 13 was

activated as its triﬂate derivative (Tf₂O, pyr, CH₂Cl₂) which

enabled clean nucleophilic displacement with lithium

Scheme 1. Retrosynthetic analysis for leucascandrolide A leading to key

building blocks.

I. Paterson, M. Tudge / Tetrahedron 59 (2003) 6833–6849

6835

w

Scheme 2. (a) 4 A molecular sieves, 208C, 20 h; acidiﬁed CHCl₃, 208C, 4 h; (b) NaBH₄, MeOH, 08C, 1 h; (c) L-Selectride , THF, 21008C, 1.5 h.

˚

trimethylsilylacetylide, in the presence of HMPA, followed

by basic methanolysis to provided the alkyne 14 (81%).¹⁴

Finally, mercury-(II) mediated hydration of the terminal

alkyne generated the methyl ketone 15, which was

essentially enantiopure. Notably, this efﬁcient reaction

sequence was performed to produce multigram quantities

of the C1–C10 subunit 15.

able levels of 1,5-stereoinduction from the enolate com-

ponent 20, indicating that the chiral aldehyde 5 was not

contributing any signiﬁcant 1,2-stereoinduction in setting

up the C11 centre in this complex aldol coupling. Moreover,

this result is fully consistent with our earlier studies⁹and

related work from the Evans group.¹⁰

Next, the newly introduced C11 stereocentre was used to

control the introduction of the neighbouring C9 centre by

employing Me₄NBH(OAc)₃to conduct a hydroxyl-directed,

1,3-anti reduction of the ketone.¹⁷This afforded diol 22

cleanly (99%, $50:1 dr) which, following cleavage of the

Preparation of the C11–C15 aldehyde 5 commenced from

the Myers chiral amide 16 and the iodide 17, where the C12

stereocentre was installed by a diastereoselective enolate

alkylation.¹⁵Thus, enolisation of 16 with LDA in THF, in

the presence of LiCl, and addition of 17 afforded the amide

18 cleanly (86%, $40:1 dr). Next, the chiral auxiliary was

reductively cleaved using lithium amidoborane to provide

the alcohol 19 in 99% yield and $95% ee (Mosher ester

analysis). This was oxidised with Dess–Martin periodinane

to the required aldehyde 5 (85%) and used directly in the

next step (Scheme 4).

We now turned to forming the C10–C11 bond with

concomitant generation of the C11 stereocentre under the

directing inﬂuence of the remote C7 oxygenated centre

(Scheme 5). This pivotal 1,5-anti aldol bond construction

between the b-oxygenated ketone 15 and the (S)-conﬁgured

aldehyde 5 proceeded smoothly using the kinetically

generated boron enolate under our reported conditions.^9a,16

Thus, treatment of methyl ketone 15 with c-Hex₂BCl, in the

presence of Et₃N in Et₂O, resulted in regiocontrolled

formation of the less substituted dicyclohexylboron enolate

20, which on reaction with aldehyde 5 provided the desired

aldol adduct 21 in 99% yield and 17:1 dr. Notably,

analogous reactions with achiral aldehydes gave compar-

Scheme 4. (a) LDA, LiCl, THF, 08C; (b) LDA, BH₃NH₃, THF, 08C;

(c) Dess–Martin periodinane, CH₂Cl₂, 208C.

Scheme 3. (a) TIPSOTf, 2,6-lutidine, CH₂Cl₂, 2788C, 2 h; (b) CSA, 2:1

MeOH/CH₂Cl₂, 208C, 1 h; (c) Tf₂O, pyr, CH₂Cl₂, 2108C, 1 h; (d) LDA,

TMSCuCH, THF, HMPA, 278 to 208C, 1 h; K₂CO₃, MeOH, 208C, 12 h;

(e) cat. Hg(OAc)₂, PPTS, wet THF, 408C, 1 h.

Scheme 5. (a) c-Hex₂BCl, NEt₃, Et₂O, 08C; 5, 278 to 2308C; (b) Me₄-

NBH(OAc)₃, 3:1 MeCN/AcOH, 240 to 2208C; (c) CSA, 2:1 MeOH/

CH₂Cl₂, 208C.

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chain via an anomeric alkylation using the silyl enol ether 6,

representing a complete C16–C23 subunit, then sub-

sequently conﬁgure the C17 stereocentre by a suitable

ketone reduction.

Lactone 25 was ﬁrst reduced to the lactol with DIBAL, then

acetylated in situ²⁰(Ac₂O, pyr, DMAP) to provide the

anomeric acetate 26 which was then treated with the silyl

enol ether 6,²¹in the presence of the mild Lewis acid

ZnBr₂,²²to afford enone 27 cleanly (81%, $50:1 dr), by

presumed axial attack on the intermediate oxocarbenium

ion, leading to the desired 2,6-trans substitution of the

tetrahydropyran ring. Since the conﬁguration of the C17

hydroxyl stereocentre could either be inverted by a

Mitsunobu-type macrocyclisation, or retained by using a

more conventional Yamaguchi-type macrolactonisation,

effort was focused on developing a highly selective

reduction in either stereochemical sense. After screening a

range of reagents and conditions, we found that reduction by

LiAlH(Ot-Bu)₃in CH₂Cl₂afforded the 1,3-syn allylic

alcohol 28 in 76% yield with a diastereomeric ratio of

$32:1. This high level of 1,3-stereoinduction may be a

simple consequence of lithium chelation with the C15 ether

oxygen or operation of the Evans polar model.²³

Scheme 6. (a) TEMPO, PhI(OAc)₂, CH₂Cl₂, 208C; (b) Me₃OBF₄, proton

sponge, CH₂Cl₂, 0 to 208C.

TBS ether (CSA, MeOH), provided the 1,5,7-triol 23. A

chemoselective d-lactonisation was now required to

introduce the second tetrahydropyran ring of leucascandro-

lide A. Gratifyingly, this was conveniently achieved using a

novel oxidative cyclisation (Scheme 6), where selective

oxidation of the primary alcohol led to lactol formation and

further oxidation generated the d-lactone 24.^5,18Thus,

prolonged treatment of triol 23 with TEMPO, in the

presence of iodobenzene diacetate as re-oxidant,¹⁹provided

lactone 24 in 92% yield. This constitutes one of the ﬁrst

examples of this TEMPO-mediated procedure being used

for the differentiation of elaborate open-chain polyols. The

remaining C9 hydroxyl group was then transformed into its

methyl ether (Me₃OBF₄, Proton sponge^w) to give 25 (84%).

Next, the resulting C17 hydroxyl in 28 was temporarily

converted into its acetate derivative (Ac₂O, pyr, DMAP)

and the PMB ether oxidatively cleaved (DDQ) to afford

alcohol 29 (99%). Subsequent oxidation of alcohol 29 to the

corresponding acid 30 (TEMPO/PhI(OAc)₂then

NaClO₂),¹⁹followed by hydrolysis of the acetate (K₂CO₃,

MeOH), provided the corresponding seco-acid, in readiness

for the challenging Mitsunobu macrocyclisation to invert

the C17 centre. Gratifyingly, by using Mitsunobu macro-

lactonisation conditions, as developed in the context of our

earlier total synthesis of laulimalide,^24,25the seco-acid was

treated with DEAD in benzene, in the presence of excess

PPh₃, to afford the 18-membered macrolide 31 in 61% yield.

With advanced intermediate 25 in hand, all that remained to

complete the 18-membered macrolide core of leucas-

candrolide A was installation of the C15 side chain and

macrocyclisation, where a ﬁnal inversion of the C5

hydroxyl-bearing stereocentre would constitute a formal

synthesis. An effective anomeric allylation approach had

been utilised by Leighton and co-workers^6ato conﬁgure the

C15 stereocentre, however, following ozonolysis to give the

aldehyde and an alkenyl organozinc addition, only moderate

levels of control were exerted over the C17 stereocentre. As

shown in Scheme 7, we opted to install the full C15 side

Scheme 7. (a) DIBAL, CH₂Cl₂; Ac₂O, pyr. DMAP, 278 to 2208C; (b) ZnBr₂, CH₂Cl₂, 08C; (c) LiAlH(Ot-Bu)₃, CH₂Cl₂, 278 to 2108C; (d) Ac₂O, Pyr,

DMAP, CH₂Cl₂, 0 to 208C; (e) DDQ, 10:1 CH₂Cl₂/pH 7 buffer, 208C; (f) TEMPO, PhI(OAc)₂, CH₂Cl₂, 208C; NaClO₂, NaHPO₄, methyl-2-butene, aq. t-BuOH,

0 to 208C; (g) K₂CO₃, MeOH, 208C; (h) DEAD, PPh₃, PhH, 208C; (i) HF.Pyr, THF, 0 to 208C; (j) Dess–Martin periodinane, pyr, CH₂Cl₂, 208C.

I. Paterson, M. Tudge / Tetrahedron 59 (2003) 6833–6849

6837

Extensive NMR analysis revealed that this cyclisation

proceeded with clean inversion and without any competing

allylic rearrangement. Finally, the TIPS ether was cleaved

using HF·pyr in THF to provide the C5-equatorial macrolide

32 (95%).

Et₃N, Et₂O) followed by addition of aldehyde 5 provided

aldol adduct 37 smoothly (99%, 17:1 dr). Next, an Evans–

Saksena reduction¹⁷provided alcohol 38 (95%, $50:1 dr),

which following acidic cleavage of the TBS ether (HCl,

MeOH, 94%), was subjected to the TEMPO-mediated

oxidative cyclisation protocol to afford d-lactone 39 (90%).

Finally, O-methylation (Me₃OBF₄, Proton-Sponge^w) gave

key intermediate 40 in 83% yield.

At this point, studies into the preparation of the C1⁰–C11⁰

oxazole side chain 3, as required for a projected Mitsunobu-

type acylation at C5, were still in their infancy. As a

consequence of this, efforts were initially focused on

inverting the C5 conﬁguration by oxidation and subsequent

reduction by equatorial hydride attack, thus securing a

formal synthesis. Whilst Dess–Martin oxidation of alcohol

32 proceeded smoothly to afford ketone 33, subsequent

reduction with ^L-Selectride^wsurprisingly afforded only

the returned C5-equatorial macrocycle 32. Presumably, the

unexpected preference for apparent axial attack on the

pyranone ring by a sterically encumbered reducing agent,

such as ^L-Selectride^w, arises here from the macrocyclic

conformational bias of 33.²⁶

To complete the synthesis of the C5-axial macrolide all that

now remained was the installation of the appropriate C15

side chain followed by macrocyclisation. By relying on the

previously developed chemistry, lactone 40 was reduced to

the corresponding lactol, acetylated in situ and subjected

to our anomeric alkylation conditions with silyl enol ether 6

to afford enone 41 (81%, $50:1 dr). Subsequent 1,3-syn

reduction (LiAlH(Ot-Bu)₃, $32:1 dr) was followed by

O-acetylation (Ac₂O, pyr, DMAP) and oxidative removal

(DDQ) of the PMB group to provide alcohol 42 (84%).

Next, alcohol 42 was oxidised to the corresponding acid 43

and the C15 acetate hydrolysed to reveal the seco-acid.

Treatment of this seco-acid under our optimised Mitsunobu

conditions (DEAD, PPh₃, degassed PhH) afforded macro-

lide 44 in 48% yield. Finally, the TIPS ether was cleaved

(TBAF, THF) to provide the C5-axial alcohol 45 in 99%

yield. At this point, our spectroscopic data for 45 matched

with that reported by the groups of Pietra³and Leighton^6a

for the macrocyclic core, indicating that we had now

achieved a formal synthesis of (þ)-leucascandrolide A.

With this last frustrating result and our stocks of advanced

intermediates in the C5-equatorial series now substantially

depleted, we decided to go back and access the required C5-

epi macrolide core from the already prepared C5-axial

tetrahydropyran 12 (Scheme 2). As summarised in

Scheme 8, by using the optimised route developed in the

C5-equatorial series, 12 was ﬁrst transformed into alcohol

34 (93%). Next, 34 was activated as its triﬂate derivative,

displaced with lithium trimethylsilylacetylide, and sub-

jected to basic methanolysis to provide alkyne 35.

Subsequent hydrative oxymercuration then generated the

desired C1–C10 ketone 36 in 63% yield over 3 steps.

With the two macrolides 32 and 45 in hand, attention was

now focused on the preparation of the oxazole-containing

side chain 3 in order to explore the viability of our planned

endgame (cf. Scheme 2) to deliver leucascandrolide A. As

shown in Scheme 9, key to the preparation of side chain 3

was a Sonogashira coupling step,²⁷where the required

oxazole triﬂate 46 was derived from ketone 47, the

As in the C5-equatorial series, the ketone 36 was coupled

with aldehyde 5 using our boron-mediated 1,5-anti aldol

methodology. Again, enolisation of ketone 36 (c-Hex₂BCl,

Scheme 8. (a) TIPSOTf, 2,6-lutidine, CH₂Cl₂, 2788C; (b) CSA, 2:1 MeOH/CH₂Cl₂, 208C; (c) Tf₂O, pyr, CH₂Cl₂, 2108C; (d) LDA, TMSC;CH, THF,

HMPA, 278 to 208C; K₂CO₃, MeOH, 208C; (e) cat. Hg(OAc)₂, PPTS, wet THF, 408C; (f) c-Hex₂BCl, NEt₃, Et₂O, 08C; 5, 278 to 2308C; (g) Me₄NBH(OAc)₃,

3:1 MeCN/AcOH, 240 to 2208C; (h) HCl, MeOH/CH₂Cl₂, 258C; (i) TEMPO, PhI(OAc)₂, CH₂Cl₂, 208C; (j) Me₃OBF₄, proton sponge, CH₂Cl₂, 0 to 208C;

(k) DIBAL, CH₂Cl₂; Ac₂O, pyr. DMAP, 278 to 2208C; (l) ZnBr₂, CH₂Cl₂, 08C; (m) LiAlH(Ot-Bu)₃, CH₂Cl₂, 278 to 2108C; (n) Ac₂O, Pyr, DMAP, CH₂Cl₂,

0 to 208C; (o) DDQ, 10:1 CH₂Cl₂/pH 7 buffer, 208C; (p) TEMPO, PhI(OAc)₂, CH₂Cl₂, 208C; NaClO₂, NaHPO₄, methyl-2-butene, aq. t-BuOH, 0 to 208C;

(q) K₂CO₃, MeOH, 208C; (r) DEAD, PPh₃, PhH, 208C; (s) TBAF, THF, 08C.

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I. Paterson, M. Tudge / Tetrahedron 59 (2003) 6833–6849

Scheme 10. Direct acylation route.

Scheme 9. (a) LDA, HMPA, THF, 278 to 208C; (b) TBAF, THF, 208C;

˚

(c) Cl₃CC(O)NCO, CH₂Cl₂, 208C; K₂CO₃, MeOH, 208C; (d) 4 A molecular

sieves, PhMe, 908C; (e) Tf₂O, 2,6-lutidine, CH₂Cl₂, 278 to 2108C;

(f) Pd(PPh₃)₄, 42, 2,6-lutidine, 1,4-dioxan, 208C; (g) DDQ, 10:1 CH₂Cl₂/pH

7 buffer, 208C; (h) TEMPO, PhI(OAc)₂, CH₂Cl₂, 208C; NaClO₂, NaHPO₄,

methyl-2-butene, aq. t-BuOH, 0 to 208C.

a-alkylation product of the N,N-dimethylhydrazone 48²⁸

with the propargylic bromide 49²⁹(LDA, THF, HMPA)

followed by TBS ether cleavage (TBAF). Treatment of the

a-hydroxy ketone 47 with trichloroacetyl isocyanate,

followed by basic hydrolysis and heating the resulting

˚

inseparable mixture to 908C, in the presence of 4 A

molecular sieves, produced the required oxazolone 50

(49%). Reaction of 50 with Tf₂O in the presence of 2,6-

lutidine then provided oxazole triﬂate 46, which was reacted

with alkyne 51^6aunder the Sonogashira coupling conditions

(Pd(PPh₃)₄, CuI, 2,6-lutidine, 1,4-dioxane) developed by

Panek and co-workers,³⁰to provide the corresponding side

chain precursor 52. Removal of the PMB group (DDQ),

followed by oxidation of the resulting alcohol 53 to the

carboxylic acid (TEMPO/PhI(OAc)₂; NaClO₂), then gave

the required C1⁰–C11⁰subunit 3 in 36% yield over 5 steps.

Following the successful preparation of the required C1⁰–

C11⁰subunit 3, the most obvious way to reach (þ)-

leucascandrolide A appeared to be via direct acylation of the

C5-axial macrolide 45, followed by Lindlar hydrogenation

of the expected ester 54 to conﬁgure the two (Z)-alkenes

(Scheme 10). However, what at ﬁrst was considered to be

the simpler approach met with difﬁculties from the onset,

presumably due to the hindered nature of the C5 axial

alcohol. Under a range of acylation conditions, employing

various activated acid derivatives of 3, or the corresponding

acid chloride, only recovered macrolide 45 could be

obtained.

Scheme 11. (a) Dess–Martin periodinane, pyr, CH₂Cl₂, 208C;

(b) ^L-Selectride^w, THF, 21008C; (c) DEAD, PPh₃, 1.5:1 THF/PhMe, 0

to 208C; b) H₂, 5% Pd/CaCO₃poisoned with lead (Lindlar catalyst),

quinoline, EtOAc, 208C.

Following this disappointing outcome, our efforts turned to

examining the alternative option of performing a Mitsunobu

I. Paterson, M. Tudge / Tetrahedron 59 (2003) 6833–6849

6839

esteriﬁcation between the C5-equatorial macrolide 32 and

side chain 3 (Scheme 11). To increase our stocks of material

in this series, the remaining C5-axial macrolide 45 could

readily be converted into the C5-equatorial macrolide 32 in

91% yield by the oxidation/reduction sequence (Dess

Martin periodinane; ^L-Selectride^w) already established (cf.

Scheme 4). To our delight, reaction of the side-chain acid 3

and macrocycle 32, in the presence of excess DEAD and

PPh₃, facilitated the smooth formation of coupled product

54 in 90% yield. Finally, double Lindlar hydrogenation of

the two triple bonds proceeded without incident, affording

the reaction mixture was stirred for 12 h, diluted with

CH₂Cl₂, and ﬁltered through a plug of MgSO₄. The organic

ﬁltrate was concentrated in vacuo, dissolved in acidiﬁed

chloroform^†(10 mmol) and stirred for 4 h. The reaction

mixture was then treated with Et₃N (139 mL, 1.00 mmol)

and concentrated in vacuo. Flash chromatography (20%

Et₂O/40–60 petroleum ether) afforded the pyranone 10^‡as a

light yellow oil (562 mg, 80%); R_f¼0.45 (50% EtOAc/40–

cm²¹(ﬁlm) 2942, 2910, 2856, 1720, 1610, 1245; ¹H NMR

(500 MHz, CDCl₃) d 7.23 (2H, d, J¼8.5 Hz), 6.87 (2H, d,

J¼8.5 Hz), 4.43 (1H, d, J¼11.7 Hz), 4.40 (1H, d,

J¼11.7 Hz), 3.80 (3H, s), 3.79–3.76 (1H, m), 3.73–3.69

(1H, m), 3.67–3.62 (1H, m), 3.61–3.53 (1H, m), 2.39–2.32

(3H, m), 2.24 (1H, dd, J¼14.3, 11.7 Hz), 1.94–1.88 (1H,

m), 1.84–1.77 (1H, m), 0.89 (9H, s), 0.06 (6H, s); ¹³C NMR

(100.6 MHz, CDCl₃) d 207.5, 159.2, 130.4, 129.2, 113.8,

77.2, 74.1, 72.7, 65.8, 55.3, 47.8, 44.1, 36.4, 25.9, 20.6,

18.3, 25.3, 25.3; m/z (CIþ) 426 ([MþNH₄]^þ, 10%);

HRMS (ESþ) Found 426.2666, [C₂₂H₄₀NO₅Si]^þrequires

426.2676.

60 petroleum ether); [a]²_D⁰¼216.4 (c. 2.5, CHCl₃); n_max

,

20

(þ)-leucascandrolide A; [a]_D¼þ40.0 (c¼0.29, EtOH), in

92% yield with clean installation of both (Z)-alkenes. The

physical and spectroscopic data for this synthetic material³¹

were identical in every respect to that reported by Pietra³

and Leighton.^6a

4. Conclusions

In summary, we have developed an efﬁcient total synthesis

of (þ)-leucascandrolide A that proceeds in 23 steps and 6%

overall yield from diene 7 and is characterised by essentially

complete stereochemical control. Key features include a

Jacobsen asymmetric hetero Diels–Alder reaction to

conﬁgure the right-hand tetrahydropyran ring, the develop-

ment of novel oxidative cyclisation methodology for the

construction of lactone motifs, along with efﬁcient anomeric

alkylation protocols for their subsequent elaboration, as well

as further illustrations of the utility of our 1,5-anti aldol

methodology and the Mitsunobu reaction for complex

polyketide synthesis. Finally, we believe that this synthetic

route to (þ)-leucascandrolide A could be developed to

provide useful quantities of this rare marine natural product,

as well as a range of structural analogues.

5.1.3. Alcohol 11. To a stirred solution of pyranone 10

(4.50 g, 11.0 mmol), in MeOH (90 mL), at room tempera-

ture, was added sodium borohydride (540 mg, 14.2 mmol).

After stirring for 1 h, the reaction mixture was decanted into

sat. aqueous NH₄Cl (100 mL), brine (100 mL) and Et₂O

(100 mL). The organic phase was separated and the aqueous

phase extracted with Et₂O. The combined organic extracts

were washed with brine, dried (MgSO₄), and concentrated

in vacuo. Preliminary ﬂash chromatography (20% Et₂O/

30–40 petroleum ether) afforded alcohol 11 (4.50 g, 99%;

13:1 dr). Further ﬂash chromatography (10% Et₂O/30–40

petroleum ether) afforded pure equatorial alcohol 11

(4.18 g, 93%) as a colourless oil; R_f¼0.36 (50% EtOAc/

40–60 petroleum ether); [a]²_D⁰¼221.0 (c. 1.3, CHCl₃);

1

n

_max, cm²¹(ﬁlm) 3412, 2932, 2845, 1605, 1245; H NMR

(500 MHz, CDCl₃) d 7.24 (2H, d, J¼8.4 Hz), 6.87 (2H, d,

J¼8.4 Hz), 4.45 (2H, br s), 3.84–3.82 (4H, m), 3.68 (1H,

dd, J¼10.3, 5.4 Hz), 3.61–3.50 (4H, m), 3.40–3.36 (1H,

m), 2.04–2.01 (1H, m), 1.94–1.91 (1H, m), 1.85–1.80 (1H,

m), 1.77–1.72 (1H, m), 1.45 (1H, d, J¼4.4 Hz), 1.19–1.09

(2H, m), 0.89 (9H, s), 0.05 (6H, s); ¹³C NMR (100.6 MHz,

CDCl₃) d 159.2, 130.7, 129.2, 113.8, 76.2, 72.7, 72.6, 68.2,

66.4, 66.3, 55.3, 41.4, 37.8, 36.2, 25.9, 18.3, 25.2, 25.3;

m/z (CIþ) 411 ([MþH]^þ, 20%), 428 ([MþNH₄]^þ, 90%);

HRMS (ESþ) Found 428.2829, [C₂₂H₄₂NO₅Si]^þrequires

428.2832.

5. Experimental

5.1. Data for compounds

5.1.1. Diene 7. To a cold (08C), stirred solution of (E)-6-(4-

methoxybenzyloxy)-hex-3-en-2-one¹²(4.40 g, 18.8 mmol),

in dry Et₂O (88 mL), was added triethylsilyl triﬂuoro-

methylsulfonate (5.10 mL, 22.5 mmol) followed by Et₃N

(3.40 mL, 24.4 mmol). After stirring for 1.5 h, the reaction

mixture was ﬁltered through a plug of dry alumina (eluting

with Et₂O) and the ﬁltrate concentrated in vacuo to give

diene 7 (6.18 g, 95%), which was used without further

puriﬁcation; R_f0.75 (20% EtOAc/40–60 petroleum ether);

¹H NMR (250 MHz, CDCl₃) d 7.25 (2H, d, J¼8.6 Hz),

6.87 (2H, d, J¼8.6 Hz), 6.04 (1H, dt, J¼15.3, 6.4 Hz), 5.94

(1H, br d, J¼15.3 Hz), 4.45 (2H, s), 4.26 (1H, br s), 4.20

(1H, br s), 3.80 (3H, s), 3.51 (2H, t, J¼6.9 Hz), 2.41 (2H, br

q, J¼6.8 Hz), 1.00 (9H, t, J¼8.2 Hz), 0.73 (6H, t,

J¼8.2 Hz).

5.1.4. Alcohol 12. To a cold (21008C), stirred solution of

pyranone 10 (4.0 g, 9.8 mmol), in THF (100 mL), was

added ^L-Selectride^w(14.7 mL, 14.7 mmol, 1 M in THF).

After 2 h, the reaction mixture was treated with sat. aqueous

NH₄Cl (100 mL) and warmed to room temperature. The

organic phase was separated and the aqueous phase

extracted with Et₂O. The combined organic extracts were

washed with brine, dried (Na₂SO₄) and concentrated in

5.1.2. Pyranone 10. To a cold (08C), stirred mixture of

aldehyde 8 (656 mL, 3.44 mmol), tridentate chromium

catalyst 9 (50 mg, 0.10 mmol), as prepared by the method

†

Chloroform (300 mL) and conc. HCl (300 mL) were stirred vigorously

for 1 h after which the phases were separated to give the acidiﬁed

chloroform layer.

There was no detectable trans-isomer from analysis of the crude reaction

of Jacobsen from (1S,2R)-cis-1-amino-2-indanol,¹¹and 4 A

˚

‡

molecular sieves (330 mg), was added diene 7 (600 mg,

450 mL, 10.2 mmol). After warming to room temperature,

product. The enantiomeric purity of 10 was determined as (95% ee by

Mosher ester analysis of the derived equatorial alcohol 11.

6840

I. Paterson, M. Tudge / Tetrahedron 59 (2003) 6833–6849

vacuo. Flash chromatography (15% Et₂O/30–40 petroleum

ether) afforded axial alcohol 12 (3.5 g, 88%) as a colourless

oil; R_f¼0.36 (50% EtOAc/40–60 petroleum ether);

[a]²_D⁰¼219.1 (c. 6.6, CHCl₃); n_max, cm²¹(ﬁlm) 3433,

2943, 2856, 1612, 1246; ¹H NMR (500 MHz, CDCl₃) d 7.24

(2H, d, J¼8.6 Hz), 6.87 (2H, d, J¼8.6 Hz), 4.42 (2H, br s),

4.27–4.25 (1H, m), 3.95–3.89 (1H, m), 3.83–3.80 (4H, m),

3.64 (1H, dd, J¼10.5, 5.4 Hz), 3.58–3.55 (2H, m), 3.50

(1H, dd, J¼10.5, 5.4 Hz), 1.80–1.73 (1H, m), 1.72–1.58

(3H, m), 1.50–1.42 (2H, m), 1.35 (1H, d, J¼2.8 Hz),

0.89 (9H, s), 0.05 (6H, s); ¹³C NMR (100.6 MHz, CDCl₃)

d 159.2, 129.6, 129.5, 114.1, 73.0, 72.7, 69.0, 67.1, 67.0,

64.9, 55.6, 39.2, 36.7, 35.5, 26.3, 18.8, 24.8, 24.8; m/z

(CIþ) 411 ([MþH]^þ, 10%), 428 ([MþNH₄]^þ, 90%);

HRMS (ESþ) Found 411.2567, [C₂₂H₃₉O₅Si]^þrequires

411.2567.

5.1.7. Alkyne 14. To a cold (2108C), stirred solution of

alcohol 13 (100 mg, 0.22 mmol) in CH₂Cl₂(2 mL) was

added pyridine (30 mL, 0.33 mmol) followed by triﬂuoro-

methanesulfonic anhydride (52 mL, 0.31 mmol). After 1 h,

the reaction mixture was ﬁltered through a plug of silica gel

(eluting with 50% Et₂O/30–40 petroleum ether), the ﬁltrate

concentrated in vacuo and the residue azeotroped with

benzene (3£2 mL) to afford the corresponding triﬂate which

was taken on to the next step. To a cold (2788C), stirred

solution of diisopropylamine (107 mL, 0.77 mmol) in THF

(3 mL) and HMPA (133 mL, 0.77 mmol) was added n-butyl

lithium (481 mL, 0.77 mmol, 1.6 M in hexanes). The

mixture was warmed to 2108C and stirred for 30 min then

recooled to 2788C and treated with trimethylsilylacetylene

(109 mL, 0.77 mmol). After 15 min, a solution of the

prepared triﬂate in THF (1.5 mL) was added to the stirred

mixture. After 1 h, the reaction mixture was warmed to

room temperature, stirred for a further 15 min and treated

with sat. aqueous NH₄Cl (3 mL). The organic phase was

separated and the aqueous phase extracted with Et₂O

(4£5 mL). The combined organic extracts were washed

with brine (10 mL), dried (MgSO₄) and concentrated in

vacuo to give the intermediate alkyne which was taken on to

the next step. To a solution of the alkyne in MeOH (5 mL)

was added K₂CO₃(41 mg, 0.30 mmol). After stirring for

12 h, the reaction mixture was treated with brine (5 mL) and

Et₂O (10 mL). The organic phase was separated and the

aqueous phase extracted with Et₂O. The combined organic

extracts were washed with brine, dried (MgSO₄) and

concentrated in vacuo. Flash chromatography (5% Et₂O/

30–40 petroleum ether) afforded alkyne 14 (85 mg, 84%) as

a colourless oil; R_f¼0.40 (10% EtOAc/40–60 petroleum

ether); [a]_D²⁰¼214.8 (c. 2.1, CHCl₃); n_max, cm²¹(ﬁlm)

3302, 2942, 2855, 1610, 1245; ¹H NMR (500 MHz, CDCl₃)

d 7.25 (2H, d, J¼8.5 Hz), 6.87 (2H, d, J¼8.5 Hz), 4.44 (1H,

d, J¼11.6 Hz), 4.41 (1H, d, J¼11.6 Hz), 3.87–3.83 (1H,

m), 3.80 (3H, s), 3.60–3.58 (1H, m), 3.54–3.51 (2H, m),

3.42–3.39 (1H, m), 2.44 (1H, ddd, J¼16.6, 5.6, 2.6 Hz),

2.31 (1H, ddd, J¼16.6, 7.7, 2.5 Hz) 2.01–2.08 (1H, m), 1.99

(1H, t, J¼2.5 Hz), 1.88–1.85 (1H, m), 1.80–1.73 (2H, m),

1.27–1.20 (2H, m), 1.05 (21H, m); ¹³C NMR (100.6 MHz,

CDCl₃) d 161.1, 132.7, 131.3, 115.7, 82.8, 75.8, 74.7, 74.6,

71.9, 70.4, 68.2, 57.3, 43.8, 42.9, 38.1, 27.7, 20.1, 14.3; m/z

(CIþ) 478.5 ([MþNH₄]^þ, 90%); HRMS (ESþ) Found

478.3360, [C₂₇H₄₈NO₄Si]^þrequires 478.3353.

5.1.5. Alcohol 13. To a cold (2788C), stirred solution of

alcohol 11 (4.07 g, 9.92 mmol), in CH₂Cl₂(80 mL), was

added 2,6-lutidine (2.85 mL, 24.5 mmol) followed by

triisopropylsilyl

triﬂuoromethylsulfonate

(4.00 mL,

14.7 mmol). After 3 h, the reaction mixture was treated

with sat. aqueous NaHCO₃(100 mL), warmed to room

temperature, and the organic phase separated. The aqueous

phase was extracted with Et₂O, the combined organic

extracts dried (MgSO₄), and the solvent removed in vacuo.

Flash chromatography (10% Et₂O/30–40 petroleum ether)

afforded the intermediate bis-silyl ether (5.16 g, 93%) as a

colourless oil; R_f¼0.61 (20% EtOAc/40–60 petroleum

ether), which was taken on to the next step. To a stirred

solution of the bis-silyl ether (5.1 g, 9.01 mmol) in CH₂Cl₂

(33 mL) and MeOH (66 mL) was added 10-camphor-

sulfonic acid (209 mg, 0.90 mmol). After 3 h, the reaction

mixture was treated with Et₃N (139 mL, 1.00 mmol) and

concentrated in vacuo. Flash chromatography (40% Et₂O/

30–40 petroleum ether) afforded alcohol 13 (3.57 g, 88%)

as a colourless oil; R_f¼0.16 (20% EtOAc/40–60 petroleum

ether); [a]_D²⁰¼27.7 (c. 1.32, CHCl₃); n_max, cm²¹(ﬁlm)

3455, 2942, 2856, 1611, 1245; ¹H NMR (400 MHz, CDCl₃)

d 7.24 (2H, d, J¼8.4 Hz), 6.87 (2H, d, J¼8.4 Hz), 4.44 (1H,

d, J¼11.6 Hz), 4.42 (1H, d, J¼11.6 Hz), 3.93–3.85 (1H,

m), 3.80 (3H, s), 3.61–3.49 (5H, m), 3.35–3.33 (1H, m),

1.95–1.71 (5H, m), 1.31–1.20 (2H, m), 1.04 (21H, m); m/z

(CIþ) 453 ([MþH]^þ, 30%), 470 ([MþNH₄]^þ, 90%);

HRMS (ESþ) Found 453.3046, [C₂₅H₄₅O₅Si]^þrequires

453.3036.

5.1.8. Alkyne 35. Prepared in 79% yield from alcohol 34 via

the procedure described for 14. R_f¼0.40 (10% EtOAc/40–

5.1.6. Alcohol 34. Prepared from alcohol 12 in 93% yield

via the procedure described for 13. R_f¼0.17 (20% EtOAc/

60 petroleum ether); [a]²_D⁰¼28.3 (c. 4.8, CHCl₃); n_max

,

40–60 petroleum ether); [a]²_D⁰¼24.3 (c. 1.32, CHCl₃);

cm²¹(ﬁlm) 3302, 2943, 2856, 1610, 1245; ¹H NMR

(500 MHz, CDCl₃) d 7.25 (2H, d, J¼8.6 Hz), 6.86 (2H, d,

J¼8.6 Hz), 4.45 (1H, d, J¼11.4 Hz), 4.43 (1H, d,

J¼11.4 Hz), 4.35–4.28 (1H, m), 4.05–3.98 (1H, m),

3.99–3.89 (1H, m), 3.80 (3H, s), 3.61–3.54 (2H, m),

2.42 (1H, dq, J¼16.5, 5.4, 2.7 Hz), 2.31 (1H, ddd, J¼16.5,

7.5, 2.5 Hz), 1.97 (1H, t, J¼2.5 Hz), 1.84 (1H, br d,

J¼12.9 Hz), 1.81–1.73 (1H, m), 1.72–1.63 (2H, m), 1.46–

1.34 (2H, m), 1.05 (21H, m); ¹³C NMR (100.6 MHz,

CDCl₃) d 157.4, 129.2, 127.5, 112.0, 79.3, 70.9, 68.5, 68.1,

67.6, 65.0, 63.4, 53.6, 37.8, 36.9, 34.6, 24.2, 16.5, 10.6; m/z

(CIþ) 461 ([MþH]^þ, 95%), 478.5 ([MþNH₄]^þ, 40%);

HRMS (ESþ) Found 461.3082, [C₂₇H₄₅O₄Si]^þrequires

461.3087.

1

n

_max, cm²¹(ﬁlm) 3455, 2943, 2866, 1610, 1245; H NMR

(500 MHz, CDCl₃) d 7.25 (2H, d, J¼8.6 Hz), 6.86 (2H, d,

J¼8.6 Hz), 4.45 (1H, d, J¼11.5 Hz), 4.40 (1H, d,

J¼11.5 Hz), 4.32–4.29 (1H, m), 4.02–4.00 (1H, m),

3.97–3.94 (1H, m), 3.80 (3H, s), 3.59–3.55 (3H, m),

3.46–3.44 (1H, m), 2.00 (1H, dd, J¼7.9, 4.4 Hz), 1.81–1.77

(1H, m), 1.72–1.67 (2H, m), 1.51 (1H, td, J¼13.3, 2.41 Hz),

1.47–1.37 (2H, m), 1.05 (21H, m); ¹³C NMR (62.9 MHz,

CDCl₃) d 159.1, 130.7, 129.1, 113.7, 72.6, 72.1, 69.1, 66.7,

66.3, 64.9, 55.2, 39.7, 36.3, 35.2, 18.1, 12.2; m/z (EIþ) 452

([M]^þ, 100%), (CIþ) 453 ([MþH]^þ, 100%), 470

([MþNH₄]^þ, 60%); HRMS (ESþ) Found 453.3032,

[C₂₅H₄₅O₅Si]^þrequires 453.3036.

I. Paterson, M. Tudge / Tetrahedron 59 (2003) 6833–6849

6841

5.1.9. Ketone 15. To a stirred solution of alkyne 14 (1.38 g,

3.00 mmol) in THF (65 mL) was added sequentially

pyridinium p-toluenesulfonate (414 mg, 4.50 mmol), H₂O

(108 mL, 6.00 mmol) and mercury-(II)-acetate (300 mg,

0.90 mmol). After 1.5 h at 458C, the reaction mixture was

treated with sat. aqueous NaHCO₃(50 mL). The organic

phase was separated and the aqueous phase extracted with

Et₂O. The combined organic extracts were washed with

brine, dried (MgSO₄) and concentrated in vacuo. Flash

chromatography afforded ketone 15 (1.27 g, 86%) as a

colourless oil; R_f¼0.23 (20% EtOAc/40–60 petroleum

ether); [a]_D²⁰¼29.4 (c. 1.7, CHCl₃); n_max, cm²¹(ﬁlm) 2943,

2855, 1714, 1610, 1245; ¹H NMR (500 MHz, CDCl₃) d 7.24

(2H, d, J¼8.6 Hz), 6.87 (2H, d, J¼8.6 Hz), 4.40 (2H, br s),

3.89–3.84 (1H, m), 3.80 (3H, s), 3.76–3.68 (1H, m), 3.54–

3.45 (2H, m), 2.66 (1H, dd, J¼15.4, 8.2 Hz), 2.40 (1H, dd,

J¼15.4, 4.5 Hz), 2.15 (3H, s), 1.91–1.85 (1H, m), 1.75–

1.71 (2H, m), 1.24–1.17 (2H, m), 1.04 (21H, m); ¹³C NMR

(100.6 MHz, CDCl₃) d 208.3, 160.1, 131.7, 130.3, 114.8,

73.8, 73.6, 73.1, 69.4, 67.4, 56.3, 50.8, 42.8, 42.7, 37.2,

31.9, 19.1, 13.3; m/z (CIþ) 496 ([MþNH₄]^þ, 3%); HRMS

(ESþ) Found 479.3193, [C₂₇H₄₇O₅Si]^þrequires 479.3193.

J¼7.1 Hz), 4.90 (1H, m), 4.60 (1H, m), 3.58 (2H, td, J¼6.5,

0.9 Hz), 2.95 (3H, s), 2.73–2.70 (1H, m), 1.45–1.40 (1H,

m), 1.46–1.39 (2H, m), 1.37–1.29 (1H, m), 1.00 (3H, d,

J¼6.8 Hz), 0.95 (3H, d, J¼6.7 Hz), 0.90 (9H, s), 0.05 (6H,

s); ¹³C NMR (125 MHz, DMSO-d6, 1208C) d 175.5, 142.9,

127.2, 126.4, 126.1, 73.9, 64.1, 62.3, 39.1, 34.3, 29.6, 29.5,

25.2, 17.3, 16.8, 14.3, 25.9, 25.9; m/z (ESþ) 394

([MþH]^þ, 8%), 416 ([MþNa]^þ, 100%); HRMS (ESþ)

Found 416.2616, [C₂₂H₃₉NO₃SiNa]^þrequires 416.2597.

5.1.12. Alcohol 19. To a cold (2788C), stirred solution of

diisopropylamine (14.0 mL, 100 mmol) in THF (90 mL)

was added n-butyl lithium (99.3 mL, 97.1 mmol, 2 M in

hexanes). After warming to 08C for 15 min, the mixture was

treated with BH₃·NH₃(2.94 g, 95.6 mmol) and stirred for an

additional 15 min. The reaction mixture was then warmed to

room temperature, stirred for 15 min, re-cooled to 08C, and

treated with a solution of amide 18 (9.40 g, 23.9 mmol).

Stirring was continued for 2 h then the reaction mixture was

cannulated into a pre-cooled (08C) mixture of sat. aqueous

NH₄Cl (100 mL), MeOH (50 mL) and Et₂O (50 mL). After

15 min, the organic phase was separated and the aqueous

phase extracted with Et₂O. The combined organic extracts

were washed with brine. dried (Na₂SO₄) and concentrated in

vacuo. Flash chromatography (20% Et₂O/30–40 petroleum

ether) afforded alcohol 19 (5.53 g, 99%) as a colourless oil;

R_f¼0.65 (50% EtOAc/40–60 petroleum ether);

[a]²_D⁰¼210.3 (c. 1.15, CHCl₃); n_max, cm²¹(ﬁlm) 3378,

5.1.10. Ketone 36. Prepared in 86% yield from 35 via the

procedure described for 15. R_f¼0.23 (20% EtOAc/40–60

petroleum ether); [a]²_D⁰¼213.2 (c. 6.2, CHCl₃); n_max, cm²¹

1

(ﬁlm) 2943, 2855, 1714, 1610, 1245; H NMR (500 MHz,

CDCl₃) d 7.25 (2H, d, J¼8.6 Hz), 6.85 (2H, d, J¼8.6 Hz),

4.42 (2H, d, J¼11.5 Hz), 4.39 (2H, d, J¼11.5 Hz), 3.89–

3.84 (1H, m), 3.80 (3H, s), 3.76–3.68 (1H, m), 4.27–4.22

(2H, m), 4.00–3.94 (1H, m), 3.52 (2H, br t, J¼6.1 Hz), 2.56

(1H, dd, J¼14.9, 8.3 Hz), 2.36 (1H, dd, J¼14.9, 4.9 Hz),

2.14 (3H, s), 1.73–1.63 (4H, m), 1.42–1.36 (2H, m), 1.04

(21H, m); ¹³C NMR (100.6 MHz, CDCl₃) d 207.6, 159.1,

130.8, 129.2, 113.7, 72.6, 69.2, 68.7, 66.7, 65.1, 55.3, 50.3,

39.4, 36.4, 30.6, 18.1, 17.7, 12.2; m/z (CIþ) 479 ([MþH]^þ,

80%), 496 ([MþNH₄]^þ, 90%); HRMS (ESþ) Found

479.3187, [C₂₇H₄₇O₅Si]^þrequires 479.3193.

1

2932, 2844, 1616; 3357, 2932, 2856; H NMR (400 MHz,

CDCl₃) d 3.58 (2H, br t, J¼6.5 Hz), 3.47 (1H, dd, J¼10.5,

5.9 Hz), 3.40 (1H, dd, J¼10.5, 6.4 Hz), 1.71 (1H, br s),

1.65–1.34 (4H, m), 1.18–1.10 (1H, m), 0.90 (3H, d,

J¼6.7 Hz,), 0.86 (9H, s), 0.03 (6H, s); ¹³C NMR

(100.6 MHz, CDCl₃) d 70.2, 65.6, 37.6, 32.9, 32.2, 31.3,

28.0, 20.4, 18.7, 23.3; m/z (ESþ) 255 ([MþNa]^þ, 25%);

HRMS (ESþ) Found 255.1757, [C₁₂H₂₈O₂SiNa]^þrequires

255.1756.

5.1.13. Aldehyde 5. To a stirred solution of alcohol 19

(2.20 g, 9.48 mmol) in CH₂Cl₂(35 mL) was added Dess–

Martin periodinane (5.20 g, 12.3 mmol). After 1.5 h, the

reaction mixture was treated with sat. aqueous NaHCO₃

(50 mL) and sat. aqueous Na₂S₂O₃(50 mL). After 15 min,

the organic phase was separated and the aqueous phase

extracted with Et₂O. The combined organic extracts were

dried (MgSO₄) and concentrated in vacuo. Flash chroma-

tography (15% Et₂O/40–60 petroleum ether) gave the

aldehyde 5 (1.85 g, 85%), as a colourless oil, which was

used directly in the next step to avoid any racemisation;

R_f¼0.3 (10% Et₂O/30–40 petroleum ether); ¹H NMR

(400 MHz, CDCl₃) d 9.61 (1H, d, J¼1.9 Hz), 3.61 (1H, br

t, J¼6.2 Hz), 2.39–2.31 (1H, m), 1.80–1.70 (1H, m), 1.61–

1.50 (2H, m), 1.47–1.36 (1H, m), 1.10 (3H, d, J¼7.0 Hz),

0.88 (9H, s), 0.03 (6H, s).

5.1.11. Amide 18. To a cold (2788C), stirred suspension of

vacuum dried LiCl (7.20 g, 169 mmol) in THF (28 mL) was

added diisopropylamine (8.90 mL, 63.5 mmol) followed by

n-butyl lithium (29.6 mL, 59.3 mmol, 2 M in hexanes).

After warming to 08C and stirring for 10 min, the reaction

mixture was cooled to 2788C, then treated with a solution

of (R,R)-N-(2-hydroxy-1-methyl-2-phenethyl)-N-methyl-

propionamide (16)¹⁵(6.24 g, 28.2 mmol) in THF (70 mL)

and stirred for a further 1 h. The reaction mixture was then

warmed to 08C for 15 min, and then to room temperature for

5 min. The mixture was cooled to 08C, then treated with a

solution of iodide 17 (16.9 g, 56.5 mmol) in THF (30 mL).

After 1.5 h, the reaction mixture was cannulated into a pre-

cooled (08C) mixture of sat. aqueous NH₄Cl (100 mL),

MeOH (50 mL) and Et₂O (50 mL). The organic phase was

separated and the aqueous phase extracted with Et₂O. The

combined organic extracts were washed with brine, dried

(Na₂SO₄) and concentrated in vacuo. Flash chromatography

(50% EtOAc/40–60 petroleum ether) afforded the amide 18

(9.56 g, 86%; $40:1 dr) as a colourless oil; R_f¼0.55 (50%

EtOAc/40–60 petroleum ether); [a]²_D⁰¼2101.8 (c. 0.55,

5.1.14. Aldol adduct 21. To a cold (08C), stirred solution of

ketone 15 (200 mg, 0.42 mmol) in Et₂O (5 mL), was added

sequentially Et₃N (94 mL, 0.67 mmol) and c-Hex₂BCl

(158 mL, 0.57 mmol). After 30 min, the reaction mixture

was cooled to 2788C and treated with a solution of freshly

prepared aldehyde 5 (141 mg, 0.61 mmol) in Et₂O (2 mL).

After 2 h, the mixture was warmed to 2308C, and

maintained at this temperature for 18 h. Following warming

1

CHCl₃); n_max, cm²¹(ﬁlm) 3378, 2932, 2844, 1616; H

NMR (500 MHz, DMSO-d6, 1208C) d 7.37 (2H, br d,

J¼7.1 Hz), 7.31 (2H, br t, J¼7.4 Hz), 7.24 (1H, br t,

6842

I. Paterson, M. Tudge / Tetrahedron 59 (2003) 6833–6849

to 08C, the reaction mixture was treated sequentially with

pH 7 buffer (1.5 mL), MeOH (1.5 mL), and hydrogen

peroxide (550 mL). After 1 h, brine (3 mL) was added, the

organic phase separated, and the aqueous phase extracted

with Et₂O. The combined organic extracts were washed

with brine, dried (Na₂SO₄), and concentrated in vacuo.

Flash chromatography (20% Et₂O/30–40 petroleum ether)

afforded aldol adduct 21 (300 mg, 99%; 17:1 dr) as a

colourless oil; R_f¼0.34 (20% EtOAc/40–60 petroleum

ether); [a]_D²⁰¼þ0.3 (c. 0.7, CHCl₃); n_max, cm²¹(ﬁlm) 3445,

2928, 2856, 1725, 1613; ¹H NMR (400 MHz, CDCl₃) d 7.24

(2H, d, J¼8.4 Hz), 6.86 (2H, d, J¼8.4 Hz), 4.39 (2H, br s),

3.89–3.85 (2H, m), 3.79 (3H, s), 3.80–3.76 (1H, m), 3.60–

3.57 (3H, m), 3.51–3.45 (3H, m), 3.07 (1H, br s), 2.72 (1H,

dd, J¼17.9, 9.3 Hz), 2.62 (1H, br dd, J¼15.2 Hz), 2.51 (1H,

dd, J¼17.2, 9.7 Hz), 2.41 (1H, dd, J¼15.0, 4.0 Hz), 1.91–

1.86 (2H, m), 1.81–1.68 (2H, m), 1.61–1.40 (4H, m), 1.27–

1.16 (3H, m), 1.04 (21H, m), 0.86–0.84 (12H, m), 0.04 (6H,

s); ¹³C NMR (100.6 MHz, CDCl₃) d 210.7, 159.4, 130.6,

129.2, 124.1, 113.8, 72.7, 72.7, 72.0, 68.4, 68.3, 66.3, 55.2,

49.5, 47.2, 41.8, 37.9, 36.2, 30.9, 30.4, 28.4, 25.9, 18.3,

18.1, 15.1, 12.3, 25.3, 25.3; m/z (ESþ) 726 ([MþNH₄]^þ,

20%), 731 ([MþNa]^þ, 100%); HRMS (ESþ) Found

731.4714, [C₃₉H₇₂O₇Si₂Na]^þrequires 731.4714.

J¼8.6 Hz), 4.41 (2H, br s), 4.22–4.13 (2H, m), 3.87–3.82

(1H, m), 3.80 (3H, s), 3.76–3.70 (1H, m), 3.64–3.55 (4H,

m), 3.51–3.45 (3H, m), 3.15 (1H, br s), 1.88–1.78 (3H, m),

1.76–1.71 (1H, m), 1.64–1.59 (1H, m), 1.55–1.43 (7H),

1.36–1.25 (2H, m), 1.16–1.09 (1H, m), 1.05 (21H, m), 0.89

(9H, s), 0.87 (3H, d, J¼7.1 Hz), 0.05 (6H, s); ¹³C NMR

(100.6 MHz, CDCl₃) d 158.1, 129.4, 128.3, 112.7, 72.4,

71.7, 71.2, 69.5, 67.1, 65.3, 62.5, 54.2, 41.2, 41.1, 40.7,

37.9, 37.5, 34.9, 29.4, 27.4, 24.9, 17.3, 17.0, 16.7, 14.1,

11.3, 27.3, 27.3; m/z (ESþ) 711 ([MþH]^þ, 10%) 728

([MþNH₄]^þ, 20%), 733 ([MþNa]^þ, 100%); HRMS (ESþ)

Found 733.4862, [C₃₉H₇₄O₇Si₂Na]^þrequires 733.4871.

5.1.17. Diol 38. Prepared in 86% yield from 37 via the

procedure described for 22. R_f¼0.20 (20% EtOAc/40–60

petroleum ether); [a]²_D⁰¼24.8 (c. 2.3, CHCl₃); n_max, cm²¹

(ﬁlm) 3440, 2941, 1613; ¹H NMR (500 MHz, CDCl₃) d 7.25

(2H, d, J¼8.6 Hz), 6.86 (2H, d, J¼8.6 Hz), 4.43 (1H, d,

J¼11.6 Hz), 4.39 (1H, d, J¼11.6 Hz), 4.29–4.24 (2H, m),

4.24–4.16 (1H, m), 4.11 (1H, br t, J¼10.9 Hz), 4.08–4.00

(1H, m), 3.80 (3H, s), 3.75 (1H, br t, J¼7.5 Hz), 3.63–3.58

(2H, m), 3.50 (2H, br t, J¼6.2 Hz), 3.35 (1H, br s), 1.77–

1.72 (2H, m), 1.70–1.41 (13H, m), 1.04 (21H, m), 0.88–

0.86 (12H, m), 0.04 (6H, s); ¹³C NMR (100.6 MHz, CDCl₃)

d 159.5, 130.9, 129.7, 114.1, 73.9, 73.0, 72.6, 71.1, 70.2,

66.2, 65.1, 64.0, 55.6, 42.4, 40.4, 39.7, 39.1, 38.9, 36.5,

30.9, 28.8, 26.4, 18.5, 18.1, 15.5, 12.9, 24.9, 24.9; m/z

(ESþ) 711 ([MþH]^þ, 95%); HRMS (ESþ) Found

711.5048, [C₃₉H₇₅O₇Si₂]^þrequires 711.5051.

5.1.15. Aldol adduct 37. Prepared in 86% yield from 36 via

the procedure described for 21. R_f¼0.34 (20% EtOAc/40–

60 petroleum ether); [a]²_D⁰¼22.8 (c. 2.15, CHCl₃); n_max

,

cm²¹(ﬁlm) 3466, 2943, 2866, 1709, 1610, 1245; ¹H NMR

(500 MHz, CDCl₃) d 7.23 (2H, d, J¼8.6 Hz), 6.85 (2H, d,

J¼8.6 Hz), 4.40 (1H, d, J¼11.5 Hz), 4.36 (1H, d,

J¼11.5 Hz), 3.89–3.85 (2H, m), 3.79 (3H, s), 3.80–3.76

(1H, m), 4.31–4.22 (2H, m), 3.98–3.90 (1H, m), 3.86–3.89

(1H, m), 3.57 (2H, br td, J¼6.5, 1.9 Hz), 3.49 (2H, br t,

J¼6.1 Hz), 3.15 (1H, d, J¼3.2 Hz), 2.69–2.57 (2H, m),

2.50 (1H, dd, J¼17.3, 9.7 Hz), 2.36 (1H, dd, J¼14.6,

4.7 Hz), 2.51 (1H, dd, J¼17.2, 9.7 Hz), 2.41 (1H, dd,

J¼15.0, 4.0 Hz), 1.91–1.86 (2H, m), 1.74–1.36 (11H, m),

1.04 (21H, m), 0.88 (9H, s), 0.87 (3H, d, J¼6.8 Hz), 0.04

(6H, s); ¹³C NMR (100.6 MHz, CDCl₃) d 210.5, 158.5,

130.2, 128.6, 113.2, 72.1, 70.6, 68.8, 68.3, 66.1, 64.4, 62.9,

54.6, 49.3, 46.5, 38.8, 37.3, 35.7, 35.0, 29.8, 27.8, 25.4,

23.5, 17.5, 14.5, 11.7, 25.8; m/z (ESþ) 709 ([MþH]^þ,

80%), 726 ([MþNH₄]^þ, 50%); HRMS (ESþ) Found

709.4900, [C₃₉H₇₃O₇Si₂]^þrequires 709.4895.

5.1.18. Triol 23. To a stirred solution of diol 22 (197 mg,

0.27 mmol) in CH₂Cl₂(1.5 mL) and MeOH (1.5 mL) was

added 10-camphorsulfonic acid (6.0 mg, 0.027 mmol).

After 3 h, the reaction mixture was treated with Et₃N

(40 mL, 0.30 mmol) and concentrated in vacuo. Flash

chromatography (Et₂O) afforded triol 23 (139 mg, 86%)

as a colourless oil; R_f¼0.20 (20% EtOAc/40–60 petroleum

ether); [a]_D²⁰¼22.1 (c. 0.80, CHCl₃); n_max, cm²¹(ﬁlm)

3389, 2942, 2856, 1610; ¹H NMR (400 MHz, CDCl₃) d 7.24

(2H, d, J¼8.6 Hz), 6.87 (2H, d, J¼8.6 Hz), 4.42 (2H, br s),

4.22 (1H, br s), 4.19–4.13 (1H, m), 3.89–3.82 (1H, m), 3.80

(3H, s), 3.76–3.70 (1H, m), 3.66–3.60 (2H, br t, J¼5.9 Hz),

3.58–3.42 (4H, m), 3.39 (1H, br s), 1.91–1.72 (5H, m),

1.69–1.47 (7H, m), 1.36–1.18 (3H, m), 1.05 (21H, m), 0.87

(3H, d, J¼6.6 Hz); ¹³C NMR (100.6 MHz, CDCl₃) d 159.1,

130.4, 129.3, 113.7, 77.2, 73.4, 72.7, 72.5, 70.5, 68.1, 66.4,

63.1, 55.3, 42.3, 42.1, 41.7, 39.1, 38.4, 36.0, 30.2, 28.4,

18.0, 15.3, 12.3; m/z (CIþ) 597 ([MþH]^þ, 100%); HRMS

(ESþ) Found 597.4187, [C₃₃H₆₁O₇Si]^þrequires 597.4186.

5.1.16. Diol 22. To a stirred suspension of tetramethyl-

ammonium triacetoxyborohydride (3.28 g, 12.5 mmol) in

MeCN (39 mL) was added AcOH (13 mL). After 1 h, the

mixture was cooled to 2358C and treated with a solution of

ketone 21 (760 mg, 1.05 mmol) in MeCN (4 mL). After

28 h, the reaction mixture was warmed to 2158C and stirred

for an additional 2 h then decanted into a mixture of sat.

aqueous NaHCO₃(20 mL), sat. aqueous sodium potassium

tartrate (20 mL) and Et₂O (20 mL). After stirring for

30 min, the organic phase was separated and the aqueous

phase extracted with Et₂O. The combined organic extracts

were washed with brine, dried (Na₂SO₄) and concentrated in

vacuo. Flash chromatography afforded diol 22 (750 mg,

99%; $50:1 dr) as a colourless oil; R_f¼0.20 (20% EtOAc/

40–60 petroleum ether); [a]²_D⁰¼21.6 (c. 0.55, CHCl₃);

5.1.19. Triol from 38. To a stirred solution of diol 38

(1.56 g, 2.15 mmol) in CH₂Cl₂(30 mL) and MeOH

(1.3 mL) was added HCl (129 mL, 0.129 mmol, 1 M in

Et₂O). After 3 h, the reaction mixture was treated with Et₃N

(80 mL, 0.60 mmol) and concentrated in vacuo. Flash

chromatography (Et₂O) afforded the corresponding triol

(1.24 g, 94%) as a colourless oil; R_f¼0.20 (20% EtOAc/40–

60 petroleum ether); [a]²_D⁰¼25.3 (c. 1.7, CHCl₃); n_max

,

cm²¹(ﬁlm) 3411, 2942, 2856, 1610, 1245; ¹H NMR

(500 MHz, CDCl₃) d 7.24 (2H, d, J¼8.6 Hz), 6.86 (2H, d,

J¼8.6 Hz), 4.43 (2H, d, J¼11.3 Hz), 4.38 (1H, d,

J¼11.3 Hz), 4.27–4.19 (2H, m), 4.10 (1H, br t,

J¼10.9 Hz), 3.80 (3H, s), 3.75–3.68 (1H, m), 3.63 (2H, br

n

_max, cm²¹(ﬁlm) 3448, 2937, 2857, 1612; ¹H NMR

(500 MHz, CDCl₃) d 7.24 (2H, d, J¼8.6 Hz), 6.86 (2H, d,

I. Paterson, M. Tudge / Tetrahedron 59 (2003) 6833–6849

6843

t, J¼6.1 Hz), 3.51–3.47 (3H, m), 1.81 (1H, br s), 1.75

(1H, br ddd, J¼13.1, 8.6, 2.3 Hz), 1.70–1.48 (11H, m),

1.24–1.17 (1H, m), 1.05 (21H, m), 0.87 (3H, d, J¼6.7 Hz);

¹³C NMR (100.6 MHz, CDCl₃) d 157.5, 128.9, 127.7,

112.1, 72.0, 71.0, 70.8, 69.2, 68.3, 65.2, 63.2, 61.5, 53.6,

40.5, 38.4, 37.8, 37.4, 36.8, 34.6, 28.6, 26.8, 16.5, 13.7,

10.6; m/z (CIþ) 597 ([MþH]^þ, 40%); HRMS (ESþ) Found

597.4187, [C₃₃H₆₁O₇Si]^þrequires 597.4186.

by brine, dried (Na₂SO₄), and concentrated in vacuo. Flash

chromatography (20% Et₂O/30–40 petroleum ether)

afforded methyl ether 25 (429 mg, 84%) as a colourless

oil; R_f¼0.52 (50% EtOAc/40–60 petroleum ether);

[a]²_D⁰¼þ28.3 (c. 4.13, CHCl₃); n_max, cm²¹(ﬁlm) 3466,

2932, 2866, 1735, 1610, 1245; ¹H NMR (500 MHz, CDCl₃)

d 7.24 (1H, d, J¼8.7 Hz), 6.86 (1H, d, J¼8.7 Hz), 4.44 (1H,

d, J¼11.6 Hz), 4.40 (1H, d, J¼11.6 Hz), 4.25 (1H, br t,

J¼9.2 Hz), 3.86–3.79 (1H, m), 3.79 (3H, s), 3.77–3.74

(1H, m), 3.60–3.54 (2H, m), 3.45–3.31 (2H, m), 3.31 (3H,

s), 2.59 (1H, br dt, J¼17.6, 4.7 Hz), 2.41 (1H, br dt, J¼17.6,

7.1 Hz), 1.87–1.70 (7H, m), 1.65–1.51 (4H, m), 1.29–1.19

(2H, m), 1.05 (21H, m), 0.98 (3H, d, J¼6.2 Hz); ¹³C NMR

(100.6 MHz, CDCl₃) d 171.8, 159.7, 131.1, 129.4, 114.0,

82.4, 73.8, 72.8, 72.7, 72.1, 68.9, 66.9, 57.4, 55.5, 43.9,

43.2, 40.2, 39.0, 36.6, 33.2, 29.8, 28.1, 18.3, 17.8, 12.6; m/z

(ESþ) 624 ([MþNH₃]^þ, 20%), 629 ([MþNa]^þ, 100%);

HRMS (ESþ) Found 624.4287, [C₃₄H₆₂NO₇Si]^þrequires

624.4296.

5.1.20. Lactone 24. To a stirred solution of triol 23 (545 mg,

0.91 mmol) in CH₂Cl₂(16 mL) was added sequentially

TEMPO (30 mg, 0.18 mmol) and iodobenzene diacetate

(913 mg, 2.7 mmol). After 12 h, the reaction mixture was

treated with 5% aqueous Na₂S₂O₃(10 mL) and sat. aqueous

NaHCO₃(10 mL). After 15 min, the organic phase was

separated and the aqueous phase extracted with Et₂O. The

combined organic extracts were dried (Na₂SO₄) and

concentrated in vacuo. Flash chromatography (30% Et₂O/

30–40 petroleum ether) afforded lactone 24 (497 mg, 92%)

as a colourless oil; R_f¼0.39 (50% EtOAc/40–60 petroleum

ether); [a]_D²⁰¼þ24.3 (c. 1.75, CHCl₃); n_max, cm²¹(ﬁlm)

3466, 2942, 2856, 1730, 1610; ¹H NMR (400 MHz, CDCl₃)

d 7.25 (1H, d, J¼8.7 Hz), 6.85 (1H, d, J¼8.7 Hz), 4.41 (1H,

d, J¼11.5 Hz), 4.37 (1H, d, J¼11.5 Hz), 4.25 (1H, br td,

J¼10.7, 1.5 Hz), 4.22 (1H, br tt, J¼9.9, 1.9 Hz), 3.87–3.80

(1H, m), 3.78 (3H, s), 3.57 (1H, br tt, J¼9.6, 2.2 Hz), 3.52–

3.49 (1H, m), 3.49 (2H, br t, J¼6.4 Hz), 2.61 (1H, ddd,

J¼17.7, 6.9, 5.1 Hz), 2.61 (1H, ddd, J¼17.6, 8.9, 6.9 Hz),

1.94–1.84 (1H, m), 1.89–1.68 (5H, m), 1.68–1.45 (6H, m),

1.31–1.19 (2H, m), 1.05 (21H, m), 0.87 (3H, d, J¼6.6 Hz);

¹³C NMR (100.6 MHz, CDCl₃) d 170.4, 157.7, 129.1,

128.1, 112.4, 80.6, 75.6, 72.1, 71.4, 66.7, 66.0, 65.3, 53.9,

41.7, 40.9, 40.6, 40.4, 34.7, 31.5, 28.9, 26.3, 16.7, 16.0,

10.9; m/z (ESþ) 610 ([MþNH₃]^þ, 20%), 615 ([MþNa]^þ,

100%); HRMS (ESþ) Found 610.4131, [C₃₃H₆₀NO₇Si]^þ

requires 610.4139.

5.1.23. Methyl ether 40. Prepared in 83% yield from

lactone 39 via the procedure described for 25. R_f¼0.52

(50% EtOAc/40–60 petroleum ether); [a]²_D⁰¼þ25.6 (c. 8.0,

CHCl₃); n_max, cm²¹(ﬁlm) 2939, 2863, 1734, 1608, 1244;

¹H NMR (400 MHz, CDCl₃) d 7.24 (1H, d, J¼8.7 Hz), 6.86

(1H, d, J¼8.7 Hz), 4.43 (2H, br s), 4.33–4.23 (1H, br t,

J¼9.3 Hz), 4.04–3.87 (2H, m), 3.78 (3H, s), 3.74 (1H, br

dd, J¼6.1 Hz), 3.58 (2H, br t, J¼6.8 Hz), 2.57 (1H, br dt,

J¼17.8, 6.4 Hz), 2.39 (1H, br dt, J¼17.6, 9.0 Hz), 1.93–

1.33 (12H, m), 1.05 (21H, m), 0.96 (3H, d, J¼5.7 Hz); ¹³C

NMR (100.6 MHz, CDCl₃) d 172.0, 159.4, 131.4, 129.4,

114.1, 82.6, 73.8, 72.8, 69.4, 68.4, 67.4, 65.7, 65.6, 57.3,

55.6, 40.5, 40.3, 40.1, 40.0, 36.8, 33.3, 29.8, 28.1, 18.5,

12.6; m/z (CIþ) 624 ([MþNH₃]^þ, 90%), 607 ([MþH]^þ,

35%); HRMS (ESþ) Found 607.4027, [C₃₄H₅₉NO₇Si]^þ

requires 607.4030.

5.1.21. Lactone 39. Prepared in 96% yield from the triol

obtained from 38 via the procedure described for 24.

R_f¼0.39 (50% EtOAc/40–60 petroleum ether); [a]²_D⁰þ20.3

(c. 7.85, CHCl₃); n_max, cm²¹(ﬁlm) 3466, 2953, 2866, 1730,

5.1.24. Silyl enol ether 6.²³To a cold (2788C), stirred

solution of 6-methyl-hept-3-en-2-one (3.00 g, 23.8 mmol)

in THF (100 mL) was added sequentially TMSCl/Et₃N

solution^§(2.1 mL, 7.40 mmol) and lithium hexamethyl-

disilazide (4.9 mL, 4.9 mmol, 1 M in THF). After 10 min,

the reaction mixture was treated with sat. aqueous NaHCO₃

(100 mL), the organic phase separated and the aqueous

phase extracted with 30–40 petroleum ether. The combined

organic extracts were dried (MgSO₄) and concentrated in

vacuo. Puriﬁcation by distillation in vacuo (50–528C,

0.5 mmHg) afforded silyl enol ether 6 as a colourless oil

(3.9 g, 96%); ¹H NMR (250 MHz, CDCl₃) d 5.99–5.82 (2H,

m), 4.23 (2H, br s), 1.98 (2H, t, J¼6.4 Hz), 1.72–1.61 (1H,

m), 0.89 (6H, d, J¼6.6 Hz), 0.19 (9H, s).

1

1610, 1245; H NMR (500 MHz, CDCl₃) d 7.23 (1H, d,

J¼8.6 Hz), 6.85 (1H, d, J¼8.6 Hz), 4.40 (2H, br s), 4.28–

4.21 (3H, m), 4.13 (1H, br t, J¼11.0 Hz), 4.05–3.97 (1H,

m), 3.78 (3H, s), 3.50 (2H, br t, J¼6.3 Hz), 2.59 (1H, ddd,

J¼17.7, 6.8, 5.1 Hz), 2.46 (1H, ddd, J¼17.7, 9.1, 7.2 Hz),

1.88–1.85 (1H, m), 1.83–1.71 (2H, m), 1.68–1.61 (3H, m),

1.58–1.49 (4H, m), 1.46–1.34 (3H, m), 1.03 (21H, m), 0.99

(3H, d, J¼6.5 Hz); ¹³C NMR (62.5 MHz, CDCl3) d 171.9,

159.1, 130.6, 129.3, 113.7, 82.0, 73.5, 72.7, 70.0, 67.5, 67.1,

64.8, 55.3, 43.1, 42.0, 40.0, 39.4, 36.3, 32.9, 29.4, 27.7,

18.1, 17.5, 12.2; m/z (ESþ) 593 ([MþH]^þ, 60%), 610

([MþNH₃]^þ, 20%), 615 ([MþNa]^þ, 100%); HRMS (ESþ)

Found 593.3877, [C₃₃H₆₁O₇Si]^þrequires 593.3873.

5.1.25. Enone 27. To a cold (2788C), stirred solution of

methyl ether 25 (100 mg, 0.16 mmol) in CH₂Cl₂(1.5 mL)

was added DIBAL (192 mL, 0.19 mmol, 1 M in CH₂Cl₂).

After 2 h, the reaction mixture was treated sequentially with

a solution of pyridine (242 mL, 1.80 mmol) and DMAP

(120 mg, 0.96 mmol) in CH₂Cl₂(1 mL) followed by Ac₂O

(138 mL, 1.48 mmol). The reaction mixture was gradually

warmed to 2358C over 12 h then ﬁltered through a plug of

5.1.22. Methyl ether 25. To a cold (08C), stirred solution of

lactone 24 (497 mg, 0.84 mmol) and Proton-Sponge^w

(1.79 g, 8.40 mmol) in CH₂Cl₂(10 mL) was added

trimethyloxonium tretaﬂuoroborate (1.24 g, 8.40 mmol).

After 2 h, the reaction mixture was treated with sat. aqueous

NaHCO₃(20 mL), the organic phase was separated and the

aqueous phase extracted with Et₂O. The combined organic

extracts were washed with 10% aqueous citric acid followed

§

Equal volumes of Et₃N and TMSCl were combined and the mixture

centrifuged. The resulting supernatant liquid was taken to be ca. 3.5 M.

6844

I. Paterson, M. Tudge / Tetrahedron 59 (2003) 6833–6849

dry alumina (eluting with 40% Et₂O/30–40 petroleum

ether) and concentrated in vacuo to give the intermediate

acetate 26. After azeotroping with toluene (3 x 2 mL), the

acetate 26 was dried under high vacuum for 3 h prior to

being used in the next step. To a cold (08C), stirred solution

of acetate 26 and silyl enol ether 6 (78 mL, 0.46 mmol) in

CH₂Cl₂was added dry ZnBr₂(8.0 mg, 0.04 mmol). After

0.5 h, the reaction mixture was warmed to 58C and treated

with an additional quantity of 6 (78 mL, 0.46 mmol)

followed by ZnBr₂(8.0 mg, 0.04 mmol). After 3 h, the

mixture was ﬁltered and the ﬁltrate concentrated in vacuo.

Flash chromatography (gradient elution 10–20% Et₂O/30–

40 petroleum ether) afforded enone 27 (96 mg, 81%) as a

colourless oil; R_f¼0.41 (20% EtOAc/40–60 petroleum

ether); [a]_D²⁰¼þ8.6 (c. 2.9, CHCl₃); n_max, cm²¹(ﬁlm) 2943,

2857, 1698, 1616, 1240; ¹H NMR (500 MHz, CDCl₃) d 7.25

(2H, d, J¼8.5 Hz), 6.86 (2H, d, J¼8.5 Hz), 6.81 (1H, br tt,

J¼15.5, 7.5 Hz), 6.10 (1H, br d, 15.8 Hz), 4.44 (1H, d,

J¼11.4 Hz), 4.39 (1H, d, J¼11.4 Hz), 4.35–4.26 (1H, m),

3.91–3.81 (1H, m), 3.79 (3H, s), 3.61–3.53 (3H, m), 3.52–

3.47 (1H, m), 3.46–3.40 (1H, m), 3.39–3.34 (1H, m), 3.29

(3H, s), 2.87 (1H, dd, J¼15.4, 6.3 Hz), 2.74 (1H, dd,

J¼15.4, 7.0 Hz), 2.09 (2H, br t, J¼7.0 Hz), 1.90–1.84 (2H,

m), 1.83–1.72 (4H, m), 1.72–1.62 (4H), 1.55–1.47 (2H,

m), 1.40–1.33 (2H, m), 1.27–1.18 (2H, m), 1.05 (21H, m),

0.94–0.91 (9H, m); ¹³C NMR (100.6 MHz, CDCl₃) d 198.3,

159.1, 146.5, 131.7, 130.8, 129.2, 113.8, 74.4, 73.1, 72.7,

72.4, 72.2, 68.8, 67.7, 66.8, 56.8, 55.2, 43.3, 42.6, 42.0,

41.7, 40.2, 38.3, 36.3, 33.9, 27.9, 27.7, 26.6, 22.4, 22.4,

18.3, 18.1, 12.3; m/z (ESþ) 734 ([MþNH₄]^þ, 5%), 739

([MþNa]^þ, 100%); HRMS (ESþ) Found 734.5386,

[C₄₂H₇₆NO₇Si]^þrequires 734.5391.

R_f¼0.25 (20% EtOAc/40–60 petroleum ether); [a]²_D⁰¼

þ12.2 (c. 3.6, CHCl₃); n_max, cm²¹(ﬁlm) 3444, 2942, 2856,

1

1610, 1245; H NMR (500 MHz, CDCl₃) d 7.24 (2H, d,

J¼8.5 Hz), 6.86 (2H, d, J¼8.5 Hz), 5.63 (1H, br dt, J¼15.0,

7.1 Hz), 5.44 (1H, dd, J¼15.2, 6.5 Hz), 4.44 (1H, d, J¼

11.4 Hz), 4.38 (1H, d, J¼11.4 Hz), 4.26–4.23 (1H, m),

3.95–3.87 (1H, m), 3.86–3.82 (1H, m), 3.79 (3H, s), 3.64–

3.59 (1H, m), 3.58–3.53 (4H m), 3.49–3.38 (2H, m), 3.33,

(3H, s), 1.93–1.85 (6H, m), 1.79–1.65 (4H, m), 1.62–1.51

(5H, m), 1.44–1.34 (3H, m), 1.31–1.17 (2H, m), 1.04 (21H,

m), 0.99 (3H, d, J¼6.5 Hz), 0.87 (3H, br d, J¼6.3 Hz), 0.86

(3H, br d, J¼5.3 Hz); ¹³C NMR (100.6 MHz, CDCl₃) d

158.3, 133.1, 129.9, 128.9, 128.5, 113.0, 76.5, 73.5, 72.3,

71.9, 71.7, 71.6, 71.4, 70.3, 67.9, 65.9, 55.7, 54.5, 41.7,

41.2, 40.8, 40.1, 38.8, 36.7, 35.6, 32.5, 27.5, 25.2, 21.6,

21.5, 17.7, 17.3, 11.6; m/z (ESþ) 736 ([MþNH₄]^þ, 20%),

741 ([MþNa]^þ, 90%); HRMS (ESþ) Found 736.5546,

[C₄₂H₇₆NO₇Si]^þrequires 736.5548.

5.1.28. Alcohol from 41. Prepared in 89% yield from enone

41 via the procedure described for 28. R_f¼0.23 (20%

EtOAc/40–60 petroleum ether); [a]²_D⁰¼þ9.1 (c. 3.8,

CHCl₃); n_max, cm²¹(ﬁlm) 3477, 2940, 2865, 1610, 1247;

¹H NMR (500 MHz, CDCl₃) d 7.23 (2H, d, J¼8.5 Hz), 6.85

(2H, d, J¼8.5 Hz), 5.63 (1H, br dt, J¼15.3, 7.1 Hz), 5.44

(1H, dd, J¼15.3, 6.4 Hz), 4.40 (1H, s), 4.28–4.21 (2H, m),

3.99–3.87 (3H, m), 3.79 (3H, s), 3.74–3.66 (2H, m), 3.58–

3.55 (3H, m), 3.31, (3H, s), 1.98–1.83 (3H, m), 1.83–1.72

(2H, m), 1.72–1.30 (15H, m), 1.04 (21H, m), 0.98 (3H, d,

J¼6.5 Hz), 0.87 (3H, br d, J¼6.6 Hz), 0.86 (3H, br d,

J¼6.6 Hz); ¹³C NMR (100.6 MHz, CDCl₃) d 159.0, 133.9,

130.8, 129.5, 129.1, 113.7, 74.4, 73.1, 72.6, 72.5, 71.1, 69.2,

68.4, 67.1, 65.3, 56.4, 55.2, 41.6, 41.2, 40.1, 39.7, 39.5,

37.1, 36.4, 33.1, 28.2, 28.1, 22.4, 22.3, 18.4, 18.1, 17.7,

12.2; m/z (ESþ) 719 ([MþH]^þ, 20%), 736 ([MþNH₄]^þ,

80%); HRMS (ESþ) Found 736.5546, [C₄₂H₇₆NO₇Si]^þ

requires 736.5548.

5.1.26. Enone 41. Prepared in 81% yield from lactone 40

via the procedures described for 27. R_f¼0.41 (20% EtOAc/

40–60 petroleum ether); [a]²_D⁰¼þ7.7 (c. 3.1, CHCl₃); n_max

,

cm²¹(ﬁlm) 2938, 2868, 1682, 1611, 1244; ¹H NMR

(400 MHz, CDCl₃) d 7.23 (2H, d, J¼8.7 Hz), 6.86 (2H, d,

J¼8.7 Hz), 6.81 (1H, br tt, J¼15.8, 7.6 Hz), 6.09 (1H, dt,

15.8, 1.2 Hz), 4.41 (2H, s), 4.33–4.25 (2H, m), 4.00–3.89

(2H, m), 3.79 (3H, s), 3.63–3.54 (2H, m), 3.54–3.45 (2H,

m), 3.27 (3H, s), 2.87 (1H, dd, J¼15.4, 6.4 Hz), 2.72 (1H,

dd, J¼15.5, 6.9 Hz), 2.08 (2H, br dd, J¼6.9, 1.3 Hz), 1.82–

1.58 (10H, m), 1.55–1.45 (2H, m), 1.45–1.26 (4H, m), 1.04

(21H, m), 0.96–0.88 (9H, m); ¹³C NMR (100.6 MHz,

CDCl₃) d 198.3, 158.9, 146.5, 131.7, 130.8, 129.1, 113.7,

74.3, 73.1, 72.6, 69.1, 68.4, 67.7, 67.3, 65.4, 56.9, 55.2,

43.3, 41.7, 40.3, 40.0, 39.7, 38.3, 36.5, 33.9, 27.9, 27.7,

26.6, 22.4, 22.3, 18.3, 18.1, 12.2; m/z (EIþ) 716 ([Mþ],

90%), (CIþ) 717 ([MþH]^þ, 60%), 734 ([MþNH₄]^þ, 80%);

HRMS (ESþ) Found 717.5121, [C₄₂H₇₃O₇Si]^þrequires

717.5125.

5.1.29. Acetate from 28. To a cold (08C), stirred solution of

alcohol 28 (70 mg, 0.10 mmol) in CH₂Cl₂(2 mL) was

added sequentially pyridine (40 mL, 0.50 mmol), DMAP

(47 mg, 0.40 mmol) and Ac₂O (37 mL, 0.4 mmol). After

24 h, the reaction mixture was treated with sat. aqueous

NH₄Cl (3 mL), the organic phase separated and the aqueous

phase extracted with Et₂O. The combined organic extracts

were washed with brine (4 mL), dried (MgSO₄) and

concentrated in vacuo. Flash chromatography (20% Et₂O/

30–40 petroleum ether) afforded the corresponding acetate

(74 mg, 100%) as a colourless oil; R_f¼0.36 (20% EtOAc/

40–60 petroleum ether); [a]²_D⁰¼þ11.0 (c. 0.4, CHCl₃);

1

n

_max, cm²¹(ﬁlm) 2932, 2855, 1730, 1610, 1245; H NMR

(500 MHz, CDCl₃) d 7.24 (2H, d, J¼8.7 Hz), 6.85 (2H, d,

J¼8.7 Hz), 5.72 (1H, br dt, J¼15.0, 7.3 Hz), 5.35 (1H, dd,

J¼15.3, 7.5 Hz), 5.25 (1H, br q, J¼8.0 Hz), 4.43 (1H, d,

J¼11.3 Hz), 4.37 (1H, d, J¼11.3 Hz), 3.86–3.80 (2H, m),

3.79 (3H, s), 3.64–3.51 (3H, m), 3.49–3.36 (4H m), 3.33,

(3H, s), 2.18–2.10 (1H, m), 2.02 (3H, s), 1.91 (2H, br t,

J¼6.8 Hz), 1.88–1.55 (13H, m), 1.52–1.43 (1H, m), 1.35–

1.26 (3H), 1.04 (21H, m), 0.89 (3H, d, J¼6.0 Hz), 0.86 (3H,

d, J¼6.6 Hz, H-22), 0.85 (3H, d, J¼6.6 Hz); ¹³C NMR

(125 MHz, CDCl₃) d 169.9, 159.1, 133.8, 130.7, 129.2,

129.1, 113.7, 74.4, 72.7, 72.7, 72.3, 72.1, 72.0, 68.7, 68.1,

66.8, 56.7, 55.2, 42.6, 42.0, 41.6, 39.9, 38.8, 36.4, 36.3,

5.1.27. Alcohol 28. To a cold (2788C), stirred solution of

enone 27 (100 mg, 0.14 mmol) in CH₂Cl₂(4 mL), was

added LiAlH(Ot-Bu)₃(536 mL, 0.54 mmol, 1 M in THF).

After warming to 2108C and stirring for 3 h, the reaction

mixture was treated with 1N tartaric acid (2 mL), the

organic phase separated and the aqueous phase extracted

with Et₂O. The combined organic extracts were washed

with brine, dried (Na₂SO₄) and concentrated in vacuo. Flash

chromatography (20% Et₂O/30–40 petroleum ether)

afforded alcohol 28 (76 mg, 76%) as a colourless oil;

I. Paterson, M. Tudge / Tetrahedron 59 (2003) 6833–6849

6845

34.9, 28.2, 28.0, 27.0, 22.3, 22.2, 21.3, 18.3, 18.0, 12.3; m/z

(ESþ) 778 ([MþNH₄]^þ, 12%), 783 ([MþNa]^þ, 100%);

HRMS (ESþ) Found 783.5215, [C₄₄H₇₆O₈SiNa]^þrequires

783.5207.

58.3, 43.3, 41.6, 41.4, 40.5, 39.6, 37.8, 36.8, 30.1, 29.7,

29.5, 28.8, 24.0, 23.9, 23.1, 19.9, 19.8, 13.9; m/z (ESþ) 641

([MþH]^þ, 70%), 658 ([MþNH₄]^þ, 100%); HRMS (ESþ)

Found 641.4821, [C₃₆H₆₉O₇Si]^þrequires 641.4812.

5.1.30. Acetate from 41. Prepared in ca. 100% yield from

the reduction product of 41 via the procedure described for

the acetate from 28. R_f¼0.36 (20% EtOAc/40–60

5.1.33. Acid 30. To a stirred solution of the alcohol 29

(65 mg, 0.10 mmol) in CH₂Cl₂(2 mL) was added TEMPO

(5 mg, 0.03 mmol) followed by iodobenzene diacetate

(97 mg, 0.30 mmol). After 2 h, the reaction mixture was

treated with 5% aqueous Na₂S₂O₃(1 mL) and sat. aqueous

NaHCO₃(1 mL). After 15 min, the organic phase was

separated and the aqueous phase extracted with Et₂O. The

combined organic extracts were dried (Na₂SO₄) and

concentrated in vacuo. The crude product was ﬁltered

through a plug of silica gel (eluting with 50% Et₂O) and the

ﬁltrate concentrated in vacuo to afford the corresponding

aldehyde which was used directly in the next step. To a

stirred solution of the intermediate aldehyde in t-BuOH

(1 mL) was added methyl-2-butene (ca. 0.5 mL) in t-BuOH

(0.5 mL). The reaction mixture was cooled (08C) and treated

with a solution of NaClO₂(36 mg, 0.3 mmol) and NaH₂PO₄

(142 mg, 0.91 mmol) in H₂O (1 mL). After 1.5 h, the

reaction mixture was diluted with brine (3 mL) and Et₂O

(3 mL). The organic phase was separated and the aqueous

phase extracted with Et₂O. The combined organic phases

were washed with brine, dried (Na₂SO₄) and concentrated in

vacuo. Flash chromatography (Et₂O) afforded the acid 30

(56 mg, 85%) which was taken on to the next step; R_f¼0.4

(50% EtOAc/40–60 petroleum ether); ¹H NMR (500 MHz,

CDCl₃) d 5.78 (1H, br dt, J¼15.0, 7.2 Hz), 5.35 (1H, dd,

J¼15.2, 7.6 Hz), 5.25 (1H, br q, J¼8.1 Hz), 3.90–3.86 (2H,

m), 3.75–3.71 (1H, m), 3.57–3.49 (1H, m), 3.48–3.39 (2H,

m), 3.31 (3H, s), 2.52 (1H, dd, J¼12.7, 3.7 Hz), 2.47 (1H, br

d, J¼12.7 Hz), 2.26–2.19 (1H, m), 2.03 (3H, s), 1.95 (2H,

br t, J¼6.8 Hz), 1.90–1.85 (3H, m), 1.81–1.69 (2H, m),

1.68–1.57 (2H, m), 1.57–1.49 (2H, m), 1.49–1.43 (2H, m),

1.38–1.22 (4H, m), 1.04 (21H, m), 0.88 (3H, d, J¼6.3 Hz),

0.87 (6H, br d, 6.7 Hz).

petroleum ether); [a]²_D⁰¼þ10.3 (c. 3.3, CHCl₃); n_max

,

cm²¹(ﬁlm) 2932, 2855, 1735, 1610, 1240; ¹H NMR

(500 MHz, CDCl₃) d 7.24 (2H, d, J¼8.5 Hz), 6.85 (2H, d,

J¼8.5 Hz), 5.72 (1H, br dt, J¼15.0, 7.2 Hz), 5.36 (1H, br

dd, J¼15.3, 7.5 Hz), 5.25 (1H, br q, J¼7.4 Hz), 4.42 (1H, d,

J¼11.7 Hz), 4.40 (1H, d, J¼11.7 Hz), 4.31–4.22 (1H, m),

4.02–3.88 (2H, m), 3.86–3.81 (1H, m), 3.79 (3H, s), 3.63–

3.52 (3H, m), 3.51–3.43 (1H, m), 3.32, (3H, s), 2.21–2.11

(1H, m), 2.00 (3H, s), 1.92 (2H, br t, J¼7.0 Hz), 1.79–1.74

(2H, m), 1.73–1.35 (13H, m), 1.35–1.25 (1H, m), 1.04

(21H, m), 1.02–0.96 (1H, m), 0.89 (3H, d, J¼5.9 Hz), 0.87

(3H, d, J¼6.6 Hz), 0.85 (3H, d, J¼6.6 Hz); ¹³C NMR

(100.6 MHz, CDCl₃) d 170.3, 159.0, 134.2, 131.3, 129.6,

129.5, 114.1, 74.8, 73.1, 73.0, 72.7, 69.5, 68.7, 68.5, 67.1,

65.8, 57.0, 55.6, 42.0, 40.6, 40.5, 40.1, 39.1, 37.0, 36.9,

35.2, 28.5, 28.5, 27.4, 22.7, 22.6, 21.8, 18.7, 18.5, 12.6; m/z

(CIþ) 778 ([MþNH₄]^þ, 100%); HRMS (ESþ) Found

778.5653, [C₄₄H₈₀NO₈Si]^þrequires 778.5653.

5.1.31. Alcohol 29. To a stirred solution of the acetate of 28

(70 mg, 0.09 mmol) in CH₂Cl₂(4 mL) and pH 7 buffer

(0.4 mL) was added 2,3-dichloro-5,6-dicyano-1,4-benzo-

quinone (90 mg, 0.40 mmol). After 3 h, the reaction mixture

was treated with sat. aqueous NaHCO₃(4 mL), the organic

phase separated and the aqueous phase extracted with

Et₂O. The combined organic extracts were washed with sat.

aqueous NaHCO₃(2£5 mL), dried (Na₂CO₃), and concen-

trated in vacuo. Flash chromatography (30% Et₂O/30–40

petroleum ether) afforded the alcohol 29 (65 mg, 99%)

which was taken on to the next step; R_f¼0.11 (20% EtOAc/

1

40–60 petroleum ether); H NMR (400 MHz, CDCl₃) d

5.73 (1H, br dt, J¼14.8, 7.6 Hz), 5.33 (1H, br dd, J¼15.3,

7.5 Hz), 5.25 (1H, br q, J¼7.8 Hz), 3.89–3.81 (3H, m),

3.65–3.60 (2H, m), 3.54–3.47 (2H, m), 3.45–3.36 (1H, m),

3.36, (3H, s), 3.14 (1H, br s), 2.25–2.17 (1H, m), 2.00 (3H,

s), 1.90–1.81 (4H, m), 1.71–1.58 (8H, m), 1.47–1.41 (3H,

m), 1.32–1.25 (3H, m), 1.03 (21H, m), 0.87–0.84 (9H, m);

¹³C NMR (100.6 MHz, CDCl₃) d 170.4, 134.5, 129.4, 75.0,

74.2, 73.3, 73.1, 72.6, 69.1, 69.0, 59.8, 57.0, 42.7, 42.4,

42.0, 39.7, 38.7, 38.1, 36.4, 35.7, 28.9, 28.4, 27.6, 22.7,

22.6, 21.7, 18.6, 18.5, 12.7.

5.1.34. Acid 43. Prepared in 98% yield from alcohol 42 via

the procedure described for 30; R_f¼0.4 (50% EtOAc/40–60

petroleum ether); [a]²_D⁰¼þ15.5 (c. 3.7, CHCl₃); n_max, cm²¹

1

(ﬁlm) 3184, 2940, 2870, 1735, 1713; H NMR (500 MHz,

CDCl₃) d 5.75 (1H, br dt, J¼15.0, 7.2 Hz), 5.37 (1H, br dd,

J¼15.3, 7.6 Hz), 5.25 (1H, br q, J¼7.8 Hz), 4.34–4.28 (1H,

m), 4.27–4.20 (1H, m), 4.09–3.97 (1H, m), 3.94–3.84 (1H,

m), 3.52–3.45 (1H, m), 3.49–3.44 (1H, m), 3.31, (3H, s),

2.50 (1H, dd, J¼15.3, 4.1 Hz), 2.43 (1H, dd, J¼15.3,

8.9 Hz), 2.25–2.18 (1H, m), 2.02 (3H, s), 1.92 (2H, br t,

J¼7.0 Hz), 1.81–1.24 (15H, m), 1.02 (21H, m), 0.89 (3H, d,

J¼6.1 Hz), 0.87 (3H, d, J¼6.6 Hz), 0.86 (3H, d, J¼6.6 Hz);

¹³C NMR (100.6 MHz, CDCl₃) d 172.6, 170.1, 134.0,

128.8, 75.2, 72.9, 72.6, 69.8, 68.5, 68.3, 64.7, 56.4, 41.5,

41.0, 40.2, 39.5, 38.8, 38.4, 36.2, 34.8, 28.2, 27.9, 27.0,

22.2, 22.1, 21.3, 18.1, 17.9, 12.1; m/z (CIþ) 672

([MþNH₄]^þ, 90%); HRMS (ESþ) Found 672.4874,

[C₃₆H₇₀NO₈Si]^þrequires 672.4871.

5.1.32. Alcohol 42. Prepared in 98% yield from the

corresponding PMB ether via the procedure described for

29. R_f¼0.11 (20% EtOAc/40–60 petroleum ether);

[a]²_D⁰¼þ15.8 (c. 2.9, CHCl₃); n_max, cm²¹(ﬁlm) 3455,

2932, 2877, 1736; ¹H NMR (400 MHz, CDCl₃) d 5.71 (1H,

br dt, J¼14.9, 7.2 Hz), 5.35 (1H, br dd, J¼15.3, 7.5 Hz),

5.21 (1H, br q, J¼7.7 Hz), 4.30–4.23 (1H, m), 4.09–3.91

(2H, m), 3.89–3.83 (1H, m), 3.83–3.73 (1H, m), 3.72–3.53

(2H, m), 3.51–3.41 (1H, m), 3.30, (3H, s), 3.19 (1H, br s),

2.22–2.13 (1H, m), 1.98 (3H, s), 1.88 (2H, br t, J¼6.8 Hz),

1.85–1.77 (1H, m), 1.73–1.23 (17H, m), 1.03 (21H, m),

0.85–0.82 (9H, m); ¹³C NMR (100.6 MHz, CDCl₃) d 171.7,

135.7, 130.8, 76.3, 74.4, 73.9, 72.8, 70.7, 70.1, 66.9, 61.9,

5.1.35. Macrolactone 31. To a stirred solution of acid 30

(56 mg, 85%) in MeOH (2 mL) was added K₂CO₃(591 mg,

4.30 mmol). After 5 h, the reaction mixture was diluted with

Et₂O (2 mL), ﬁltered, and the ﬁltrate concentrated in vacuo to

give the crude product which was ﬁltered through a small pad

6846

I. Paterson, M. Tudge / Tetrahedron 59 (2003) 6833–6849

of silica gel (eluting with 2% MeOH/Et₂O). Concentration

of the ﬁltrate in vacuo afforded the seco-acid which was

azeotroped from toluene (3£2 mL) and used directly in the

next step. To a stirred solution of triphenylphosphine

(58 mg, 0.22 mmol) in degassed benzene (6 mL) was

added sequentially diethylazodicarboxylate (29 mL,

J¼1.3 Hz), 2.58 (1H, dd, J¼13.2, 3.9 Hz), 2.40 (1H, dd,

J¼13.2, 11.5 Hz), 2.38 (1H, br dd, J¼14.0, 12.2 Hz), 2.07–

2.01 (2H, m), 1.96–1.84 (4H, m), 1.78–1.57 (4H, m), 1.56–

1.43 (4H, m), 1.35–1.21 (4H, m), 1.18 (3H, d, J¼7.1 Hz),

1.05–0.98 (1H, m), 0.89 (3H, d, J¼6.6 Hz), 0.87 (3H, d,

J¼6.6 Hz); ¹³C NMR (125 MHz, CDCl₃) d 169.3, 132.3,

130.1, 73.6, 73.5, 73.0, 72.1, 70.8, 68.0, 63.0, 57.3, 43.1,

42.8, 41.6, 41.1, 40.8, 39.2, 35.5, 35.5, 31.0, 28.1, 27.1,

24.2, 22.2, 18.3; m/z (ESþ) 439 ([MþH]^þ, 5%), 456

([MþNH₄]^þ, 100%); HRMS (ESþ) Found 456.3325,

[C₂₅H₄₆NO₆]^þrequires 456.3325.

0.184 mmol) and

a solution of seco-acid (21 mg,

0.034 mmol) in degassed benzene (1.0 mL). After 15 min,

the reaction mixture was concentrated in vacuo. Flash

chromatography (15% Et₂O/30–40 petroleum ether)

afforded macrolactone 31 (16 mg, 65%) as a colourless

oil; R_f¼0.65 (50% EtOAc/40–60 petroleum ether);

[a]²_D⁰¼þ57.2 (c. 0.8, CHCl₃); n_max, cm²¹(ﬁlm) 2942,

2866, 1741; ¹H NMR (500 MHz, CDCl₃) d 5.72 (1H, br dt,

J¼14.5, 7.2 Hz), 5.41–5.32 (2H, m), 3.98–3.85 (2H, m),

3.68 (1H, br t, J¼11.3 Hz), 3.59–3.48 (2H, m), 3.36 (3H, s),

3.17 (1H, br t, J¼11.1 Hz), 2.56 (1H, dd, J¼14.6, 3.8 Hz),

2.42–2.35 (2H, m), 2.02 (1H, br td, 13.5, 2.0 Hz), 1.98–

1.79 (6H, m), 1.69–1.56 (4H, m), 1.56–1.48 (2H, m), 1.48–

1.40 (1H, m), 1.36–1.28 (2H, m), 1.22 (1H, br td, J¼13.2,

1.9 Hz), 1.18 (3H, d, J¼7.1 Hz), 1.07 (21H, m), 1.05–0.96

(1H, m), 0.88 (3H, d, J¼6.6 Hz), 0.86 (3H, d, J¼6.6 Hz);

¹³C NMR (125 MHz, CDCl₃) d 169.5, 132.3, 130.2, 73.7,

73.6, 73.0, 72.2, 70.7, 68.5, 62.9, 57.3, 43.2, 42.9, 41.8,

41.6, 39.3, 35.6, 31.1, 28.1, 27.2, 24.2, 22.2, 18.2, 18.1,

17.7, 12.3, 12.3; m/z (ESþ) 595 ([MþH]^þ, 30%), 612

([MþNH₄]^þ, 40%), 617 ([MþNa]^þ, 60%); HRMS (ESþ)

Found 617.4234, [C₃₄H₆₂O₆SiNa]^þrequires 617.4213.

5.1.38. Alcohol 45. To a cold (08C), stirred solution of

macrolactone 44 (37 mg, 0.062 mmol) in THF (3 mL) was

added tetrabutylammonium ﬂuoride (316 mL, 0.316 mmol,

1 M in THF). After 5 h, the reaction mixture was diluted

with sat. aqueous NH₄Cl (3 mL) followed by Et₂O (3 mL).

The organic phase was separated and the aqueous phase

extracted with Et₂O. The combined organic extracts were

washed with brine, dried (Na₂SO₄) and concentrated in

vacuo. Flash chromatography (60% Et₂O/30–40 petroleum

ether) afforded alcohol 45 (27 mg, 99%) as a colourless

amorphous solid. R_f¼0.1 (50% EtOAc/40–60 petroleum

ether); [a]²_D⁰¼þ26.0 (c. 0.1, EtOH); n_max, cm²¹(ﬁlm) 3444,

2921, 2866, 1735; ¹H NMR (500 MHz, C₆D₅N) d 6.37 (1H,

d, J¼3.1 Hz), 5.85 (2H, m), 5.59 (1H, ddt, J¼15.4, 6.9,

1.3 Hz), 4.68 (1H, dddd, J¼11.6, 3.7, 1.7 Hz), 4.46 (1H, m),

4.22 (1H, br dd, J¼11.5 Hz), 4.10 (1H, br d, J¼10.7 Hz),

3.97 (1H, br dd, J¼10.0 Hz), 3.80 (1H, tt, J¼11.0, 2.2 Hz),

3.41 (3H, s), 2.73 (1H, dd, J¼13, 3.7 Hz), 2.53 (1H, br dd,

J¼11.9 Hz), 2.52 (1H, dd, J¼13.1, 11.6 Hz), 2.15 (1H, br

ddd, J¼13.0, 11.5, 2.1 Hz), 1.96 (1H, br d, J¼13.0 Hz),

1.93–1.86 (4H, m), 1.77 (1H, ddd, J¼14.7, 10.5, 2.0 Hz),

1.67 (1H, br dddd, J¼14.0, 13.2, 4.6 Hz), 1.65 (1H, br ddd,

J¼13.7, 11.3, 3.0 Hz), 1.51–1.55 (2H, m), 1.45–1.35 (3H,

m), 1.27–1.21 (1H, m), 1.17–1.15 (1H, m), 1.12 (3H, d,

J¼7.0 Hz), 1.08 (1H, ddd, J¼14.3, 12.0, 2.4 Hz), 0.83 (3H,

d, J¼6.6 Hz), 0.82 (3H, d, J¼6.6 Hz); ¹³C NMR (125 MHz,

CDCl₃) d 170.2, 131.9, 131.5, 73.9, 73.9, 70.9, 69.8, 69.7,

63.8, 63.1, 56.7, 43.9, 43.4, 41.7, 40.0, 39.7, 39.5, 35.9,

31.4, 28.3, 27.4, 24.3, 22.3, 22.2, 18.4; m/z (ESþ) 439

([MþH]^þ, 50%), 456 ([MþNH₄]^þ, 95%); HRMS (ESþ)

Found 439.3057, [C₂₅H₄₃O₆]^þrequires 456.3059. This

spectrocopic and speciﬁc rotation data was in agreement

with that reported by Pietra³and Leighton.^6a

5.1.36. Macrolactone 44. Prepared in 48% yield from 43

via the procedure described for 31. R_f¼0.65 (50% EtOAc/

40–60 petroleum ether); [a]²_D⁰¼þ60.7 (c. 1.95, CHCl₃);

1

n

_max, cm²¹(ﬁlm) 2939, 2869, 1740; H NMR (500 MHz,

CDCl₃) d 5.70 (1H, br dt, J¼15.0, 7.2 Hz), 5.38 (1H, br dd,

J¼15.2, 6.7 Hz), 5.31 (1H, br dd, J¼11.1, 6.7 Hz), 4.38–

4.31 (1H, m), 4.20 (1H, br t, J¼11.1 Hz), 3.91–3.79 (2H,

m), 3.58 (1H, br t, J¼10.6 Hz), 3.52 (1H, br t, J¼10.7 Hz),

3.35 (3H, s), 2.47 (1H, dd, J¼13.0, 3.7 Hz), 2.41 (1H, br t,

J¼14.2 Hz), 2.29 (1H, br td, J¼13.0), 1.95 (1H, br t,

J¼11.7 Hz), 1.94–1.78 (2H, m), 1.72–1.39 (11H, m),

1.33–1.25 (1H, m), 1.16 (3H, d, J¼7.0 Hz), 1.14–0.95

(23H, m), 0.86 (6H, d, J¼6.6 Hz); ¹³C NMR (62.5 MHz,

CDCl₃) d 169.9, 132.0, 130.0, 73.7, 73.6, 70.7, 69.4, 69.3,

65.5, 63.1, 57.3, 43.3, 43.1, 41.6, 41.6, 39.5, 39.3, 35.7,

30.9, 28.1, 27.2, 24.0, 22.3, 18.2, 18.1, 17.7, 17.2, 12.3; m/z

(CIþ) 595 ([MþH]^þ, 30%), 612 ([MþNH₄]^þ, 100%);

HRMS (ESþ) Found 595.4394, [C₃₄H₆₃O₆SiN]^þrequires

595.4394.

5.1.39. Ketone 33. To a stirred solution of alcohol 32 or 45

(9.0 mg, 0.021 mmol) in CH₂Cl₂(0.5 mL) was added

sequentially pyridine (3 mL, 0.041 mmol) and Dess–Martin

periodinane (17.0 mg, 0.041 mmol). After 1.5 h, the

reaction mixture was ﬁltered through a short column of

silica gel (eluting with 50% Et₂O/30–40 petroleum ether)

and the ﬁltrate concentrated in vacuo. Flash chromato-

graphy afforded ketone 33 (9.0 mg, 99%) as a colourless

glass; R_f¼0.65 (50% EtOAc/40–60 petroleum ether);

[a]²_D⁰¼þ53.0 (c. 1.5, EtOH); n_max, cm²¹(ﬁlm) 2954,

2868, 1738, 1715; ¹H NMR (500 MHz, CDCl₃) d 5.75–5.66

(1H, m), 5.45–5.30 (2H, m), 4.02 (1H, tt, J¼11.2, 2.6 Hz),

3.86 (1H, br dd, J¼11.5, 11.5 Hz), 3.59–3.44 (3H, m), 3.37

(3H, s), 2.63 (1H, dd, J¼13.2, 3.6 Hz), 2.51–2.40 (2H, m),

2.39–2.21 (4H, m), 2.09 (1H, br td, J¼13.3, 1.4 Hz), 1.96–

1.81 (2H, m), 1.76–1.55 (3H, m), 1.53–1.44 (3H, m), 1.41

(1H, br d, J¼10.7 Hz), 1.32–1.28 (2H, m), 1.15 (3H, d,

5.1.37. Alcohol 32. To a cold (08C), stirred solution of

macrolactone 31 (13 mg, 0.022 mmol) in THF (1.5 mL) was

added HF·pyr (100 mL, 1.1 mmol). After 4 h, the reaction

mixture was treated with sat. aqueous NaHCO₃(5 mL) and

Et₂O (2 mL). The organic phase was separated and the

aqueous phase extracted with Et₂O. The combined organic

extracts were washed with brine, dried (Na₂SO₄), and

concentrated in vacuo. Flash chromatography (Et₂O) gave

alcohol 32 (9.0 mg, 95%) as a colourless oil; R_f¼0.1 (50%

EtOAc/40–60 petroleum ether); [a]²_D⁰¼þ56.0 (c. 0.1,

EtOH); n_max, cm²¹(ﬁlm) 3433, 2932, 2866, 1730; ¹H

NMR (500 MHz, CDCl₃) d 5.72 (1H, td, J¼15.0, 7.2 Hz),

5.45–5.30 (2H, m), 3.94 (2H, m), 3.74 (1H, tq, J¼11.3,

2.0 Hz), 3.54 (2H, m), 3.37 (3H, s), 3.23 (1H, br t,

I. Paterson, M. Tudge / Tetrahedron 59 (2003) 6833–6849

6847

J¼7.1 Hz), 1.04 (1H, br tt, J¼12.6, 1.3 Hz), 0.84 (1H, d,

J¼6.6 Hz), 0.83 (1H, d, J¼6.6 Hz); ¹³C NMR (125 MHz,

CDCl₃) d 205.6, 168.5, 132.8, 129.8, 74.3, 73.5, 73.4, 71.2,

63.1, 57.3, 63.0, 47.9, 47.4, 43.4, 42.7, 41.5, 39.6, 39.0,

35.6, 31.0, 28.1, 27.1, 24.2, 22.2, 18.3; m/z (ESþ) 437

([MþH]^þ, 5%), 454 ([MþNH₄]^þ, 100%); HRMS (ESþ)

Found 437.2905, [C₂₅H₄₁O₆]^þrequires 437.2903.

the aqueous phase extracted with Et₂O. The combined

organic phases were washed with brine, dried (MgSO₄) and

concentrated in vacuo to give the crude product which was

used directly in the next step. To a stirred solution of the

˚

crude product in toluene was added 4 A molecular sieves

(2 g). After heating at 1108C for 1.5 h, the reaction mixture

was cooled, ﬁltered and concentrated in vacuo. Flash

chromatography (50% Et₂O/30–40 petroleum ether)

afforded oxazolone 50 as a yellow semi-solid (800 mg,

5.1.40. Alcohol 32. To a cold (21008C), stirred solution of

ketone 33 (26 mg, 0.06 mmol), in THF (100 mL), was

added ^L-Selectride^w(90 mL, 0.09 mmol, 1 M in THF).

After 1.5 h, the reaction mixture was treated with sat.

aqueous NH₄Cl (2 mL) and warmed to room temperature.

The organic phase was separated and the aqueous phase

extracted with Et₂O. The combined organic extracts were

washed with brine (10 mL), dried (Na₂SO₄) and concen-

trated in vacuo. Flash chromatography (70% Et₂O/30–40

petroleum ether) afforded alcohol 32 as a colourless oil

(24 mg, 91%) with data as already listed (5.1.37).

49%); R_f¼0.15 (20% EtOAc/40–60 petroleum ether); n_max

,

cm²¹(ﬁlm) 3156, 2935, 2854, 1746, 1613; ¹H NMR

(250 MHz, CDCl₃) d 9.85 (1H, br s), 7.25 (2H, d,

J¼8.6 Hz), 6.85 (2H, d, J¼8.6 Hz), 6.62 (1H, s), 4.50

(2H, s), 4.10 (2H, t, J¼1.8 Hz), 3.78 (3H, s), 2.57–2.53 (2H,

m), 2.51–2.48 (2H, m); ¹³C NMR (100.6 MHz, CDCl₃) d

158.8, 157.2, 129.1, 128.8, 125.3, 124.2, 113.3, 83.8, 77.3,

70.7, 56.6, 54.7, 22.8, 16.8; m/z (CIþ) 288 ([MþH]^þ, 20%),

305 ([MþNH₄]^þ, 95%); HRMS (ESþ) Found 305.1499,

[C₁₆H₂₁N₂O₄]^þrequires 305.1501.

5.1.41. Ketone 47. To a cold (2788C), stirred solution of

diisopropylamine (8.50 mL, 62.4 mmol) in THF (100 mL)

and HMPA (15.5 mL, 89.2 mmol) was added n-butyl

lithium (23.8 mL, 59.5 mmol, 2.5 M in hexanes). After

warming to 08C and stirring for 15 min, the mixture was

cooled to 2788C and the hydrazone 48²⁸(13.3 mL,

59.5 mmol) was added. After 30 min, the reaction mixture

was treated with a solution of the propargylic bromide 49²⁹

(8.00 g, 29.7 mmol) in THF (20 mL). After 2 h, the reaction

mixture was quenched with sat. aqueous NH₄Cl and

warmed to room temperature. The organic phase was

separated and the aqueous phase extracted with Et₂O. The

combined organic extracts were washed with brine, dried

(Na₂SO₄) and concentrated in vacuo. The crude product was

ﬁltered through a plug of silica gel (eluting with Et₂O) and

the ﬁltrate concentrated in preparation for the the next step.

To a cold (08C), stirred solution of the alkylated hydrazone

intermediate in THF (60 mL) was added tetrabutyl-

ammonium ﬂuoride (65.0 mL, 65.0 mmol, 1 M in THF).

After warming to room temperature for 2 h, the reaction

mixture was treated with sat. aqueous NH₄Cl (200 mL), the

organic phase separated and the aqueous phase extracted

with Et₂O. The combined organic extracts were dried

(Na₂SO₄) and concentrated in vacuo. Flash chromatography

afforded ketone 47 (5.00 g, 65%) as a light yellow oil;

R_f¼0.3 (60% EtOAc/40–60 petroleum ether); n_max, cm²¹

(ﬁlm) 3433, 2921, 2843, 1719; ¹H NMR (400 MHz, CDCl₃)

d 7.25 (2H, d, J¼8.5 Hz), 6.86 (2H, d, J¼8.5 Hz), 4.46 (2H,

s), 4.25 (2H, s,), 4.06 (2H, t, J¼2.1 Hz), 3.78 (3H, s), 3.07

(1H, br s), 2.64–2.58 (2H, m), 2.57–2.53 (2H, m); ¹³C

NMR (100.6 MHz, CDCl₃) d 207.2, 158.8, 129.8, 129.1,

113.3, 83.2, 70.6, 67.7, 56.6, 54.7, 36.7, 29.7, 12.7; m/z

(CIþ) 280 ([MþNH₄]^þ, 100%); HRMS (ESþ) Found

280.1550, [C₁₅H₂₂NO₄]^þrequires 280.1549.

5.1.43. Oxazole 52. To a cold (2108C), stirred solution of

oxazolone 50 (40 mg, 0.14 mmol) in CH₂Cl₂(2 mL) was

added sequentially 2,6-lutidine (500 mL, 4.26 mmol) and

triﬂuoromethanesulfonic anhydride (587 mL, 3.57 mmol).

After 1 h, the reaction mixture was diluted with H₂O

(10 mL), the organic phase separated and the aqueous phase

extracted with Et₂O. The combined organic extracts were

dried (MgSO₄) and concentrated in vacuo. Puriﬁcation by

ﬂash chromatography (20% Et₂O/30–40 petroleum ether)

afforded the intermediate triﬂate 46 which was used directly

in the next reaction. To a stirred solution of the prepared

triﬂate in 1,4-dioxan (6 mL) was added Pd(PPh₃)₄. After

10 min, the reaction mixture was treated sequentially with

alkyne 51^6a(335 mL, 0.297 mmol), copper-(I)-iodide

(64.0 mg, 0.29 mmol) and 2,6-lutidine (857 mL,

7.41 mmol). After 7 h, the reaction mixture was diluted

with EtOAc (4 mL) and 10% aqueous citric acid (4 mL), the

organic phase was separated and the aqueous phase

extracted with EtOAc. The combined organic extracts

were washed with brine (10 mL), dried (Na₂SO₄), and

concentrated in vacuo. Flash chromatography (70%

Et₂O/30–40 petroleum ether) afforded the oxazole 52

(445 mg, 49%) as a yellow oil; R_f¼0.35 (60% EtOAc/40–

60 petroleum ether); n_max, cm²¹(ﬁlm) 3313, 2932, 2844,

1725, 1703, 1610, 1245; ¹H NMR (400 MHz, CDCl₃) d 7.43

(1H, s), 7.23 (2H, d, J¼8.7 Hz), 6.85 (2H, d, J¼8.7 Hz),

5.14 (1H, br s), 4.44 (2H, s), 4.19 (2H, d, J¼7.5 Hz), 4.06

(2H, t, J¼2.0 Hz), 3.78 (3H, s), 3.68 (3H, s), 2.72 (2H, t,

J¼7.1 Hz), 2.57 (2H, tt, J¼7.0, 1.8 Hz); ¹³C NMR

(100.6 MHz, CDCl₃) d 160.5, 157.7, 146.9, 141.6, 136.9,

130.9, 130.7, 115.0, 89.3, 86.7, 72.6, 72.2, 58.4, 56.5, 53.8,

32.4, 26.9, 19.3; m/z (CIþ) 383 ([MþH]^þ, 100%), 400

([MþNH₄]^þ, 20%); HRMS (ESþ) Found 383.1603,

[C₂₁H₂₃N₂O₅]^þrequires 383.1607.

5.1.42. Oxazolone 50. To a stirred solution of ketone 47

(1.50 g, 5.70 mmol) in CH₂Cl₂(40 mL) was added

trichloroacetyl isocyanate (1.70 mL, 14.3 mmol). After

1 h, the reaction mixture was concentrated in vacuo and

the residue dissolved in MeOH (60 mL). Stirring was

continued and the reaction mixture was treated with K₂CO₃

(4.00 g, 28.5 mmol). After 1 h, brine (100 mL) and Et₂O

(100 mL) were added, the organic phase was separated and

5.1.44. Alcohol 53. To a stirred solution of oxazole 52

(265 mg, 0.69 mmol) in CH₂Cl₂(7 mL) and pH 7 buffer

(0.7 mL) was added 2,3-dichloro-5,6-dicyano-1,4-benzo-

quinone (234 mg, 1.04 mmol). After 3 h, the reaction

mixture was treated with sat. aqueous NaHCO₃(10 mL),

the organic phase separated and the aqueous phase

extracted with EtOAc. The combined organic extracts

were washed with sat. aqueous NaHCO₃, dried (Na₂SO₃),

6848

I. Paterson, M. Tudge / Tetrahedron 59 (2003) 6833–6849

and concentrated in vacuo. Puriﬁcation by ﬂash chroma-

tography (Et₂O) afforded the alcohol 53 (60 mg, 98%) as a

colourless solid; Mp¼95–988C; R_f¼0.30 (80% EtOAc/40–

60 petroleum ether); n_max, cm²¹(ﬁlm) 3299, 2932, 2877,

1719; ¹H NMR (400 MHz, CDCl₃) d 7.43 (1H, s), 5.28 (1H,

br s), 4.22–4.18 (4H, m), 2.70 (2H, t, J¼7.1 Hz), 2.57 (2H,

tt, J¼7.0, 1.9 Hz); ¹³C NMR (100.6 MHz, CDCl₃) d 159.0,

148.2, 142.8, 138.2, 90.7, 87.2, 81.9, 73.8, 55.1, 53.7, 33.8,

28.1, 20.5; m/z (CIþ) 263 ([MþH]^þ, 50%); HRMS (ESþ)

Found 263.1029, [C₁₃H₁₅N₂O₄]^þrequires 263.1032.

1.04 (1H, ddd, J¼17.1, 11.0, 2.5 Hz), 0.85 (3H, d,

J¼6.7 Hz), 0.84 (3H, d, J¼6.7 Hz); ¹³C NMR (125 MHz,

CDCl₃) d 169.3, 152.9, 139.5, 137.8, 132.4, 130.2, 88.3,

88.1, 73.9, 73.7, 73.6, 73.2, 71.3, 70.9, 69.9, 69.8, 69.3,

63.1, 57.2, 52.6, 43.3, 42.8, 41.6, 39.3, 39.1, 35.6, 35.6,

35.3, 31.1, 31.0, 28.1, 27.1, 24.6, 24.3, 22.2, 22.1, 18.3,

18.1; m/z (CIþ) 697 ([MþH]^þ, 80%); HRMS (ESþ) Found

697.3689, [C₃₈H₅₃N₂O₁₀]^þrequires 697.3700.

5.1.47. Synthetic (1)-leucascandrolide A (1). To a stirred

solution of ester 54 (25 mg, 0.036 mmol) in EtOAc (2 mL)

was added palladium 5% wt. on CaCO₃poisoned with lead

(Lindlar cat.) (5 mg). After 10 min, the reaction mixture was

treated with quinoline (4 mL, 0.04 mmol) and stirring was

continued for 3 h under a baloon of H₂. The reaction mixture

was ﬁltered through Celite^w(eluting with EtOAc) and

concentrated in vacuo. Flash chromatography (40% Et₂O/

30–40 petroleum ether) afforded (þ)-leucascandrolide A

(23 mg, 92%) as a colourless glass; R_f¼0.4 (60% EtOAc/

40–60 petroleum ether); [a]²_D⁰¼þ40.0 (c. 0.3, EtOH), cf.

Lit.³[a]_D²⁰¼þ41.0 (c. 0.29, EtOH); n_max, cm²¹(ﬁlm) 3346

(N–H), 2942 (C–H), 2890 (C–H), 1725 (CvO), 1708

(CvO), 1632 (CvC); ¹H NMR (500 MHz, C₅D₅N) d 8.34

(1H, br t, J¼5.4 Hz,₀NH), 7.61 (1H, s, H-7⁰), 6.41 (1H, dt,

J¼11.8, 1.6 Hz, H-9 ), 6.31 (1H, dt, J¼11.5, 7.3 Hz, H-3⁰),

6.27 (1H, dt, J¼12.0, 6.0 Hz, H-10⁰), 5.97 (1H, dt, J¼11.5,

1.7 Hz, H-2⁰), 5.82 (1H, br dt, J¼15.5, 7.2 Hz, H-19), 5.76

(1H, br dd, J¼11.7, 6.6 Hz, H-17), 5.59 (1H, ddt, 15.4, 6.9,

1.3 Hz, H-18), 5.41 (1H, m, H-5), 4.78 (2H, br t, J¼4.9 Hz,

H-11⁰), 4.31 (1H, dddd, J¼11.8, 11.5, 3.3, 2.1 Hz, H-3),

4.09 (1H, br d, J¼12.3 Hz, H-11), 3.90 (1H, br t,

J¼12.0 Hz, H-9), 3.87 (1H, br dd, J¼11.7, 11.3 Hz, H-7),

3.81 (1H, br dd, J¼10.6, 10.5 Hz, H-15), 3.73 (3H, s,

OCH₃), 3.39 (3H, s, OCH₃), 3.21 (2H, br q, J¼7.5 Hz, H-4⁰),

2.74 (2H, br t, J¼7.4 Hz, H-5⁰), 2.71 (1H, dd, J¼13.0,

3.7 Hz, H-2), 2.49 (1H, br dd, J¼14.1, 12.0 Hz, H-10), 2.45

(1H, dd, J¼13.1, 11.6 Hz, H-2), 2.06 (1H, ddd, J¼11.8,

11.3, 2.3 Hz, H-8), 1.96 (1H, br d, J¼13.7 Hz, H-4), 1.90-

1.88 (1H, m, H-16), 1.89 (1H, br d, J¼13.9 Hz, H-6), 1.88

(2H, br dd, J¼7.0, 6.9 Hz, H-20), 1.84–1.86 (1H, m, H-13),

1.78 (1H, ddd, J¼14.0, 10.5, 2.2 Hz, H-16), 1.62 (1H, ddd,

J¼14.2, 11.5, 2.7 Hz, H-6), 1.55–1.53 (1H, m, H-21), 1.51

(1H, ddd, J¼14.0, 3.1 Hz, H-4), 1.50–1.47 (1H, m, H-14),

1.43–1.41 (1H, m, H-12), 1.33–1.31 (1H, m, H-8), 1.30

(1H, br d, J¼13.8 Hz, H-13), 1.25 (1H, br d, J¼14.1 Hz,

H-14), 1.12 (3H, d, J¼7.0 Hz, H-24), 1.08 (1H, ddd,

J¼14.4, 11.6, 2.7 Hz, H-10), 0.83 (3H, d, J¼6.6 Hz, H-22),

0.82 (3H, d, J¼6.6 Hz, H-23); ¹³C NMR (125 MHz, CDCl₃)

d 169.3, 165.3, 160.1, 157.1, 149.2, 141.1, 136.4, 133.9,

132.4, 130.1, 120.7, 116.6, 73.6, 73.3, 70.8, 70.0, 69.6, 67.3,

63.1, 57.3, 52.2, 43.3, 42.8, 41.6, 39.4, 39.3, 35.6, 35.5,

35.5, 31.0, 28.1, 27.7, 27.2, 25.7, 24.3, 22.2, 18.3; m/z

(ESþ) 701 ([MþH]^þ, 70%), 723 ([MþNa]^þ, 100%);

HRMS (ESþ) Found 701.4014, [C₃₈H₅₇N₂O₁₀]^þrequires

701.4013. This spectroscopic data was in agreement with

that reported by Pietra and co-workers for natural (þ)-

leucascandrolide A.^3,31

5.1.45. Acid 3. To a stirred solution of alcohol 53 (52 mg,

0.14 mmol) in CH₂Cl₂(2 mL) was added TEMPO

(8 mg, 0.06 mmol) followed by iodobenzene diacetate

(188 mg, 0.59 mmol). After 2 h, the reaction mixture was

treated with 5% aqueous Na₂S₂O₃(1 mL) and sat. aqueous

NaHCO₃(1 mL). After 15 min, the organic phase was

separated and the aqueous phase extracted with Et₂O, the

combined organic extracts were dried (Na₂SO₄) and

concentrated in vacuo. The crude product was ﬁltered

through a small plug of silica gel (eluting with 50% Et₂O)

and the ﬁltrate concentrated in vacuo to afford the

corresponding aldehyde intermediate which was used

directly in the next step. To a stirred solution of the above

aldehyde in t-BuOH (1 mL) was added methyl-2-butene (ca.

0.5 mL) in t-BuOH (0.5 mL), followed by cooling to 08C

and addition of a solution of NaClO₂(62 mg, 0.68 mmol)

and NaH₂PO₄(309 mg, 2.04 mmol) in H₂O (1 mL). After

1.5 h, the reaction mixture was diluted with brine (4 mL)

and EtOAc (4 mL), the organic phase was separated and the

aqueous phase extracted with EtOAc. The combined

organic phases were washed with brine (5 mL), dried

(Na₂SO₄) and concentrated in vacuo. Trituration with Et₂O

afforded the acid 3 (90 mg, 98%) as a light yellow solid;

mp¼154–1558C; R_f¼0.1 (EtOAc); ¹H NMR (400 MHz,

CD₃OD) d 7.74 (1H, s), 4.13 (2H, br s), 3.66 (3H, s), 2.78

(2H, t, J¼7.1 Hz), 2.67 (2H, t, J¼6.9 Hz); ¹³C NMR

(100.6 MHz, CD₃OD) d 156.5, 147.9, 141.2, 138.5, 134.7,

91.2, 88.6, 75.5, 71.2, 58.3, 31.9, 25.7, 18.8; m/z (ESþ) 277

([MþH]þ, 50%), 294 ([MþNH₄]^þ, 55%), 299 ([MþNa]^þ,

100%), (ES2) 275 ([M2H]², 100%); HRMS (ESþ) Found

277.0823, [C₁₃H₁₃N₂O₅]^þrequires 277.0824.

5.1.46. Ester 54. To a cold (08C), stirred solution of alcohol

32 (25 mg, 0.057 mmol) and acid 3 (79 mg, 0.258 mmol) in

toluene (2 mL) and THF (1.3 mL) was added triphenyl-

phosphine (300 mg, 1.14 mmol) and diethyl azodicar-

boxylate (33 mL, 0.19 mmol). After warming to room

temperature and stirring for 14 h, the reaction mixture was

concentrated in vacuo. Flash chromatography (40% Et₂O/

30–40 petroleum ether) gave the ester 54 as a colourless

glass (35 mg, 90%); R_f¼0.4 (50% EtOAc/40–60 petroleum

ether); [a]_D²⁰¼þ26.3 (c. 2.1, CHCl₃); n_max, cm²¹(ﬁlm)

2938, 2868, 1682, 1611, 1244; ¹H NMR (500 MHz, CDCl₃)

d 7.41 (1H, t, J¼0.9 Hz), 5.73 (1H, m), 5.36 (1H, ddt,

J¼12.2, 6.3, 1.1 Hz), 5.26 (1H, br t, J¼2.9 Hz), 4.96 (1H, br

s), 4.25 (2H, d, J¼6.2 Hz), 4.04 (1H, dddd, J¼11.4, 11.4,

4.0, 1.9 Hz), 3.89 (1H, br d, J¼10.2 Hz), 3.71 (3H, s), 3.60–

3.51 (3H, m), 3.34 (3H, s), 2.83 (2H, t, J¼7.2 Hz), 2.71 (2H,

td, J¼7.0, 0.8 Hz), 2.56 (1H, dd, J¼13.1, 4.0 Hz), 2.44 (1H,

br dd, J¼13.9, 12.2 Hz), 2.32 (1H, dd, J¼13.1, 11.4 Hz),

1.92–1.86 (5H, m), 1.77 (1H, br tt, J¼8.2, 1.4 Hz), 1.74–

1.73 (1H, m), 1.61–1.34 (9H, m), 1.18 (3H, d, J¼7.1 Hz),

Acknowledgements

We thank the EPSRC (studentship to M. T. and

I. Paterson, M. Tudge / Tetrahedron 59 (2003) 6833–6849

6849

12. The enone was prepared from 3-buten-1-ol in 4 steps as

described in Ref. 5.

GR/N08520), the EC (Network HPRN-CT-2000-00018),

and Merck, Pﬁzer, and Novartis Pharma AG for support.

13. For a review, see: Jorgensen, K. A. Angew. Chem. Int. Ed.

2000, 39, 3559.

14. This homologation sequence was adapted from Evans and

co-workers: Evans, D. A.; Fitch, D. M.; Smith, T. E.; Cee, V. J.

J. Am. Chem. Soc. 2000, 122, 10033.

References

1. For recent reviews on marine natural products, see: (a) Blunt,

J. W.; Copp, B. R.; Munro, M. H. G.; Northcote, P. T.; Prinsep,

M. R. Nat. Prod. Rep. 2003, 20, 1. (b) Faulkner, D. J. Nat.

Prod. Rep. 2002, 19, 1. (c) Faulkner, D. J. Nat. Prod. Rep.

2001, 18, 1. (d) Newman, D. J.; Cragg, G. M.; Snader, K. M.

Nat. Prod. Rep. 2000, 17, 215.

15. Myers, A.; McKinstry, L. J. Org. Chem. 1996, 61, 2428.

16. For a review of asymmetric boron aldol reactions, see:

Cowden, C. J.; Paterson, I. Org. React. 1997, 51, 1.

17. Evans, D. A.; Chapman, K. T.; Carreira, E. M. J. Am. Chem.

Soc. 1988, 110, 3560.

18. Additional examples of this TEMPO-based methodology for

selective d-lactone formation have recently been reported by

the Forsyth group, see: Hansen, T. M.; Florence, G. J.; Lugo-

Mas, P.; Chen, J.; Abrams, J. N.; Forsyth, C. J. Tetrahedron

Lett. 2003, 44, 57.

2. For reviews on marine macrolide synthesis, see: (a) Norcross,

R. D.; Paterson, I. Chem. Rev. 1995, 95, 2041. (b) Yeung,

K.-S.; Paterson, I. Angew. Chem. Int. Ed. 2002, 41, 4632.

3. D’Ambrosio, M.; Guerriero, A.; Debitus, C.; Pietra, F. Helv.

Chim. Acta 1996, 79, 51.

19. De Mico, A.; Margarita, R.; Parlanti, L.; Vescovi, A.;

Piancatelli, G. J. Org. Chem. 1997, 62, 6974.

20. Dahankar, V. H.; Rychnovsky, S. D. J. Org. Chem. 1996, 61,

8317.

4. D’Ambrosio, M.; Tato, M.; Pocsfalvi, G.; Debitus, C.; Pietra,

F. Helv. Chim. Acta 1999, 82, 347.

5. For an initial account of some of this work, see: Paterson, I.;

Tudge, M. Angew. Chem. Int. Ed. 2003, 42, 343.

21. Silyl enol ether 6 was prepared from isovaleraldehyde as

described in Ref. 5.

6. For completed total syntheses of leucascandrolide A, see:

(a) Hornberger, K. R.; Hamblett, C. L.; Leighton, J. L. J. Am.

Chem. Soc. 2000, 122, 12894. (b) Fettes, A.; Carreira, E. M.

Angew. Chem. Int. Ed. 2002, 41, 4098. (c) Wang, Y.; Janjic, J.;

Kozmin, S. A. J. Am. Chem. Soc. 2002, 124, 13670.

7. For formal syntheses of leucascandrolide A based on Ref. 6a,

see: (a) Kopecky, D. J.; Rychnovsky, S. D. J. Am. Chem. Soc.

2001, 123, 8420. (b) Wipf, P.; Reeves, J. T. Chem. Commun.

2002, 2066.

22. Paterson, I. Tetrahedron Lett. 1979, 1519.

23. Evans, D. A.; Dart, M. J.; Duffy, J. L.; Yang, M. G. J. Am.

Chem. Soc. 1996, 118, 4322.

24. Mitsunobu, O. Synthesis 1981, 1.

25. (a) Paterson, I.; De Savi, C.; Tudge, M. Org. Lett. 2001, 3,

3149. (b) Paterson, I.; De Savi, C.; Tudge, M. Org. Lett. 2001,

3, 213.

26. Attempts to rationalise this outcome via molecular modelling

of 33 using the MM2 force ﬁeld in MacroModel have, as yet,

proved inconclusive. Mohamadi, F.; Richards, N. G. J.; Guida,

W. C.; Liskamp, R.; Lipton, M.; Cauﬁeld, C.; Chang, G.;

Hendrickson, T.; Still, W. C. J. Comput. Chem. 1990, 11, 440.

27. Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett.

1975, 4467.

8. For the synthesis of various leucascandrolide fragments, see:

(a) Crimmins, M. T.; Carroll, C. A.; King, B. W. Org. Lett.

2000, 2, 597. (b) Wipf, P.; Uto, Y. J. Org. Chem. 2000, 65,

1037. (c) Wipf, P.; Graham, T. H. J. Org. Chem. 2001, 66,

3242. (d) Dakin, L. A.; Langille, N. F.; Panek, J. S. J. Org.

Chem. 2002, 67, 6812. (e) Kozmin, S. A. Org. Lett. 2001, 3,

755.

28. Jefford, C. W.; Rossier, J.-C.; Boukouvalas, J.; Huang, P. Helv.

Chim. Acta 1994, 77, 661.

9. (a) Paterson, I.; Gibson, K. R.; Oballa, R. M. Tetrahedron Lett.

1996, 37, 8585. (b) Paterson, I.; Collett, L. A. Tetrahedron

Lett. 2001, 42, 1187.

´

10. Evans, D. A.; Coleman, P. J.; Cote, B. J. Org. Chem. 1997, 62,

788.

29. Banﬁ, L.; Guanti, G.; Basso, A.; Eur, J. Org. Chem. 2000, 939.

30. Langille, N. F.; Dakin, L. A.; Panek, J. S. Org. Lett. 2002, 4,

2485.

11. Dossetter, A. G.; Jamison, T. F.; Jacobsen, E. N. Angew.

Chem. Int. Ed. 1999, 38, 2398.

31. For copies of NMR spectra, see the supporting information for

Ref. 5.

Article Doi

A fully stereocontrolled total synthesis of (+)-leucascandrolide A

DOI: 10.1016/S0040-4020(03)00814-7

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Article abstract of DOI:10.1016/S0040-4020(03)00814-7

Full text of DOI:10.1016/S0040-4020(03)00814-7

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