Synthesis of simplified analogues of eleutherobin via a Claisen rearrangement/RCM strategy

Tetrahedron: Asymmetry 20 (2009) 921–944

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Tetrahedron: Asymmetry

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Synthesis of simpliﬁed analogues of eleutherobin via a Claisen

rearrangement/RCM strategy

S. Y. Frankie Mak ^a, Gary C. H. Chiang ^a, James E. P. Davidson ^a, John E. Davies ^a, Andrew Ayscough ^b,

a,d,

Gilles Pain ^b, Jonathan W. Burton ^a,c,, Andrew B. Holmes

*

^aDepartment of Chemistry, University of Cambridge, Lensﬁeld Road, Cambridge CB2 1EW, UK

^bBritish Biotech Pharmaceuticals Ltd, Watlington Road, Oxford, UK

^cChemistry Research Laboratory, University of Oxford, Mansﬁeld Road, Oxford OX1 3TA, UK

^dSchool of Chemistry, Bio21 Institute, University of Melbourne, Victoria 3010, Australia

a r t i c l e i n f o

a b s t r a c t

Article history:

The enantioselective synthesis of a number of simpliﬁed analogues of the cytotoxic natural product eleu-

therobin is reported.

Received 18 February 2009

Accepted 4 March 2009

Available online 22 April 2009

Special edition of Tetrahedron: Asymmetry

in honour of Professor George Fleet’s 65th

birthday

1. Introduction

rare alcyanoacean Eleutherobia sp. of coral),²has made eleutherobin

the subject of intensive synthetic research.

Eleutherobin 1, a diterpenoid ﬁrst isolated in 1995 by Fenical

et al.¹from the rare alcyonacean Eleutherobia sp., found in Western

Australia is a potent anti-mitotic compound with an IC₅₀range of

10–15 nM in vitro against a number of human tumour cell lines.^1,2

The total synthesis of eleutherobin has been accomplished inde-

pendently by Nicolaou et al.^3,4and Danishefsky et al.^5,6, from

which valuable structure–activity relationship (SAR) data for

eleutherobin 1 and related ‘eleuthesides’ were obtained. A formal

synthesis of eleutherobin has been reported by Gennari et al.^7,8

and many other synthetic endeavours have also been reported.⁹

Work by Andersen et al. also provided interesting information

regarding the antimitotic pharmacophore of eleutherobin.¹⁰All

of these biological evaluation studies suggested that the C-8

urocanic acid side chain, the C-4 acetal and the C-15 arabinose

domain are important determinants for antimitotic activity. The

C-4/C-7 ether bridge of the sarcodictyins (natural products with

very close structural homology to eleutherobin) was also sug-

gested to be a key hydrogen bond acceptor in the pharmaco-

phore model proposed by Giannakakou.¹¹We have recently

TM

Although structurally dissimilar to Taxol , it has been shown that

eleutherobin has the same mode of cytotoxic action, namely micro-

tubule stabilisation and mitotic arrest of the cancerous cells.²Epo-

thilones A and B, discodermolide, the sarcodictyins, laulimalide,

peluroside and dictyostatin are other members of this emerging

class of anti-cancer compounds. Apart from its impressive cytotoxic

properties, eleutherobinalsopossesses interestingstructural motifs,

including the C-4/C-7-bridged oxabicycle, the arabinose domain and

theurocanicacidsidechain. All thesefactors, togetherwithitsscarce

availabilityfromnaturalsources (0.01–0.02%of thedry weightof the

O

reported the synthesis of two eleutherobin analogues

2 and

16

11

O

3¹²which exhibited microtubule stabilising properties in the

micromolar range even though they lacked the methyl acetal

and arabinose domains of the natural product and, for com-

pound 2, the urocanic acid ester, suggesting that biological activ-

ity may be due to the [6.2.1]-bicyclic ether itself. Herein we

report full details of the synthesis of the [6.2.1]-bicyclic ethers

2 and 3. We also report the synthesis of a number of other com-

pounds related to the [6.2.1]-bicyclic core of eleutherobin includ-

ing analogues in which the bridging oxygen is on either face of

the bicyclic structure. Additionally we report a number of inter-

esting aspects of the chemistry of medium-ring ethers and doc-

ument the difﬁculty of forming [6.2.1]-bicyclic ethers, containing

8

9

NMe

H

17

N

6

5

12

13

10

7

O

3

14

18

1

O

4

OR

O

OMe

H

2

H

15

O

20

OAc

19

2; R = H

3; R =

OH

O

NMe

1

N

* Corresponding authors. Tel.: +44 1865 285119; fax: +44 1865 285002 (J.W.B.).

E-mail addresses: jonathan.burton@chem.ox.ac.uk (J.W. Burton), aholmes@

unimelb.edu.au (A.B. Holmes).

doi:10.1016/j.tetasy.2009.03.010

922

S. Y. Frankie Mak et al. / Tetrahedron: Asymmetry 20 (2009) 921–944

a C-4 methyl acetal (eleutherobin numbering), using ring-closing

metathesis (RCM).

2. Results and discussion

Our previous studies towards medium-ring oxacycles has in-

volved exploiting the Claisen rearrangement of a vinyl-substituted

ketene-acetal (e.g., 4) to deliver a medium-ring lactone (e.g., 5),^13,14

a reaction originally reported by Petrzilka for the synthesis of a 10-

membered lactone (Fig. 1).¹⁵For this work our synthetic strategy

involved the conversion of a medium-ring lactone into the corre-

O

OTBDPS

9

sponding 2,9-divinyl

D

⁵-oxonene 6 which would undergo ring-

closing metathesis to deliver the desired [6.2.1]-bicyclic ether 7;

a strategy we had successfully employed in the synthesis of the

bicyclic ethers 2 and 3.¹²

Figure 2. X-ray crystal structure of the enol ether 9 showing 50% probability

ellipsoids.

Claisen

O

rearrangement

one another as evidenced by an NOE between H-2 and H-9 which

was absent in the minor diastereomer 10b. The mixture of sele-

nides 10 was readily converted into the aldehyde 11¹⁸by a se-

quence involving: oxidation of the selenides to the corresponding

selenoxides, Pummerer rearrangement and basic methanolysis.

Aldehyde 11 was isolated as a single diastereomer. The cis-conﬁg-

uration of the C-2 and C-9 side chains in 11 was assigned by X-ray

crystallography of a later intermediate (epoxide 19b) and is consis-

tent with previous experience regarding the base-catalysed equil-

ibration of related 2,9-disubstituted medium-ring ethers.^23,24

Wittig methylenation of aldehyde 11 proceeded without inci-

dent to give diene 12. The primary silyl-protecting group of 12

was selectively removed with buffered pyridinium hydroﬂuoride;

the use of TBAF resulted in the removal of both silyl-protecting

groups. Oxidation²⁵of the resulting primary alcohol 13 and subse-

quent Wittig methylenation gave the ﬁrst RCM substrate 14.

RCM

R'

R' = H or OMe

O

₂O

9

O

R'

OR

O

OR

4

5

6

7

Figure 1. Synthetic strategy.

2.1. Synthesis of ﬁrst-generation analogues

The synthesis of the ﬁrst analogues 2 and 3 began from the

previously reported nine-membered lactone 8,^16,17available in

multi-gram quantities from 2-deoxy-D-ribose using a Claisen rear-

rangement to form the nine-membered lactone. The lactone 8 was

converted into the known aldehyde 11 using the previously re-

ported sequence (Scheme 1).¹⁸Thus, methylenation of the lactone

8 with dimethyl titanocene^19,20gave the corresponding enol ether

9 the structure of which was conﬁrmed by single crystal X-ray

analysis (Fig. 2).²¹

Exposure of the

D

⁵-oxonene 14 to the ﬁrst-generation Grubbs’

catalyst 17²⁶for 18 h at room temperature gave the desired

[6.2.1]-oxabicyclic ether 15 in 69% yield, along with the bis-cyclo-

pentene 16 (Scheme 2). Ethers 15 and 16 were readily distin-

guished by ¹H NMR TOCSY experiments which conﬁrmed that

the bridged bicyclic ether 15 contained a single spin system

whereas the bis-cyclopentene 16 contained two isolated spin sys-

tems. The structure of 15 was conﬁrmed by X-ray crystal structure

of a later intermediate, alcohol 2.¹²

O

₂O ₉

O

(ii)

OTBDPS

+

H

X

PhSe

nOe

OTBDPS

PhSe

OTBDPS

8; X = O

(i)

10a

10b

(iii)-(v)

9; X = CH₂

TBDPS O

(i) or (ii)

O

+

(viii), (ix)

(vii)

OTBDPS

(iii)

OTBDPS

O

₂O

9

OTBDPS

14

15

NMes

16

X

OH

MesN

14

13

11; X = O

(vi)

PCy₃

12; X = CH₂

Cl

Ru

PCy₃

17

Ru

PCy₃

Ph

Scheme 1. Elaboration of the lactone 8. Reagents and conditions: (i) Cp₂TiMe₂,

reﬂux, 66%; (ii) PhSeCl, then LiAlH₄, THF, ꢀ78 °C, 10a:10b, 3:1, 45%; (iii) m-CPBA,

THF, ꢀ78 °C; (iv) NaOAc, Ac₂O, THF, reﬂux; (v) K₂CO₃, MeOH/CH₂Cl₂, 81% from 10;

(vi) nBuLi, MePPh₃^þBr^ꢀ, ꢀ78 °C, THF, 90%; (vii) HFꢁpyridine, pyridine, THF, 89%;

(viii) IBX, DMSO, 94%; (ix) nBuLi, MePPh₃^þBr^ꢀ, ꢀ78 °C, THF, 93%.

18

Scheme 2. RCM of the oxonene 14. Reagents and conditions: (i) 5 mol % 17, CH₂Cl₂,

rt, 18 h, 15 69%, 16 22%; (ii) 5 mol % 18, CH₂Cl₂, 40 °C, 15 25%, 16 25%; (iii) 10 mol %

17, CH₂Cl₂, rt, 3 days, <20% conversion.

The addition of phenylselenyl chloride to the enol ether and

subsequent reduction with lithium aluminium hydride^18,22gave

selenides 10 as a 3:1 mixture of diastereomers which could be sep-

arated by HPLC. The conﬁguration of the diastereomers was as-

signed on the basis of a ¹H NMR NOESY experiment. Thus, in the

major diastereomer 10a the C-2 and C-9 side chains are cis to

In order to determine whether or not the bis-cyclopentene 16

was formed directly from triene 14 or from the bicyclic ether 15,

the latter was re-exposed to the reaction conditions with catalyst

17. ¹H NMR analysis of the reaction mixture after three days at

room temperature showed only 20% conversion of the bicycle 15

into the bis-cyclopentene 16, suggesting that 16 was directly

S. Y. Frankie Mak et al. / Tetrahedron: Asymmetry 20 (2009) 921–944

923

formed from triene 14 more rapidly than from the bicyclic ether

15. Exposure of the

⁵-oxonene 14 to the second-generation Grub-

synthesised above. Although this newly developed route was less

efﬁcient than the original route to the synthesis of [6.2.1]-bicyclic

ether 15, it served independently to conﬁrm the assignments of the

major and minor products of the RCM of the triene 14 as well as

eliminated the undesired ring-opening/ring-closing metathesis

pathway of the same substrate.

Completion of the synthesis of the ﬁrst eleutherobin analogue

was accomplished as follows. Deprotection of the silyl group in

15 with TBAF revealed the crystalline secondary alcohol 2 whose

X-ray structure has been reported previously.¹²The secondary

alcohol 2 was coupled with the mixed anhydride 22 thus complet-

ing the synthesis of the ﬁrst eleutherobin analogue 3.

D

bs’ catalyst 18²⁷resulted in the formation of a ca. 1:1 mixture of 15

and 16 in a combined yield of 50%. The change in the product ratio

could be attributed to the higher activity of the second-generation

catalyst 18, favouring the equilibration of the strained [6.2.1]-bicy-

clic ether 15 to the thermodynamically more stable bis-cyclopen-

tene 16.

We explored an alternative route to the [6.2.1]-bicyclic ether

which involved protection of the endo-cyclic alkene in 14 to cir-

cumvent its involvement in the metathesis reactions. Treatment

of the diene 13 with mCPBA gave a 3:1 separable mixture of diaste-

reomeric epoxides 19 (Scheme 3). The relative conﬁguration of the

major diastereomer, epoxide 19b, was determined by single crystal

X-ray analysis (Fig. 3).²¹

2.2. Studies towards second-generation analogues

2.2.1. Substrate synthesis

Having successfully completed the synthesis of alcohol 2 and

ester 3, we decided to prepare the corresponding analogues 23

and 24 bearing a methylacetal at C-4 (eleutherobin numbering,

Fig. 4). This was to be achieved by methoxyselenation of an exo-

cyclic enol ether—a transformation we had previously demon-

strated in the eight-membered lactone series.²²We were mindful

of the fact that an allylic oxygen functionality is frequently detri-

mental to RCM²⁹and that methyl ethers in particular had been

shown to be poor substrates for such reactions.³⁰The RCM of ace-

tal-containing substrates such as 6 (R⁰= OMe) to form [6.2.1]-bicy-

clic ethers such as 23 and 24 was therefore likely to be very

challenging. However, we were encouraged by reports that homo-

allylic alcohols³¹can be good substrates for RCM reactions. We

therefore elected to synthesise a range of substrates (e.g., 6,

R⁰= OMe) to determine whether they would undergo RCM to give

the desired [6.2.1]-bicyclic acetals (e.g., 23).

O

(i)

+

O

OTBDPS

OH

OTBDPS

OH

13

19a

19b

(ii), (iii)

O

(v)

(iv)

O

OTBDPS

15

21

20

(vi)

O

(vii)

O

OH

O

NMe

O

N

O

tBu

O

NMe

N

2

3

22

O

OH

O

NMe

MeO

N

Scheme 3. Synthesis of analogue 3. Reagents and condition_ꢀs: (i) mCPBA, THF, 0

°C?rt, 19a 17%, 19b 63%; (ii) IBX, DMSO, 73%; (iii) MePPh₃^þBr , nBuLi, THF, ꢀ78 °C,

98%; (iv) 5 mol % 17, CH₂Cl₂, rt, 86%; (v) WCl₆, nBuLi, ꢀ78 °C?rt, 53%; (vi) TBAF,

THF, 0 °C?rt, 61%; (vii) 22, DMAP, Et₃N, THF, 50%.

23

24

Figure 4. Second-generation analogues.

Due to the incorporation of a potentially acid-sensitive methyl

acetal in the proposed synthetic intermediates we decided to begin

the second-generation analogue synthesis with the known differ-

entially protected lactone 25³²such that the primary TBDPS group

could be removed selectively under basic conditions. Lactone 25

was readily converted into enol ether 26 which on treatment with

phenylselenyl chloride in methanol gave a separable 3:1 mixture of

acetals 27 (Scheme 4).²²The major acetal 27b was readily con-

verted into aldehyde 29 using the sequence of reactions which

was analogous to that used for the synthesis of aldehyde 11. Meth-

ylenation of aldehyde 29 gave alkene 30, which provided crystals

suitable for X-ray analysis thus conﬁrming the stereochemical

assignment of acetals 27 (Fig. 5).²¹

O

OTBDPS

OH

19b

Acetal 30 was readily converted into the RCM precursor 31

using standard procedures. Triene 31 could also be synthesised

using the following sequence: reduction of the selenides 28 with

lithium aluminium hydride;²²removal of the silyl group to give

diol 32; double Swern oxidation³³of the diol 32 to give dialdehyde

33 and double methylenation of the dialdehyde to give triene 31.

Mindful of the possibility of participation of the endo-cyclic alkene

in 31 in the proposed RCM reactions we treated the alkene 31 with

mCPBA which gave a single epoxide 34 presumed to have the con-

ﬁguration shown by analogy with the epoxidation of 13.

Figure 3. X-ray structure of the epoxide 19b showing water of crystallisation (50%

probability ellipsoids).

Epoxide 19b was oxidised (IBX)²⁵and the resulting aldehyde

was methylenated to give the second RCM precursor 20. Diene

20 was treated with the ﬁrst-generation Grubbs’ catalyst 17²⁶in

dichloromethane to give the desired ring-closed product 21 in

86% yield. Epoxide removal was accomplished using the Sharpless

protocol²⁸to give the [6.2.1]-bicyclic ether 15, identical to that

924

S. Y. Frankie Mak et al. / Tetrahedron: Asymmetry 20 (2009) 921–944

As noted above, given the profound effect that allylic and homo-

allylic substituents can have on alkene metathesis reactions, we at-

tempted to remove the benzyl group from ether 31 to give the

corresponding secondary alcohol. Disappointingly under a range

of conditions (LiDBB,³⁴DDQ), the deprotection failed. We therefore

returned to the bis-silyl-protected exo-cyclic enol ether 9 and con-

verted it into a partly separable 3:1 mixture of selenides 37

(Scheme 6); the conﬁguration of the major diastereomer of 37a

was assigned by X-ray crystallography of a later intermediate, lactol

42. Selenides 37 were converted into a separable mixture of the

aldehydes 39 as before, and the major diastereomeric aldehyde

39a was methylenated to give the terminal alkene 40. Attempted

removal of the primary silyl group in 40 with buffered pyridinium

hydroﬂuoride resulted in decomposition of the substrate conﬁrm-

ing our concerns regarding the acid lability of substrates containing

a methyl acetal. We postulated that methyl acetal 39a would be less

acid sensitive due to the adjacent carbonyl group. This was born out

by experiment. Thus, exposure of aldehyde 39a to buffered pyridi-

nium hydroﬂuoride removed both silyl-protecting groups to give an

equilibrium mixture of aldehyde 41 and the lactol 42 (1:10 ratio,

40%); the deprotection could also be accomplished in 59% using

TBAF. Lactol 42 was crystallised from CHCl₃and its structure was

conﬁrmed by single crystal X-ray analysis (Fig. 6).²¹

(ii)

O

+

OBn

MeO

PhSe

MeO

OTBDPS PhSe

X

OTBDPS

25; X = O

OTBDPS

27b

27a

(i)

26; X = CH₂

(iii), (iv)

(vi)

(v)

O

OBn

MeO

30

MeO

O

MeO

OTBDPS

PhSe

OTBDPS

OAc

29

28

(vii)-(ix)

(x), (xi)

(xiii)

(xii)

O

OBn

(xiv)

OBn

O

OBn

OH

MeO

31

MeO

O

MeO

HO

32

33

O

OBn

MeO

34

(i)

O

9

+

OTBDPS

Me O

PhSe

MeO

PhSe

Scheme 4. Preparation of metathesis substrates. Reagents and conditions: (i)

Cp₂TiMe₂, PhMe, reﬂux, 86%; (ii) PhSeCl, Et₃N, MeOH, THF, 27a:27b, 1:3 72%; (iii)

NaHCO₃, NaIO₄, MeOH, CH₂Cl₂, H₂O; (iv) NaOAc, Ac₂O, THF, reﬂux; (v) K₂CO₃,

MeOH, CH₂Cl₂; 73% from 27b; (vi) NaH, DMSO, MePPh₃^þBr^ꢀ, 85%; (vii) TBAF, TH_ꢀF,

0 °C?rt, 99%; (viii) TPAP, NMO, CH₂Cl₂, 4 Å MS, 93%; (ix) NaH, DMSO, MePPh₃^þBr ,

85%; (x) LiAlH₄, THF, 0 °C, 55% from 27b; (xi) TBAF, THF, 0 °C?rt; 89%; (xii) (COCl)₂,

DMSO, CH₂Cl₂, then Et₃N, 92%; (xiii) Tebbe reagent, THF, ꢀ40 °C?rt, 45%; (xiv)

mCPBA, CH₂Cl₂, 0 °C?rt, 57%.

37b

37a

(ii), (iii)

(iv)

OTBDPS

+

O

OTBDPS

MeO

O

Me O

O

MeO

OTBDPS PhSe

38

OTBDPS

39a

OTBDPS

OAc

(v)

39b

(vi)

O

OBn

O

OTBDPS

OH

MeO

O

Me O

HO

OTBDPS

30

O

40

41

42

Scheme 6. Synthesis of the lactol 42. Reagents and conditions: (i) PhSeCl, Et₃N,

MeOH, THF, 37a:37, 3:1, 44%; (ii) NaHCO₃, NaIO₄, MeOH, CH₂Cl₂, H₂O; (iii) NaOAc,

Ac₂O, THF,_ꢀreﬂux; (iv) K₂CO₃, MeOH, CH₂Cl₂, 63% from 37; (v) NaH, DMSO,

MePPh₃^þBr , 76%; (vi) TBAF, THF, 0 °C?rt, 41:42, 1:10, 59%.

Figure 5. X-ray crystal structure of the acetal 30 showing 50% probability

ellipsoids.

(i)

(ii)-(v)

O

OBn

MeO

O

MeO

O

MeO

OTBDPS

29

35

36

O

OH

MeO

HO

Scheme 5. Synthesis of the oxonane 36. Reagents and conditions: (i) H₂, PtO₂,

EtOAc, 100%; (ii) NaH, DMSO, MePPh₃^þBr^ꢀ, 54%; (iii) TBAF, THF, 0 °C?rt, 81%; (iv)

TPAP, NMO, 4 Å MS, CH₂Cl₂, 86%; (v) NaH, DMSO, MePPh₃^þBr^ꢀ, 93%.

O

42

Additionally we prepared oxonane 36 from aldehyde 29 using

standard procedures (Scheme 5). Oxonane 36 would prevent the

formation of the undesired bis-cyclopentene by-products in the

RCM reactions.

Figure 6. X-ray crystal structure of the lactol 42 showing chloroform of crystal-

lisation (50% probability ellipsoids).

S. Y. Frankie Mak et al. / Tetrahedron: Asymmetry 20 (2009) 921–944

925

The lactol is another interesting eleutherobin analogue which

TBDPSO

MeO

(i) or (ii)

OTBDPS

possesses the key nine-membered ether and methylacetal but re-

places the ﬁve-membered ether with a six-membered lactol.

We ultimately succeeded in preparing the silyl-protected RCM

precursors 48 and 49a, and the unprotected RCM precursor 50

by starting from the known vinyl-substituted lactone 43 which

we had previously used in a formal synthesis of ent-obtuse-

nyne.³⁵The vinyl-substituted lactone 43 was converted into a

6:1 inseparable mixture of selenides 45 using the previously

developed procedure (Scheme 7); the conﬁguration of the major

diastereomer was tentatively assigned as 45a on the basis of

precedent from the synthesis of the selenides 27. A Pummerer

rearrangement²²of the selenoxides derived from the selenides

45 gave the corresponding acetates 46 as an inseparable mixture

of diastereomers, which were converted into a 6:1 inseparable

mixture of diastereomeric aldehydes 47. Methylenation of the

O

HO

MeO

R

54

55

48; R = H

49a; R = Me

(ii)

O

OTBDPS

Me O

49b

Scheme 8. Attempted RCM reactions. Reagents and conditions: (i) 5 mol % 17,

CH₂Cl₂, 52% from 49a; 30% from 48; (ii) 5 mol % 18, CH₂Cl₂, 45 °C, 50% from 49a, 35%

from 49b, 50% from 48.

none of them yielded the desired [6.2.1]-bicyclic acetals corre-

sponding to 23 when exposed to either Grubbs’ ﬁrst- or second-

generation catalysts, 17 or 18. For example, exposure of the ben-

zyl-protected triene 31 to Grubbs’ I at room temperature or 40 °C

resulted in recovery of starting material whereas the use of Grubbs’

II resulted in decomposition of the substrate. Disappointingly sub-

strate 34 (with the endo-cyclic double bond protected as an epox-

ide) returned only starting material on exposure to either Grubbs’ I

or Grubbs’ II in dichloromethane at reﬂux. Similarly, oxonane 36

was inert to exposure to Grubbs’ II whereas using the highly active

catalyst 53³⁶resulted in the decomposition of the substrate. One

possible explanation for the lack of reactivity of the benzyl-pro-

tected substrates is the formation of a stable ruthenium chelate

(e.g., 52), which shuts down the metathesis reaction. Unfortunately

the addition of titanium(IV) iso-propoxide to the metathesis reac-

tion with the epoxide 34, as recommended by Fürstner,³⁷still re-

sulted in the recovery of starting material.

(ii)

O

+

O

OTBDPS

MeO

PhSe

MeO

PhSe

X

43; X = O

45b

45a

(i)

(iii), (iv)

44; X = CH₂

(v)

O

2

OTBDPS

MeO

PhSe

MeO

O

OAc

47

46

(vi) or

(vii)

O

H

nOe

(viii)

nOe

O

OTBDPS

MeO

R

MeO

H

MesN

Cl

NMes

48; R = H

51

O

(ix)

49a; R = Me

Ru

iPrO

PrO

OBn

[Ru]

i

O

Me O

OH

MeO

52

53

50

The replacement of the benzyloxy group in substrates 31 and 34 by

a weakly coordinating silyloxy group would potentially alleviate the

proposed problem. However, exposure of either of the trienes 48 or

49a to Grubbs’ I or II did not give the desired [6.2.1]-bicyclic acetal

but rather gave the cyclopentene 55 in moderate yield (Scheme 8).

The cyclopentene 55 most probably arises by a ring-opening/ring-

closing metathesis sequence analogous to that observed for the

oxonene 14, giving the bis-cyclopentene 54 as an intermediate

which then undergoes hydrolysis in situ to deliver product 55. Sim-

ilarly the diastereomeric acetal 49b also yielded cyclopentene 55 on

treatment with Grubbs’ II.

Epoxide 51 also proved unreactive in the metathesis reaction;

even with the highly active catalyst 53³⁶only starting material

was recovered from the reaction mixture. The secondary alcohol

50 was also investigated as a substrate for the RCM reaction with

Grubbs’ ﬁrst- and second-generation catalysts but only decomposi-

tion of the substrate was observed.

Scheme 7. Preparation of further metathesis substrates. Reagents and conditions:

(i) Tebbe reagent, DMAP, ꢀ40 °C?rt, 86%; (ii) PhSeCl, MeOH, Et₃N, THF, 45a:45b,

6:1, 56%; (iii) buffered NaIO₄, MeOH, CH₂Cl₂, H₂O; (iv) NaOAc, Ac₂O, THF, reﬂux; (v)

K₂CO₃, MeOH, CH₂Cl₂, 6:1 mixture of C-2 diastereomers, 78% from 45; (vi) NaH,

DMSO, MePPh₃^þBr^ꢀ, 64%; (vii) KHMDS, EtPPh₃^þBr^ꢀ, THF, ꢀ78 °C?rt; 49a 51%, 49b

9%; (viii) mCPBA, THF, 0 °C, 65%; (ix) TBAF, THF, 0 °C?rt, 75%.

mixture of aldehydes 47 gave the trienes 48 which were isolated

as a 10:1 mixture of diastereomers (major diastereomer shown);

propenylation of the mixture of aldehydes 47 gave the corre-

sponding trienes from which the diastereomers 49a (shown in

Scheme 7) and 49b (shown in Scheme 8) could be isolated in

pure form. Triene 48 was exposed to mCPBA to give the epoxide

51 as a single diastereomer; the structure of 51 was assigned

using a ¹H NMR NOESY experiment. The silyl group was re-

moved from the triene 49 thus providing the alcohol 50 for fur-

ther RCM experiments.

Attempts to effect the RCM of substrates bearing methyl acetals

to give [6.2.1]-bicyclic acetals had universally failed regardless of

the protecting group or the presence of additives such as tita-

nium(IV) iso-propoxide. This observation is in accordance with

the studies of Hoye and others which report the difﬁculty which

2.2.2. Ring-closing metathesis studies

We had invested signiﬁcant synthetic effort in the preparation

of a good number of RCM precursors. We were disappointed that

926

S. Y. Frankie Mak et al. / Tetrahedron: Asymmetry 20 (2009) 921–944

can be encountered when trying to effect RCM of allylic methyl

ethers.^29,30The exact explanation for the recalcitrant nature of

these substrates under RCM conditions is not clear, but it further

highlights the ﬁne balance of allylic and homoallylic substituents

which is required in order to effect successful RCM with challeng-

ing substrates.³¹We also attempted to form the desired [6.2.1]-

bicyclic methyl acetals by pinacol and McMurry couplings of the

dialdehyde 33, as well as investigated tandem methylenation/

RCM of the dialdehyde using the Tebbe reagent or dimethyl titano-

cene. All the above reactions were also unsuccessful.

propyl-substituted enol ether 64 was occasionally isolated as a

minor side product during methylenation of the lactone 63 and it

most probably arises from hydrolysis of a titanacyclobutane

formed by cycloaddition of the titanium carbene with the terminal

oleﬁn in enol ether derived from 63.

We had previously investigated the intramolecular hydrosila-

tion of a number of closely related medium-ring exo-cyclic enol

ethers and had been unable to predict the stereochemical outcome

of these reactions.^{18,22,32,35,41}We screened a large number of cata-

lysts and reaction conditions in the intramolecular hydrosilation of

the enol ether 65. Ultimately we found that exposure of the silane

to 1 equiv of (Me₂SiH)₂NH and 3 mol % of platinum bis(1,3-divinyl-

1,1,3,3-tetramethylsiloxane)⁴²catalyst gave the diols 66 as an

inseparable 1:1 mixture of diastereomers after Tamao–Fleming

oxidation (Scheme 10).^43,44The mixture of diols was converted

into the p-methoxybenzylidene acetals 67, which were separated

and hydrolysed back to the corresponding diols for characterisa-

tion purposes.

The relative conﬁguration of diols 66 was assigned on the bases

of ¹H NMR COSY and NOESY experiments coupled with molecular

modelling analysis⁴⁵of the more polar acetal which indicated that

it had the structure 67b derived from the cis-diol 66b (Fig. 8). The

less polar acetal derived from the mixture of diols was presumed to

have the structure 67a; however, full ¹H NMR assignment was

hampered by overlapping resonances. The structure of the diol

66a and hence that of the acetal 67a were conﬁrmed based on that

of a later synthetic intermediate, the diol 80.

2.3. Synthesis of further eleutherobin analogues

The failure of RCM reactions with the allylic methyl acetals re-

quired a redesign of the synthetic route such that the methyl acetal

could potentially be incorporated after formation of the [6.2.1]-

bicyclic structure. Our target became the [6.2.1]-bicyclic ketone

56 (Fig. 7). The formation of the bridgehead enolate³⁸from 56 fol-

lowed by oxidation would install the requisite bridgehead hemi-

acetal which could then be converted into the necessary methyl

acetal. The ketone would be prepared by the RCM of the triene

57 which would in turn be prepared from diol 58, which itself

would be available from the vinyl-substituted lactone 43 by an

enolate oxidation/methylenation/intramolecular hydrosilation se-

quence which we had developed previously.^22,32,35This sequence

also lends itself to the possibility of forming a [6.2.1]-bicyclic

methyl acetal 59 from the corresponding endo-cyclic enol ether

60 which would be available by elimination from the correspond-

ing b-alkoxy aldehyde derived from the diol 58.

Acetal 67b was rapidly processed into the RCM substrate 70

using standard procedures (Scheme 11). Exposure of the triene

Lactone 43³⁵readily underwent enolate oxidation with the

Davis oxaziridine to deliver alcohol 62 as a single diastereomer

(Scheme 9). The conﬁguration of the newly installed stereocentre

in 62 was assigned on the basis of precedent from the oxidation

of closely related substrates^32,35and was conﬁrmed by NOE mea-

surements and NMR analysis of later intermediates. Protection of

the newly installed alcohol, methylenation of the lactone^39,40and

silyl group exchange gave the hydrosilation substrate 65. The iso-

(i)

O

+

O

HO

65

OTBDPS

66a

66b

(ii)

H

O

H

O

OTBDPS

H

PMP

O

67a

67b

O

43

O

P'O

HO

OP

Scheme 10. Reagents and conditions: (i) 3 mol % Pt[(CH₂@CHSiMe₂)₂O]₂,

(Me₂SiH)₂NH, toluene then H₂O₂, THF, MeOH, water, 66a:66b, 1:1, 70%; (ii)

MeOC₆H₄CH(OMe)₂, PTSA, toluene, 90 °C, 67a 39%, 67b 42%.

56

57

58

HO

O

OP

60

OP

MeO

59

61

H

O

Figure 7. Retrosynthesis of the ketone 56.

O

OTMS

H

Ph

O

2.40

2.43

1.99

67b-TMS

2.41

(i)

(iii)-(v)

predicted measured

O

H

O

43

RO

OTBDPS

O

Si

OTBDPS

J_{11a, 4a}

1.6 Hz

2.2 Hz

H

O

11

H

OTBDPS

H

O

J_{4a, 4ax}

2.4 Hz

1.8 Hz

62; R = H

65

O _11a

6

(ii)

63; R = TMS

4a

H

PMP

J_{4a, 4eq}

J_{11a, 11}

1.7 Hz

1.0 Hz

10.0

O

H

4

O

TMSO

OTBDPS

10.7 Hz

67b

64

J_{11a, 11'}

6.8 Hz

6.3 Hz

Scheme 9. Elaboration of the lactone 43. Reagents and conditions: (i) KHMDS, THF,

ꢀ78 °C then ( )-2-(phenylsulfonyl)-3-phenyloxaziridine, then ( )-camphor-10-

sulfonic acid, 62%; (ii) TMSCl, Et₃N, THF, 89%; (iii) Tebbe reagent, DMAP, ꢀ40 °C?rt,

76–89%; (iv) TBAF, THF, 0 °C?rt, 76%; (v) (Me₂SiH)₂NH, NH₄Cl, 65 °C, 100%.

Figure 8. Global minimum conformation of 67b-TMS corresponding to the acetal

TBDPS-analogue 67b. The distances on the molecular model are in Ångstrom.

Selected ¹H NMR NOE correlations are shown on structure 67b. Coupling constants

were calculated using the Altona equation.

S. Y. Frankie Mak et al. / Tetrahedron: Asymmetry 20 (2009) 921–944

927

with TPAP⁴⁶delivered a second [6.2.1]-bicyclic ketone 77 with

the bridging oxygen on the opposite face of the [6.2.1]-bicycle

compared with the ketone 75.

(i)

(ii)

O

PMBO

HO

PMBO

67b

OTBDPS

(iii)

OTBDPS

We aimed to use the trans-diol 66a resulting from the hydrosi-

lation/oxidation of silane 65 for the synthesis of the enol ether

corresponding to 61. The benzylidiene acetal 67a, underwent reg-

ioselective cleavage with DIBAL-H⁴⁷and oxidation⁴⁶to give alde-

hyde 78 (Scheme 13). Aldehyde 78 was methylenated to give the

divinyl-substituted oxonene 79 in good yield. Double deprotection

of the divinyl oxonene 79 delivered the diol 80 which had a non-

X

69; X = O

70; X = CH₂

68

(iv)

OPMB

+

O

zero speciﬁc rotation {½a _D²⁴

¼ þ155:0 (c 0.20, CHCl₃)} and six reso-

ꢂ

O

PMBO

OTBDPS

nances in the ¹³C NMR, indicating that it was C₂-symmetric and

thus conﬁrming the structure of diol 66a. Not surprisingly expo-

sure of triene 79 to Grubbs’ second-generation catalyst 18²⁷deliv-

ered the corresponding bis-cyclopentene 81 in low yield along

with recovered starting material. Ring-closing metathesis of 79

would have resulted in the formation of a thermodynamically

unfavoured ‘inside–outside’ [6.2.1]-bicyclic ether.⁴⁸

72

71

Scheme 11. Construction of the desired [6.2.1] oxabicyclic motif 72. Reagents and

conditions: (i) DIBAL-H, CH₂Cl₂, ꢀ78?ꢀ10 °C; (ii) TPAP, NMO, 4 Å MS, CH₂Cl₂, 61%

from 67b; (iii) KHMDS, MePPh₃^þBr^ꢀ, THF, ꢀ78 °C?rt; 86%; (iv) 40 mol % 18, CH₂Cl₂,

45 °C, 72:71, 1:1, 88%.

Exposure of aldehyde 78 to pyrrolidine and PPTS gave an insep-

arable mixture of the desired eliminated product, starting material

and the cis-aldehyde 69, presumably formed by epimerisation of

the starting material (Scheme 14). Propenylation of the mixture

of aldehydes allowed separation of the desired enol ether 82. Treat-

ment of enol ether 82 with Grubbs’ second-generation catalyst²⁷

did not deliver the desired [6.2.1]-bicyclic enol ether but rather

delivered the [4.4.1]-bicyclic ether 83 in 76% yield, a structural mo-

tif present in a number of natural products.⁴⁹The [4.4.1]-bicyclic

ether 83 most probably arises via the formation of ruthenium

alkylidene 86, which undergoes metathesis to yield cyclopentene

87 (Fig. 9). The geometry of the enol ether precludes the formation

of a bis-cyclopentene (corresponding to 81) and instead the forma-

tion of the seven-membered ether 88 occurs followed by RCM to

deliver the product 83. This was, at ﬁrst sight, a surprising result;

however, it is likely that the [4.4.1]-bicyclic ether is thermodynam-

ically more stable than the corresponding [6.2.1]-bicyclic ether 85

due to the increased strain involved with placing a bridgehead

OPMB

OH

(i)

O

71 and 72

+

PMBO

74

OH

73

(iii)

(ii)

OTBDPS

O

HO

O

PMBO

OTBDPS

O

76

77

75

Scheme 12. Synthesis of the [6.2.1]-bicyclic ketones 75 and 77. Reagents and

conditions: (i) TBAF, THF, 0 °C?rt, 74 48%, 73 43%; (ii) TPAP, NMO, 4 Å MS, CH₂Cl₂,

75 66%, 77 89%; (iii) BCl₃ꢁSMe₂, CH₂Cl₂, 0 °C?rt, 51%.

70 to Grubbs’ second-generation catalyst in dichloromethane at re-

ﬂux gave the desired [6.2.1]-bicyclic ether 72 along with bis-cyclo-

pentane 71 as an inseparable 1:1 mixture in 89% yield.

double bond on

a

[6.2.1]-bicyclic system compared with a

OTBDPS

Treatment of the mixture of bicyclic structures 71 and 72 with

TBAF gave the corresponding separable secondary alcohols 73 and

74 (Scheme 12); ¹H NMR TOCSY experiments of the alcohols

conﬁrmed their structures showing that bicycle 74 consisted of a

single spin system while bis-cyclopentene 73 consisted of two

separate spin systems. Oxidation of the secondary alcohol 74 with

TPAP gave the desired [6.2.1]-bicyclic ketone 75 in 66% yield.

Treatment of the mixture of 71 and 72 with boron trichloride-di-

methyl sulﬁde complex gave the [6.2.1]-bicyclic alcohol 76 in

51% yield; none of the corresponding bis-cyclopentene derived

from 71 could be detected. Oxidation of the secondary alcohol 76

(iii)

(i), (ii)

O

78

O

OTBDPS

83

82

Scheme 14. Reagents and conditions: (i) Pyrrolidine, PPTS, Et₂O; (ii) KHMDS,

EtPPh₃^þBr^ꢀ, THF, ꢀ78 °C?rt, 23%; (iii) 40 mol % 18, CH₂Cl₂, 45 °C, 76%.

A

O

OTBDPS

[Ru]

OTBDPS

82

86

84

85

[Ru]

B

(i), (ii)

(iii)

O

[Ru]

67a

PMBO

OTBDPS

O

78

79

(iv), (v)

OH

O

(vi)

[Ru]

O

HO

OTBDPS

OPMB

87

88

OTBDPS

O

80

81

Scheme 13. Elaboration of the acetal 67a. Reagents and conditions: (i) DIBAL-H,

CH₂Cl₂, ꢀ78?ꢀ10 °C; (ii) TPAP, NMO, 4 Å MS, CH₂Cl₂, 86% from 67a; (iii) KHMDS,

MePPh₃^þBr^ꢀ, THF, ꢀ78 °C?rt; 84%; (iv) DDQ, CH₂Cl₂, water, 91%; (v) TBAF, THF,

66%; (vi) 10 mol % 18, CH₂Cl₂, 45 °C, 13%.

83

Figure 9. Proposed mechanism for the formation of the enol ether 83.

928

S. Y. Frankie Mak et al. / Tetrahedron: Asymmetry 20 (2009) 921–944

[4.4.1]-bicyclic system. Hence, even if the desired [6.2.1]-bicycle 85

did form in the metathesis reaction, it would likely undergo isom-

erisation to the thermodynamically more favoured [4.4.1]-bicyclic

ether 83. Molecular modelling⁴⁵of simpliﬁed analogues of the

[6.2.1]-bicyclic ether 85 and the [4.4.1]-bicyclic ether 83 where

the TBDPS group had been replaced by a TMS conﬁrmed that the

[4.4.1]-bicyclic ether was indeed more stable (ca. 20 kJ mol^ꢀ1) than

the corresponding [6.2.1]-bicyclic ether.

ried out under an atmosphere of dry nitrogen or argon. Solvents

were puriﬁed by standard techniques.

4.1.1. (8S,9R)-8-(tert-Butyldiphenylsilanyloxy)-9-(tert-butyldiphenyl-

silanyloxymethyl)-2-methylene-2,3,4,7,8,9-hexahydrooxonine 9

To a stirred solution of lactone 8,^16,17(410 mg, 0.62 mmol) in

toluene (10 mL), in the dark, was added a solution of dimethyltit-

anocene (4.0 mL of a 94 mg/mL solution in toluene, 1.8 mmol). The

solution was heated at reﬂux for 1 h, and was then allowed to cool

to ambient temperature. The solvent was removed in vacuo and

the resultant crude material was dissolved in 20:1 hexane–ether,

resulting in formation of a precipitate. This mixture was puriﬁed

by ﬂash chromatography (Brockmann grade III basic alumina; hex-

ane–ether, 20:1) yielding the enol ether 9 as a colourless gum that

crystallised on standing (274 mg, 66%) and could be recrystallised

from hot acetonitrile (ꢃ30 mg/mL, adding CH₂Cl₂dropwise until

dissolved and then allowing to cool overnight); mp 113.5–115

°C; (Found: C, 76.3; H, 8.1. C₄₂H₅₂O₃Si₂requires C, 76.31; H,

3. Conclusions

In conclusion, we have developed an efﬁcient route to the syn-

thesis of a number of protected [6.2.1]-bicyclic ethers, analogous to

the core of eleutherobin, by RCM of divinyl-substituted oxonenes.

Moreover, we have reported the full details of the transformation

of ether 15 into eleutherobin analogue 3.¹²We have also demon-

strated the difﬁculty in constructing [6.2.1]-bicyclic ethers con-

taining a methyl acetal using RCM. The analogues 75 and 77

contain the necessary functionality to allow their conversion into

the corresponding methyl acetals. A further analogue, the lactol

7.93); R_f0.48 (hexane–ether, 10:1); ½a _D²⁵

¼ ꢀ30:0 (c 0.43, CHCl₃);

ꢂ

m_max(CHCl₃)/cm^ꢀ11638; d_H(500 MHz; CDCl₃) 7.55–7.62 (8H, m,

Ar), 7.26–7.41 (12H, m, Ar), 5.51–5.57, (2H, m, H-5, H-6), 4.47

(1H, s, C@CHH), 4.08 (1H, t, J 7.1, H-9), 4.04 (1H, s,C @CHH), 3.88

(1H, dd, J 11.0, 1.6, CHHOSi), 3.78–3.81 (1H, m, H-8), 3.55 (1H,

dd, J 11.0 and 7.1, CHHOSi), 2.40–2.52 (2H, m, H-4 and H-7),

2.23–2.32 (1H, m, H-3), 2.16–2.23 (1H, m, H-3), 2.08–2.16 (1H,

m, H-7), 1.94–2.03 (1H, m, H-4), 1.00 and 0.99 [2ꢄ9H, s, C(CH₃)];

d_C(100 MHz; CDCl₃) 166.1 (C@CH₂), 135.9, 136.8, 135.7, 133.8,

133.5, 130.1, 129.6, 129.4, 127.6, 127.5, 127.2, 88.4 (C@CH₂), 86.4

(C-9), 73.0 (C-8), 65.9 (CH₂OSi), 32.7, 32.4, 27.0 and 26.8

[2 ꢄ C(CH₃)₃], 19.2 and 19.1 [2 ꢄ C(CH₃)₃]; m/z (CI; NH₃) 678

[(M+NH₄)⁺, 5%], 661 [(M+H)⁺, 100%]; [Found: (M+H)⁺, 661.353.

C₄₂H₅₃O₃Si₂requires M, 661.3533].

42, which contains a methyl acetal and the core

D

⁵-oxonene but

has a six-membered ring lactol in place of the dihydrofuran of

eleutherobin, has also been prepared. Unexpectedly, we also pre-

pared the [4.4.1]-bicyclic ether 83 in good yield from the enol ether

82, a structural motif present in a number of natural products.

Overall the studies reported not only give us access to a range of

novel bicyclic ethers but will also enable us to deﬁne a synthetic

route such that a total synthesis of eleutherobin itself may be ap-

proached with conﬁdence.

4. Experimental

4.1. General experimental

4.1.2. (2R,5Z,8S,9R)- and (2S,5Z,8S,9R)-8-tert-Butyldiphenylsil-

anyloxy)-9-(tert-butyldiphenylsilanyloxymethyl)-2-phenylsel-

anylmethyl-2,3,4,7,8,9-hexahydrooxonines 10a and 10b

¹H NMR spectra were recorded on Bruker DPX-250 (250 MHz),

DRX-400 (400 MHz) and DRX-500 (500 MHz) spectrometers.

Chemical shifts are quoted in ppm relative to tetramethylsilane

(d = 0 ppm) and are referenced to the solvent residual. Coupling

constants (J) are given in hertz. Where useful, the FID was zero

ﬁlled (128k) and sine-bell shifted (SSB = 30) prior to Fourier Trans-

formation in order to provide baseline resolved multiplets and, as a

result easily identiﬁable and measurable coupling constants. ¹³C

NMR spectra were recorded on Bruker DPX-250 (62.5 MHz, DRX-

400 (100 MHz) and DRX-500 (125 MHz) spectrometers in the sol-

vent mentioned above with proton decoupling. Chemical shifts

are quoted in ppm relative to tetramethylsilane (d = 0 ppm). The

attached proton test (APT) was used to assign signals in particular

cases. Infrared spectra were recorded in a Perkin–Elmer 1600 FT IR

spectrophotometer or on a Perkin–Elmer Spectrum One FT IR spec-

trophotometer coupled to a universal sampling accessory. The

sample was prepared by dropping a solution onto an IR diamond

lens and allowing the solvent to evaporate. Mass spectra were car-

ried out at the EPSRC Mass Spectrometry Service Centre, University

of Swansea, or the Department of Chemistry, University of Cam-

bridge. In Swansea, Electron Impact (EI) and Chemical Ionisation

(CI) low resolution mass spectra were carried out on a VG model

12-253 under ACE conditions and a Quattro II low resolution triple

Quadrupole MS. Accurate mass measurements for EI and CI were

performed on +VG ZAB-E and Finnigan MAT 900 XLT instruments.

In Cambridge, EI and CI low resolution and accurate mass spectra

were obtained on a KRATOS MS-890 and on a Micromass TOF

instrument. Electrospray mass spectra were determined with an

ES Bruker FTICR. Optical rotations were measured using a Per-

kin–Elmer 241 polarimeter. Melting points were measured on a

Koﬂer block and are uncorrected. Non-aqueous reactions were car-

A solution of phenylselenenyl chloride (122 mg, 0.63 mmol) in

THF (5 mL) was added dropwise to a stirred solution of enol ether

9 (200 mg, 0.3 mmol) in THF (10 mL) at ꢀ78 °C. After the addition

was complete, the solution was stirred for 5 min followed by the

dropwise addition of a solution of LiAlH₄(0.9 mL of a 1.0 M solu-

tion in THF, 0.9 mmol). After 5 min at ꢀ78 °C, the reaction mixture

was allowed to warm to ambient temperature over 2 h, and was

then quenched by the careful addition of saturated aqueous

ammonium chloride (10 mL) followed by water (10 mL). The layers

were separated, and the aqueous layer was extracted with ether

(3 ꢄ 10 mL), and the combined organic extracts were washed with

brine (20 mL) and dried (MgSO₄). The solvent was removed in va-

cuo and puriﬁcation by ﬂash chromatography (Brockmann grade III

basic alumina; light petroleum–ether, 25:1) yielded starting mate-

rial 9 (69 mg, 34%), and a mixture of the diastereomeric selenides

10 as a pale yellow oil (113 mg, 45%). For the purposes of charac-

terisation the selenides 10 were separated by HPLC (hexane–ether,

25:1?10:1). Data for 10a: (Found: C, 70.4; H, 7.1. C₄₈H₅₈O₃SeSi₂re-

quires C, 70.47; H, 7.15); R_f0.32 (hexane–ether, 10:1); ½a _D²⁵

¼ þ14:6

ꢂ

(c 0.43, CHCl₃); m

_max(CHCl₃)/cm^ꢀl3019s; d_H(500 MHz; C₆D₆) 7.19–

7.60 (25H, m, Ar), 5.48–5.58 (2H, m, H-5 and H-6), 3.88–3.92 (lH, m,

H-2), 3.68–3.70 (2H, m, H-8, CHHOSi), 3.45–3.52 (2H, m, H-9,

CHHSe), 3.38 (1H, dd, J 10.8, 7.6, CHHOSi), 2.88 (1H, dd, J 11.9, 9.5,

CHHSe), 2.38–2.48 (2H, m, H-4 and H-7), 1.86–2.01 (3H, m, H-3,

H-4, H-7), 1.48–1.54 (1H, m, H-3), 0.98 and 0.92 [2 ꢄ 9H, s,

C(CH₃)₃]; d_C(62.5 MHz; CDCl₃) 135.9, 135.8, 135.7, 133.9, 133.6,

133.5, 133.4, 132.2, 131.0, 130.3, 129.6, 129.5, 129.0, 127.6, 127.5,

127.2, 126.5, 85.8, 81.78, 73.5, 67.0, 33.1, 31.1, 30.8, 27.0 and

26.96 [C(CH₃)₃], 22.8, 19.2 and 19.1 [C(CH₃)₃]; m/z (ES, NH₃) 836

[(M+NH₄)⁺, 25%]; [Found (M+NH₄)⁺, 836.3419. C₄₈H₆₂NO₃SeSi₂re-

S. Y. Frankie Mak et al. / Tetrahedron: Asymmetry 20 (2009) 921–944

929

quires M, 836.3433]. Data for 10b: R_f0.28 (hexane–ether, 10:1);

lowed to warm to room temperature over 20 min. The reaction

mixture was quenched by the careful addition of a saturated aque-

ous solution of NH₄Cl (5 mL) and the solution became colourless.

The layers were separated, and the aqueous layer was extracted

with ether (3 ꢄ 7 mL). The combined organic extracts were washed

with brine (15 mL) and dried (MgSO₄). The solvent was removed in

vacuo and puriﬁcation by ﬂash chromatography (hexane–ether,

10:1) yielded the title compound 12 as a clear and colourless oil

(23.9 mg, 90%); (Found: C, 76.3; H, 8.1. C₄₃H₅₄O₃Si₂requires C,

½

a ²_D¹

ꢂ

¼ þ0:5 (c 0.89, CHCl₃); m_max(CHCl₃)/cm^ꢀ12932, 2859; d_H

(500 MHz; CDCl₃) 7.11–7.25 (5H, m, Ar), 7.30–7.45 (14H, m, Ar),

7.52–7.55 (2H, m, Ar), 7.62–7.65 (2H, m, Ar), 7.67–7.69 (2H, m,

Ar), 5.18–5.25 (1H, m, H-5), 4.58–4.65 (1H, m, H-6), 4.07 (1H, dd,

J 11.7, 2.8, CHHOSi), 3.83 (1H, td, J 9.4, 2.8, H-9), 3.56 (1H, dd, J

12.2, 3.0, CHHSe), 3.49 (1H, dd, J 11.7, 9.8, CHHOSi), 3.34–3.44

(2H, m, H-2, H-8), 2.88 (1H, dd, J 12.2, 9.9, CHHSe), 2.57–2.65 (1H,

m, H-7), 2.43–2.52 (1H, m, H-4), 1.84 (1H, dd, J 13:7, 7.5, H-7),

1.69–1.78 (2H, m, H-3, H-4), 1.41–1.48 (1H, m, H-3), 1.06 and

0.75 [2 ꢄ 9H, s, C(CH₃)₃]; d_H(62.5 MHz; CDCl₃) 135.84, 135.76,

135.69, 134.1, 133.6, 133.4, 133.3, 129.6, 128.9, 127.7, 127.69,

127.6, 127.5, 127.1, 127.0, 82.1, 72.2, 72.1, 64.0, 34.3, 32.4, 31.4,

27.0 and 26.8 [2 ꢄ C(CH₃)₃], 22.1, 19.3 and 19.1 [2 ꢄ C(CH₃)₃]; m/z

(ES, NH₃) 836 [(M+NH₄)⁺, 20%], 696; [Found (M+NH₄)⁺, 836.3436.

C₄₈H₆₂NO₃SeSi₂requires M, 836.3434].

76.5; H, 8.1); R_f0.55 (hexane–ether, 10:1); ½a _D²⁵

¼ þ19:5 (c 0.95,

ꢂ

CHCl₃); m_max(CHCl₃)/cm^ꢀ12930, 2950, 2858; d_H(500 MHz; CDCl₃)

7.62 (2H, d, J 6.8, Ar), 7.57–7.60 (6H, m, Ar), 7.38 (2H, t, J 4.3, Ar),

7.24–7.35 (10H, m, Ar), 5.74 (1H, ddd, J 17.3, 10.5, 6.6, CH@CHH),

5.58–5.60 (2H, m, H-5, H-6), 5.10 (1H, d, J 17.3, trans CHH@CH),

4.94 (1H, d, J 10.4, cis CHH@CH), 4.30 (1H, t, J 10.0, H-2), 4.12

(1H, m, H-8), 3.55–3.60 (2H, m, H-9, CHHOSi), 3.45–3.49 (1H, m,

CHHOSi), 2.56–2.61 (2H, m, H-7 and H-4), 1.87–1.90 (2H, m, H-7,

H-4), 1.51–1.61 (2H, m, 2 ꢄ H-3), 1.01 [9H, s, (CH₃)₃C] and 0.97

[9H, s, (CH₃)₃C]; d_C(62.5 MHz; CDCl₃) 140.7, 136.0, 135.8, 134.2,

134.0, 133.9, 133.7, 133.6, 130.2, 129.7, 128.6, 127.6, 114.2 (Ar

and CH@CH), 82.6, 79.7, 73.7, 66.0, 32.2, 30.4, 22.7, 27.2 and 19.4

[C(CH₃)₃], 26.9 and 19.2 [C(CH₃)₃]; m/z (CI; NH₃) 692 [(M+NH₄)⁺,

100%], 675 [(M+H)⁺, 5]; [m/z (ES) Found: (M+NH₄)⁺, 692.3952.

C₄₃H₅₈NO₃Si₂requires M, 692.3955].

4.1.3. (2R,5Z,8S,9R)-8-tert-Butyldiphenylsilanyloxy)-9-(tert

butyldiphenylsilanyloxymethyl)-2,3,4,7,8,9-hexahydrooxonine-

2-carbaldehyde 11

A solution of mCPBA (100%; 411 mg, 2.38 mmol) in THF (6 mL)

was added over 5 min to a stirred solution of selenides 10 (1.50 g,

1.83 mmol) in THF (100 mL) at ꢀ78 °C. After 20 min, NaOAc

(451 mg, 5.5 mmol) and Ac₂O (0.87 mL, 9.17 mmol) were added

and the resultant suspension was stirred at ꢀ78 °C for a further

5 min. After this time, the reaction mixture was allowed to warm

to ambient temperature over 30 min and was then heated at reﬂux

for 80 min. The reaction mixture was allowed to cool to ambient

temperature, and was quenched by the addition of water (40

mL). The layers were separated, the aqueous layer was extracted

with EtOAc (3 ꢄ 30 mL), and the combined organic extracts were

washed with brine (50 mL) and dried (MgSO₄). The solvent was re-

moved in vacuo and the resultant crude material was dissolved in

CH₂Cl₂(40 mL) and MeOH (20 mL). An excess of K₂CO₃(2.5 g) was

added and the mixture was stirred for 16 h. After this time water

(30 mL) was added and the layers were separated. The aqueous

layer was extracted with CH₂Cl₂(3 ꢄ 30 mL) and the combined or-

ganic extracts were washed with brine (50 mL) and dried (MgSO₄).

The solvent was removed in vacuo and puriﬁcation by ﬂash chro-

matography (hexane–ether, 10:1) yielded the aldehyde 11 as a col-

ourless oil (1.00 g, 81%); R_f0.38 (CH₂Cl₂–hexane, 2:1);

4.1.5. (2R,5Z,8S,9R)-8-(tert-Butyldiphenylsilanyloxy)-9-

hydroxymethyl-2-vinyl-2,3,4,7,8,9-hexahydrooxonine 13

To a stirred solution of the diene 12 (200 mg, 0.30 mmol) in THF

(5 mL) and pyridine (1 mL) in a polypropylene bottle was added

HFꢁpyridine (0.4 mL) and the reaction mixture was allowed to stir

for 16 h at room temperature. The reaction mixture was diluted

with ether (20 mL) and was then quenched by the addition of a sat-

urated aqueous solution of NaHCO₃(10 mL). The organic phase was

separated and the aqueous layer was extracted with ether (3 ꢄ 20

mL). The combined organic extracts were washed with 2 M HCl (20

mL), then with brine (10 mL) and were dried (MgSO₄). The solvent

was removed in vacuo and puriﬁcation by ﬂash chromatography

(petroleum ether 40–60;ether, 2:1) afforded the alcohol 13 as a

colourless oil (115 mg, 89%); (Found: C, 74.4; H, 8.4. C₂₇H₃₆O₃Si re-

quires C, 74.3; H, 8.3); R_f0.26 (hexane–ether, 2:1); ½a _D²⁵

¼ þ48:8 (c

ꢂ

1.135, CHCl₃); m

_max(CHCl₃)/cm^ꢀ13568, 3042; d_H(500 MHz; CDCl₃)

½

a ²_D⁵

ꢂ

¼ þ62:7 (c 1.21, CHCl₃); m_max(CDCl₃)/cm^ꢀl1729; d_H

7.68 (4H, t, J 7.8, Ar), 7.36–7.44 (6H, m, Ar), 5.83 (1H, ddd, J 17.3,

10.3, 7.1, CH@CHH), 5.59–5.67 (2H, m, H-5, H-6), 5.21 (1H, d, J

17.3, trans CH@CHH), 5.09 (1H, d, J 10.3, cis CH@CHH), 3.91–3.98

(2H, m, H-2, H-8), 3.56–3.60 (1H, m, CHHOH), 3.42 (1H, dt, J 11.3,

5.6, H-9), 3.34–3.37 (1H, m, CHHOH), 2.51–2.60 (1H, m, H-7),

2.47–2.51 (1H, m, H-4), 2.08–2.09 (1H, m, H-7), 2.05–2.07 (1H,

m, H-4), 1.56–1.62 (2H, m, 2 ꢄ H-3), 1.08 [9H, s, (CH₃)₃C]; d_C

(62.5 MHz; CDCl₃) 140.8, 135.9, 134.1, 133.5, 129.8, 127.7, 127.3,

115.2, 86.3, 83.7, 72.6, 63.2, 33.1, 30.9, 27.1, 22.7, 27.1, 19.4; m/z

(CI) 437 [(M+H)⁺, 20%], 274 (100); [m/z (ES) Found: (M+H)⁺,

437.2514. C₂₇H₃₇O₃Si requires M, 437.2512].

(500 MHz; CDCl₃) 10.02 (1H, d, J 1.6,CHO), 7.79–7.81 (4H, m, Ar),

7.71 (2H, d, J 6.6, Ar), 7.64 (2H, d, J 7.0, Ar), 7.22–7.32 (10H, m,

Ar), 7.17 (2H, t, J 7.4, Ar), 5.85–5.90 (1H, m, H-6), 5.50–5.56 (1H,

m, H-5), 4.07–3.97 (3H, m, H-2, H-8, CHHOSi), 3.67–3.76 (2H, m,

H-9, CHHOSi), 2.69 (1H, br t, H-7), 2.43–2.35 (1H, m, H-4), 2.04–

2.12 (1H, m, H-7), 1.72–1.80 (1H, m, H-4), 1.60–1.68 (2H, 2 ꢄ H-

3), 1.23 and 1.10 [2 ꢄ 9H, s, C(CH₃)₃]; d_H(62.5 MHz; C₆D₆) 204.6

(CO), 136.99, 135.97, 135.9, 135.8,133.9, 133.50, 133.47, 130.3,

129.84, 129.77, 129.74, 127.9, 127.3, 87.6, 87.0, 73.5, 67.4, 29.9,

27.9, 27.0, 26.9, 21.8, 19.2, 19.1; m/z (CI; NH₃) 694 [(M+NH₄)⁺,

20%], 677 [(M+H)⁺, 65%], 196 (100); [Found: (M+H)⁺, 677.348.

C₄₂H₅₃O₄Si₂requires M, 677.3482].

4.1.6. (2R,5Z,8S,9S)-8-(tert-Butyldiphenylsilanyloxy)-2-vinyl-

2,3,4,7,8,9-hexahydrooxonine-9-carbaldehyde

4.1.4. (2R,5Z,8S,9R)-8-(tert-Butyldiphenylsilanyloxy)-9-(tert-

butyldiphenylsilanyl-oxymethyl)-2-vinyl-2,3,4,7,8,9-

hexahydrooxonine 12

To a stirred solution of methyltriphenylphosphonium bromide

(29.7 mg, 0.083 mmol) in THF (3 mL) was added n-BuLi (52 lL of

a 1.6 M solution in hexane, 0.084 mmol) at ꢀ78 °C. The solution

immediately turned yellow and the mixture was stirred for a fur-

ther 20 min at room temperature until all the phosphonium salt

had dissolved. The reaction mixture was recooled to ꢀ78 °C and

a solution of aldehyde 11 (26.6 mg, 0.039 mmol) in THF (1 mL,

0.5 mL rinse) was added slowly. The reaction mixture was then al-

To a stirred solution of the alcohol 13 (22 mg, 0.05 mmol) in

DMSO (5 mL) was added IBX (21.5 mg, 0.077 mmol). The reaction

mixture was stirred at room temperature for 16 h. The reaction

mixture was quenched by the addition of water (10 mL) and the

layers were separated. The aqueous layer was extracted with ether

(3 ꢄ 10 mL). The combined organic extracts were washed with

brine (10 mL) and dried (MgSO₄). The solvent was removed in va-

cuo and puriﬁcation by ﬂash chromatography (EtOAc) furnished

the title compound as a colourless oil (20.5 mg, 94%); R_f0.40

(EtOAc); ½a ²_D⁵

ꢂ

¼ þ30:3 (c 0.37, CHCl₃); m_max(CHCl₃)/cm^ꢀ11733;

d_H(250 MHz; CDCl₃) 9.50 (1H, d, J 1.9, CHO), 7.62–7.71 (4H, m,

930

S. Y. Frankie Mak et al. / Tetrahedron: Asymmetry 20 (2009) 921–944

Ar), 7.34–7.47 (6H, m, Ar), 5.81 (1H, ddd, J 17.3, 10.4, 6.8,

CHH@CH), 5.66–5.72 (2H, m, H-5, H-6), 5.12 (1H, d, J 17.3, trans

CHH@CH), 5.05 (1H, d, J 10.3, cis CHH@CH), 4.23–4.29 (1H, m, H-

8), 3.93 (1H, dd, J 6.2, 15.3, H-2), 3.68 (1H, dd, J 1.7, 7.7, H-9),

2.44–2.65 (2H, m, H-4, H-7), 1.91–2.09 (2H, m, H-4, H-7), 1.62–

1.73 (2H, m, 2 ꢄ H-3), 1.08 [9H, s, (CH₃)₃C]; d_C(62.5 MHz; CDCl₃)

200.7 (CHO), 138.9, 136.0, 135.9, 133.8, 132.9, 131.5, 130.0,

129.8, 127.7, 127.6, 126.3, 115.4, 88.3, 83.9, 71.9, 32.3, 30.6, 22.3,

27.0 and 19.3 [C(CH₃)₃]; m/z (CI; NH₃) 452 [(M+NH₄)⁺, 80%], 435

[(M+H)⁺, 5], 274 (100); [m/z (ES) Found: (M+NH₄)⁺, 452.2624.

C₂₇H₃₈NO₃Si requires M, 452.2621].

1.05 [9H, s, (CH₃)₃C]; d_C(125 MHz; CDCl₃, 25 °C) 136.1, 135.9,

134.2, 134.0, 131.4, 129.8, 129.7, 129.5, 128.9, 127.7, 127.6,

127.5, 125.9, 92.5, 87.5, 70.6, 28.6, 27.9, 21.8, 27.1 and 19.4

[C(CH₃)₃]; m/z (CI; NH₃) 422 [(M+NH₄)⁺, 85%], 405 [(M+H)⁺, 10],

327 (100); [m/z (ES) Found: (M+H)⁺, 405.2258. C₂₆H₃₃O₂Si requires

M, 405.2250]. Data for 16: R_f0.27 (petroleum ether 40–60:ether,

10:1); m_max(neat)/cm^ꢀ12927, 2855; ½a _D²²

¼ ꢀ6:0 (c 0.52, CHCl₃);

ꢂ

d_H(250 MHz; CDCl₃) 7.72–7.77 (4H, m, Ar), 7.36–7.44 (6H, m,

Ar), 5.94–5.96 (1H, m, CH@CH), 5.88–5.90 (1H, m, CH@CH), 5.78–

5.81 (2H, m, CH@CH), 4.76–4.77 (1H, m, H-1⁰), 4.29 (1H, q, J 6.6,

H-2), 4.10 (1H, d, J 5.7, H-1), 2.40–2.50 (2H, m), 2.09–2.22 (3H,

m), 1.80–1.85 (1H, m), 1.09 [9H, s, (CH₃)₃C]; d_C(62.5 MHz; CDCl₃)

136.0, 136.0, 135.9, 135.8, 134.8, 134.5, 134.2, 133.4, 131.8, 130.8,

129.6, 127.6, 127.5, 127.4, 84.2, 80.2, 73.9, 38.7, 31.0, 30.9, 27.0 and

19.3 [C(CH₃)₃]; m/z (ES) 422 [(M+NH₄)⁺, 100%]; [Found: (M+NH₄)⁺,

422.2516. C₂₆H₃₆NO₂Si requires M, 422.2515].

4.1.7. (2R,5Z,8S,9R)-8-(tert-Butyldiphenylsilanyloxy)-2,9-

divinyl-2,3,4,7,8,9-hexahydrooxonine 14

To a stirred solution of methyltriphenylphosphonium bromide

(188 mg, 0.52 mmol) in THF (4 mL) was added n-BuLi (0.31 mL

of a 1.6 M solution in hexane, 0.50 mmol) at ꢀ78 °C. The solution

immediately turned yellow and the mixture was allowed to warm

to room temperature over 30 min, until all the phosphonium salt

had dissolved. The reaction mixture was cooled to ꢀ78 °C and a

solution of (2R,5Z,8S,9S)-8-(tert-butyldiphenylsilanyloxy)-2-vinyl-

2,3,4,7,8,9-hexahydrooxonine-9-carbaldehyde (91 mg, 0.21 mmol)

in THF (1 mL, 0.5 mL rinse) was added via cannula. The reaction

mixture was allowed to warm to room temperature over 1 h, be-

fore being quenched by the careful addition of a saturated aqueous

solution of NH₄Cl (10 mL). The organic phase was separated and

the aqueous layer was extracted with ether (3 ꢄ 10 mL). The com-

bined organic extracts were washed with brine (15 mL) and dried

(MgSO₄). The solvent was removed in vacuo and puriﬁcation by

ﬂash chromatography (petroleum ether 40–60:ether, 10:1) affor-

ded the title compound 14 as a colourless oil (0.085 g, 93%);

(Found: C, 77.8; H, 8.4. C₂₈H₃₆O₂Si requires C, 77.7; H, 8.4); R_f

The [6.2.1]-bicyclic ether 15 was also prepared by reduction of

the epoxide 21.

To a stirred solution of WCl₆(38 mg, 0.95 mmol) in THF at

ꢀ78 °C was added nBuLi (0.12 mL of a 1.6 M solution in hexane)

over 2 min. The solution was stirred for a further 15 min, until

the solution was a cloudy green colour. A solution of the epoxide

21, (4 mg, 0.01 mmol) in THF (1 mL, 0.5 mL rinse) was added via

cannula. The reaction mixture was allowed to stir at ꢀ78 °C for a

further 1 h, and was then allowed to warm to 0 °C over 1 h to give

a clear green solution. The reaction mixture was then allowed to

warm to room temperature over 2 h. The reaction mixture was

quenched by the addition of 1.5 M sodium potassium tartrate solu-

tion (5 mL) and NaOH (2 M; 5 mL) and the layers were separated.

The aqueous layer was extracted with ether (3 ꢄ 5 mL) and the

combined organic extracts were washed with brine (10 mL) and

dried (MgSO₄). The solvent was removed in vacuo and puriﬁcation

by ﬂash chromatography (petroleum ether 40–60:ether, 10:1) gave

the title compound 15 (2.2 mg, 53%) as a colourless oil.

0.51 (hexane–ether, 10:1); ½a _D²⁵

¼ þ66:5 (c 1.8, CHCl₃); m_max

ꢂ

(CHCl₃)/cm^ꢀ12929, 2856; d_H(500 MHz; CDCl₃) 7.63–7.68 (4H, m,

Ar), 7.32–7.42 (6H, m, Ar), 5.77 (1H, ddd, J 17.2, 10.5, 6.3,

CH@CHH), 5.68 (1H, ddd, J 17.3, 10.4, 6.6, CH⁰@CH⁰H⁰), 5.60–5.65

(2H, m, H-5, H-6), 5.14 (1H, ddd, J 17.2, 1.5, 1.5, trans CHH@CH),

5.07 (1H, ddd, J 17.3, 1.5, 1.5, trans CH⁰H⁰@CH⁰), 5.02 (1H, d, J

10.4, cis CH⁰H⁰@CH⁰), 4.97 (1H, d, J 10.5, cis CHH@CH), 3.96 (1H,

q, J 6.3, H-8), 3.87 (1H, ddd, J 7.5, 4.7, 1.9, H-2), 3.67 (1H, t, J 6.9,

H-9), 2.44–2.49 (1H, m, H-7), 1.94–1.98 (1H, m, H-4), 1.88–1.92

(2H, m, H-7, H-4), 1.59–1.64 (2H, m, 2 ꢄ H-3), 1.05 [9H, s,

(CH₃)₃C]; d_C(62.5 MHz; CDCl₃) 140.2, 138.3, 136.2, 136.0, 134.4,

133.7, 131.2, 129.6, 127.5, 126.7, 116.5, 114.1, 84.7, 75.8, 65.8,

32.3, 30.7, 19.4, 27.1 and 15.3 [C(CH₃)₃]; m/z (CI; NH₃) 450

[(M+NH₄)⁺, 80%], 433 [(M+H)⁺, 100]; [m/z (ES) Found: (M+H)⁺,

433.2564. C₂₈H₃₇O₂Si requires M, 433.2563].

4.1.9. (1S,3S,4R,6R,9S) and (1R,3S,4R,6R,9R)-3-(tert-Butyldiphenyl-

silanyloxy)-4-hydroxymethyl-6-vinyl-5,10-dioxabicyclo[7.1.0]-

decanes 19b and 19a

To a stirred solution of the alcohol 13 (34 mg, 0.078 mmol) in

CH₂Cl₂(1 mL) was added mCPBA (100%; 18.5 mg, 0.11 mmol) at

0 °C. The reaction mixture was allowed to warm to room temper-

ature and the reaction mixture was stirred at this temperature for

14 h. The reaction mixture was quenched by the addition of NaH-

SO₃(5 mL), and the layers were separated. The aqueous layer was

extracted with CH₂Cl₂(3 ꢄ 5 mL), and the combined organic ex-

tracts were washed with a saturated aqueous solution of NaHCO₃

(10 mL) and then with brine (10 mL) and were dried (MgSO₄).

The solvent was removed in vacuo and puriﬁcation by ﬂash chro-

matography (petroleum ether 40–60:ether, 1:1) gave epoxide

19b (22 mg, 63%) as a white solid and epoxide 19a (6 mg, 17%)

as a clear and colourless oil. Data for 19b: mp 68–69 °C (hexane);

4.1.8. (1R,2S,4Z,8R,9Z)-2-(tert-Butyldiphenylsilanyloxy)-11-oxabi-

cyclo[6.2.1]-undeca-4,9-diene 15 and [(1S,2R)-(tert-butyldi-

phenylsilanyloxy)-2-[(R)-cyclopent-2-enyloxy]-1-cyclopent-3-

ene 16

To a stirred solution of Grubbs’ ruthenium catalyst 17 (1 mg,

0.002 mmol, 5 mol %) in CH₂Cl₂(1 mL) was added a solution of

the triene 14 (14 mg, 0.032 mmol) in CH₂Cl₂(1 mL, 0.5 mL rinse)

via cannula. The mixture was stirred for 18 h at room temperature.

The solvent was removed in vacuo and puriﬁcation by ﬂash chro-

matography (petroleum ether 40–60:ether, 10:1) gave the

[6.2.1]-bicyclic ether 15 (9 mg, 69%) and the bis-cyclopentene 16

(3 mg, 22%). Data for 15: R_f0.21 (petroleum ether 40–60:ether,

R_f0.22 (petroleum ether 40–60:ether, 1:1); ½a _D²⁵

¼ þ27:3 (c 0.52,

ꢂ

CHCl₃); m_max(CHCl₃)/cm^ꢀ13474, 3071, 2930, 2857; d_H(500 MHz;

CDCl₃) 7.62–7.69 (4H, m, Ar), 7.37–7.46 (6H, m, Ar), 5.77 (1H,

ddd, J 17.3, 10.3, 6.9, CH@CHH), 5.23 (1H, d, J 17.3, trans CHH@CH),

5.13 (1H, d, J 10.3, cis CH@CHH), 4.11–4.15 (1H, dd, J 14.9, 6.8, H-6),

4.04–4.07 (1H, m, H-3), 3.38–3.50 (3H, m, H-1, H-4, CH₂OH), 3.27–

3.32 (1H, m, CH₂OH), 3.05 (1H, dt, J 11.0, 3.1, H-9), 2.10–2.17 (1H,

m, H-2), 1.98–2.01 (1H, m, H-8), 1.68–1.77 (2H, m, 2 ꢄ H-7), 1.43–

1.59 (2H, m, H-2, H-8), 1.10 [9H, s, (CH₃)₃C]; d_C(62.5 MHz; CDCl₃)

139.9, 135.9, 135.8, 133.3, 133.2, 130.0, 127.8, 116, 83.2, 80.3, 70.5,

56.9, 53.9, 62.4, 30.5, 29.4, 22.0, 27.1 and 19.3 [C(CH₃)₃]; m/z (CI;

NH₃) 470 [(M+NH₄)⁺, 55%], 453 [(M+H)⁺, 65], 274 (100); [m/z (ES)

Found: (M+H)⁺, 453.2461. C₂₇H₃₇O₄Si requires M, 453.2461]. Data

10:1); ½a ²_D²

ꢂ

¼ þ18:0 (c 0.51, CHCl₃); m_max(neat)/cm^ꢀ13014, 2930,

2856; d_H(400 MHz; CDCl₃, -30 °C) 7.61–7.74 (4H, m, Ar), 7.30–

7.46 (6H, m, Ar), 5.71–5.78 (2H, m, alkene), 5.60–5.67 (1H, m, al-

kene), 5.52 (1H, d, J 5.9), 5.23 and 5.18 (2H, br s, H-1 and H-8),

3.55 (1H, d, J 6.4, H-2), 2.29–2.37 (2H, m), 1.94–1.98 (1H, m),

1.80–1.91 (1H, m), 1.60–1.66 (1H, m), 1.53 (1H, dd, J 14.4, 6.7),

for 19a: R_f0.09 (petroleum ether 40–60:ether, 1:1); ½a _D²⁵

¼ þ56

ꢂ

(c 0.3, CHCl₃); m_max(CHCl₃)/cm^ꢀ13443, 3071, 2930, 2857; d_H

S. Y. Frankie Mak et al. / Tetrahedron: Asymmetry 20 (2009) 921–944

931

(500 MHz; CDCl₃) 7.64–7.65 (4H, m, Ar), 7.37–7.46 (6H, m, Ar),

5.85 (1H, ddd, J 17.2, 10.3, 6.4 CH₂@CH), 5.24 (1H, d, J 17.2, trans

CHH@CH), 5.07 (1H, d, J 10.3, cis CHH@CH), 4.39 (1H, q, J 6.6),

4.24–4.27 (1H, m), 4.07 (1H, q, J 7.4), 3.97–3.98 (1H, m), 3.91

(1H, q, J 7.2), 3.49–3.51 (1H, m, H-1), 3.22–3.24 (1H, m, H-9)

1.86–2.07 (3H, m, ring CH₂), 1.63–1.76 (3H, m, ring CH₂), 1.06

[9H, s, (CH₃)₃C]; d_C(62.5 MHz; CDCl₃) 139.2, 135.8, 133.6, 133.4,

130.0, 127.8, 115.4, 85.6, 81.9, 81.5, 80.8, 73.4, 62.1, 37.8, 31.6,

27.7, 26.9 and 19.1 [C(CH₃)₃]; m/z (CI; NH₃) 470 [(M+NH₄)⁺, 45%],

453 [(M+H)⁺, 10]; [m/z (ES) Found: (M+NH₄)⁺, 470.2728.

C₂₇H₄₀NO₄Si requires M, 470.2727].

4.17–4.22 (1H, m, H-3), 4.13–4.17 (1H, m, H-6), 3.82 (1H, t, J

6.6, H-4), 3.39 [1H, dt, J 11.1, 3.5, CH(O)CH], 3.01 [1H, dt, J

11.1, 3.7, CH(O)CH], 1.93–2.10 (2H, m), 1.60–1.85 (3H, m),

1.42–1.47 (1H, m), 1.08 [9H, s, (CH₃)₃C]; d_C(62.5 MHz; CDCl₃)

139.3, 137.2, 136.2, 135.9, 133.7, 133.4, 129.9, 129.8, 127.7,

127.6, 117.3, 114.9, 80.9, 77.2, 74.2, 57.5, 53.8, 29.3, 28.0, 27.1

[C(CH₃)₃], 21.0, 19.3 [C(CH₃)₃]; m/z (CI; NH₃) 466 [(M+NH₄)⁺,

30%], 449 [(M+H)⁺, 100]; [(ES) Found: (M+H)⁺, 449.2517.

C₂₈H₃₇O₃Si requires M, 449.2512].

4.1.12. (1R,2S,4S,6R,9R,10Z)-2-(tert-Butyldiphenylsilanyloxy)-

(5,12-dioxatricyclo-[7.2.1.0^4,6]dodecane 21

4.1.10. (1S,3S,4R,6R,9R)-3-(tert-Butyldiphenylsilanyloxy)-6-

vinyl-5,10-dioxabicyclo-[7.1.0]decane-4-carbaldehyde

To a stirred solution of Grubbs’ ruthenium catalyst 17 (1 mg,

0.002 mmol, 5 mol %) in CH₂Cl₂(1 mL) was added a solution of

the alkene 20 (5 mg, 0.012 mmol) in CH₂Cl₂(1 mL, 0.5 mL rinse)

via cannula. The mixture was stirred for 3 h after which the solu-

tion had become brown, indicating catalyst decomposition. There-

fore, more catalyst 17 (1 mg, 0.002 mmol, 5 mol %) in CH₂Cl₂(1 mL)

was added and the reaction mixture was heated at reﬂux for 1 h

and was then stirred for 16 h at room temperature. The solvent

was removed in vacuo and puriﬁcation by ﬂash chromatography

(hexane–ether, 1:1) furnished the title compound 21 as a clear

and colourless oil (4 mg, 87%); R_f0.34 (hexane–ether, 1:1);

To a stirred solution of alcohol 19b (24 mg, 0.053 mmol) in

DMSO (3 mL) was added IBX (26 mg, 0.093 mmol). The reaction

mixture was stirred at room temperature for 16 h. The reaction

mixture was quenched by the addition of water (10 mL) and

the layers were separated. The aqueous layer was extracted with

ether (3 ꢄ 10 mL). The combined organic extracts were washed

with brine (10 mL) and dried (MgSO₄). The solvent was removed

in vacuo, and puriﬁcation by ﬂash chromatography (hexane–ether

1:1) furnished the title compound as a colourless oil (17 mg,

73%); R_f0.24 (hexane–ether, 1:1); ½a _D²⁵

ꢂ

¼ þ21:3 (c 0.56, CHCl₃);

½

a ²_D⁵

ꢂ

¼ ꢀ37 (c 0.2, CHCl₃); m_max(CHCl₃)/cm^ꢀ12927, 2855; d_H

v_max(CHCl₃)/cm^ꢀ11735; d_H(500 MHz; CDCl₃) 9.29 (1H, d, J 1.2,

CHO), 7.62–7.67 (4H, m, Ar), 7.36–7.47 (6H, m, Ar), 5.73 (1H,

(500 MHz; CDCl₃) 7.69–7.74 (4H, m, Ar), 7.38–7.46 (6H, m, Ar),

5.64 (1H, d, J 5.9, CH@CH), 5.44 (1H, d, J 5.9, CH@CH), 4.97 and

5.15 (2H, s, H-1, H-9), 3.97 (1H, d, J 6.5, H-2), 3.59 [1H, dt, J 11.6,

3.4, CH(O)CH], 3.01 [1H, dt, J 10.9, 3.6, CH(O)CH], 1.96–2.11 (4H,

m, ring CH₂), 1.75–1.80 (2H, m, 2 ꢄ H-8), 1.11 [9H, s, (CH₃)₃C]; d_C

(62.5 MHz; CDCl₃) 135.9, 133.9, 133.4, 131.1, 129.9, 129.7, 128.7,

127.8, 127.6, 91.5, 86.3, 73.4, 60.2, 55.9, 29.4, 28.4, 27.0

[C(CH₃)₃], 22.0, 19.3 [C(CH₃)₃]; m/z (CI; NH₃) 438 [(M+NH₄)⁺,

30%], 421 [(M+H)⁺, 100]; [m/z (ES) Found: (M+H)⁺, 421.2206.

C₂₆H₃₃O₃Si requires M, 421.2199].

ddd,

J 17.2, 10.4, 6.8, CH@CHH), 5.16 (1H, d, J 17.2, trans

CH@CHH), 5.12 (1H, d, J 10.4, cis CH@CHH), 4.39–4.42 (1H, m,

H-3), 4.15 (1H, dd, J 14.2, 6.5, H-6), 3.77 (1H, dd, J 6.2, 1.2, H-

4), 3.42 (1H, dt, J 10.9, 3.2), 3.04 (1H, dt, J 11.2, 3.4), 2.15–2.19

(1H, m), 2.00–2.04 (1H, m), 1.77–1.82 (2H, m), 1.43–1.51 (2H,

m), 1.09 [9H, s, (CH₃)₃C]; d_C(62.5 MHz; CDCl₃) 199.8 (CHO),

138.2, 136.0, 135.8, 133.0, 132.6, 130.2, 130.1, 127.9, 116.5,

85.4, 80.3, 70.0, 57.0, 53.5, 30.3, 29.4, 21.5, 27.1 and 19.2

[C(CH₃)₃]; m/z (CI; NH₃) 468 [(M+NH₄)⁺, 60%], 451 [(M+H)⁺, 20],

274 (100); [m/z (ES) Found: (M+H)⁺, 451.2311. C₂₇H₃₅O₄Si re-

quires M, 451.2304].

4.1.13. (1R,2S,4Z,8R,9Z)-2-Hydroxy-11-oxabicyclo[6.2.1]-

undeca-4,9-diene 2

To a stirred solution of the [6.2.1]-bicyclic ether 15 (12 mg, 0.03

mmol) in THF (2 mL) was added TBAF (0.3 mL of a 1.0 M solution in

THF, 0.3 mmol) at 0 °C. The reaction mixture was stirred for a fur-

ther 20 min at 0 °C, and was then stirred for 36 h at room temper-

ature. The reaction mixture was quenched by addition of water (5

mL) and ether (5 mL) and the layers were separated. The aqueous

layer was extracted with ether (3 ꢄ 5 mL) and the combined organ-

ic extracts were washed with brine (10 mL) and dried (MgSO₄). The

solvent was removed in vacuo and puriﬁcation by ﬂash chromatog-

raphy (ether) furnished alcohol 2 as a white solid (3 mg, 61%); mp

4.1.11. (1S,3S,4R,6R,9R)-3-(tert-Butyldiphenylsilanyloxy)-4,6-

divinyl-5,10-dioxabicyclo-[7.1.0]-decane 20

Methyltriphenylphosphonium bromide (22 mg, 0.062 mmol)

was dried in a Schlenk tube using a heat gun under vacuum.

The phosphonium salt was dissolved in THF (1 mL) and n-BuLi

(28

lL of a 1.6 M solution in hexane, 0.044 mmol) was added

at ꢀ78 °C. The solution immediately turned yellow in colour

and was allowed to warm to room temperature over 30 min.

The reaction mixture was cooled to ꢀ78 °C and a solution of

(1S,3S,4R,6R,9R)-3-(tert-butyldiphenylsilanyloxy)-6-vinyl-5,10-di-

oxabicyclo-[7.1.0]decane-4-carbaldehyde (5 mg, 0.011 mmol) in

THF (1 mL, 0.5 mL rinse) was added via cannula. The reaction

mixture was again allowed to warm to room temperature over

30 min and by this time the reaction mixture had become a clou-

dy pale yellow. The reaction mixture was quenched by the care-

ful addition of a saturated aqueous solution of NH₄Cl (5 mL) and

the solution became colourless. The organic phase was separated

and the aqueous layer was extracted with ether (3 ꢄ 7 mL). The

combined organic extracts were washed with brine (15 mL) and

dried (MgSO₄). The solvent was removed in vacuo and puriﬁca-

tion by ﬂash chromatography (hexane–ether, 2:1) provided the

title compound 20 as a clear and colourless oil (5 mg, 98%); R_f

85–86 °C (ether); R_f0.37 (ether); ½a _D²⁵

¼ ꢀ1:0 (c 0.42, CHCl₃); m_max

ꢂ

(CHCl₃)/cm^ꢀ13426, 2915, 2845; d_H(500 MHz; CDCl₃) 5.80–5.83

(2H, m, H-4, H-5), 5.66 (1H, d, J 6.0, CH@CH), 5.53 (1H, d, J 6.0,

CH@CH), 5.12 and 5.21 (2H, s, H-1, H-8), 3.68 (1H, t, J 8.5, H-2),

2.59–2.64 (1H, m), 2.43–2.45 (1H, m), 2.17–2.22 (1H, m), 2.05–

2.07 (1H, m), 1.78–1.89 (2H, m); d_C(62.5 MHz; CDCl₃) 134.5,

132.1, 131.5, 128.3, 92.1, 87.2, 68.7, 28.3, 27.3, 21.8; m/z (CI) 167

[(M+H)⁺, 70%]; [m/z (ES) Found: (M+H)⁺, 167.1072. C₁₀H₁₅O₂re-

quires M, 167.1072].

4.1.14. (1R,2S,4Z,8R,9Z)-2-(N(s)-Methyl urocanic acid)-11-

oxabicyclo[6.2.1]undeca-4,9-dien-2-yl ester 3

To a stirred solution of the alcohol 2 (4.8 mg, 0.029 mmol) in

CH₂Cl₂(0.5 mL) was added DMAP (4 mg, 0.32 mmol), NEt₃(0.061

mL) and a solution of the mixed anhydride 22 (94.5 mg, 0.4 mmol)

in CH₂Cl₂(0.5 mL, 0.5 mL rinse) via cannula. The reaction mixture

was allowed to stir at room temperature for 20 h, before being

quenched by the addition of a saturated aqueous solution of NaHCO₃

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

0.55 (hexane–ether, 1:1);

½

a ²_D⁵

ꢂ

¼ þ21:6 (c 0.31, CHCl₃); m_max

(CHCl₃)/cm^ꢀ12930, 2857, 1643; d_H(250 MHz; CDCl₃) 7.64–7.69

(4H, m, Ar), 7.32–7.46 (6H, m, Ar), 5.72 (1H, ddd, J 17.0, 10.5,

6.0, CH@CHH), 5.52 (1H, ddd, J 17.0, 10.5, 6.5, CH@CHH), 5.12

(1H, dd, J 17.0, 1.5, trans CH@CHH), 5.06–5.14 (2H, m, trans

CH@CHH, cis CH@CHH), 5.03 (1H, dd, J 10.5, 1.5, cis CH@CHH),

932

S. Y. Frankie Mak et al. / Tetrahedron: Asymmetry 20 (2009) 921–944

extracted with CH₂Cl₂(3 ꢄ 5 mL). The combined organic extracts

were washed with brine (5 mL) and dried (MgSO₄). The solvent

was removed in vacuo and puriﬁcation by ﬂash chromatography

9:1); ½a ²_D⁵

ꢂ

¼ þ63:3 (c 0.35, CHCl₃); m_max(CHCl₃)/cm^ꢀ13069, 3015;

d_H(250 MHz; CDCl₃) 7.78–7.80 (2H, m, Ar), 7.58–7.66 (4H, m, Ar),

7.19–7.47 (14H, m, Ar), 5.79–5.87 (1H, m, CH@CH), 5.52–5.62

(1H, m, CH@CH), 4.78 (1H, d, J 11.3, OCHHPh), 4.50 (1H, d, J

11.3, OCHHPh), 4.22 (1H, d, J 11.0, H-9), 4.13–4.16 (1H, m, CHHO-

Si), 3.82 (1H, d, J 11.0, H-8), 3.72 (1H, d, J 9.5, CHHOSi), 3.24–3.42

(2H, m, CH₂Se), 2.81 (3H, s, OMe), 2.70–2.74 (1H, m), 2.41–2.50

(1H, m), 2.03–2.26 (2H, m), 1.59–1.73 (2H, m), 1.18 [9H, s,

(CH₃)₃C]; d_C(62.5 MHz; CDCl₃) 138.9, 136.1, 135.8, 134.0, 133.9,

133.0, 132.8, 130.6, 129.7, 129.6, 128.4, 127.6, 127.5, 127.4,

127.1, 125.1, 105.6, 76.6, 75.7, 72.8, 71.1, 63.0, 49.3, 32.8, 32.6,

25.0, 19.6, 27.1 and 19.8 [C(CH₃)₃]; m/z (ES) 723 [(M+Na)⁺, 60%],

119 (100); [m/z (ES). Found: (M+Na)⁺, 723.2385. C₄₀H₄₈NaO₄SeSi

requires M, 723.2385].

(CH₂Cl₂–EtOAc–EtOH, 5:5:1) afforded the title compound

3

(4.4 mg, 50%) as a clear and colourless oil. For characterisation pur-

poses, it was necessary to repurify the product 3 by preparative TLC

(two solvent tanks, run sequentially, MeCN–CH₂Cl₂, 1:1 and MeCN–

CH₂Cl₂–EtOH, 5:5:1); R_f0.18 (CH₂Cl₂–EtOAc–EtOH, 5:5:1);

½

a ²_D⁵

ꢂ

¼ þ36:5 (c 0.2, CHCl₃); v_max(CHCl₃)/cm^ꢀ13013w, 2921ms,

2850, 1703, 1638; d_H(500 MHz; CDCl₃) 7.61 (1H, d, J 15.7, H-12),

7.44 (1H, s, H-16), 7.08 (1H, s, H-15), 6.62 (1H, d, J 15.7, H-13),

5.84–5.87 (2H, m, H-4 and H-5), 5.52–5.62 (2H, m, H-9 and H-10),

5.20–5.24 (2H, m, H-1 and H-8), 4.99 (1H, d, J 7.3, H-2), 3.69 (3H, s,

NMe), 2.69 (1H, br s, ring CHH), 1.84–196 (2H, m, ring CH₂) and

2.35–2.54 (3H, m, ring CH₂); d_C(62.5 MHz; CDCl₃) 167.2 (C@O),

139.1, 138.7, 136.7, 132.7, 132.3, 128.2, 124.7, 122.2, 116.0 (alkene),

88.6, 70.5, 65.8 (C-1, C-2 and C-8), 33.5 (NMe), 29.7, 21.8 and 15.3 (C-

3, C-6 and C-7); m/z (CI; NH₃) 301 [(M+H)⁺, 100%] and 249 (20);

[m/z (ES) Found: (M+H)⁺, 301.1553. C₁₇H₂₁N₂O₃requires M,

301.1552].

4.1.17. (2R,5Z,8S,9R)-8-Benzyloxy-9-(tert-butyldiphenylsilanyl-

oxymethyl)-2-methoxy-2,3,4,7,8,9-hexahydro-oxonin-2-

carbaldehyde 29

To a stirred solution of selenide 27b (0.303 g, 0.43 mmol) in a

mixture of CH₂Cl₂(10 mL) and MeOH (20 mL), was added water

(2.6 mL) until material started to come out of solution. NaHCO₃

(47 mg, 0.56 mmol) and NaIO₄(0.30 g, 1.4 mmol) were then added

and the cloudy white suspension was stirred at room temperature

for 2 h. The reaction mixture was quenched by the addition of

water (20 mL) and the layers were separated. The aqueous layer

was extracted with CH₂Cl₂(3 ꢄ 30 mL) and the combined organic

extracts were washed with brine (30 mL) and dried (MgSO₄). The

solvent was removed in vacuo to furnish the corresponding selen-

oxide as a yellow foam, which was dissolved in THF (15 mL) and

cooled to ꢀ78 °C. NaOAc (0.135 g, 1.64 mmol) and Ac₂O (0.25

mL, 2.6 mmol) were added and the resultant suspension was stir-

red at ꢀ78 °C for 5 min and was then allowed to warm to room

temperature over 0.5 h. The reaction mixture was heated at reﬂux

for 1.25 h and was then allowed to cool to room temperature, be-

fore being quenched by the addition of water (10 mL). The organic

phase was separated and the aqueous layer was extracted with

EtOAc (3 ꢄ 15 mL). The combined organic extracts were washed

with brine (15 mL) and dried (MgSO₄). The solvent was removed

in vacuo and the resultant crude material 28 was dissolved in a

mixture of CH₂Cl₂(5 mL) and MeOH (2 mL). An excess of K₂CO₃

(ꢃ0.25 g) was added and the mixture was stirred for 18 h at room

temperature. After this time, water (10 mL) was added, and the

layers were separated. The aqueous layer was extracted with

CH₂Cl₂(3 ꢄ 10 mL), and the combined organic extracts were

washed with brine (10 mL) and dried (MgSO₄). The solvent was re-

moved in vacuo and puriﬁcation by ﬂash chromatography (hex-

ane–ether, 10:1) furnished the aldehyde 29 as a colourless oil

(0.177 g, 73%); R_f0.25 (petroleum ether 40–60:ether, 8:1);

4.1.15. (5Z,8S,9R)-8-Benzyloxy-9-(tert-butyldiphenylsilanyl-

oxymethyl)-2-methylene-2,3,4,7,8,9-hexahydrooxonine 26

To a stirred solution of lactone 25³²(1.24 g, 2.41 mmol) in tol-

uene (30 mL), in the dark, was added a solution of dimethyltitano-

cene (14 mL of a 71 mg/mL solution in toluene, 4.76 mmol). The

solution was heated at reﬂux for 1 h and was then allowed to cool

to rt. The solvent was removed in vacuo giving a yellow precipitate.

This residue was dissolved in CH₂Cl₂(20 mL) and evaporated onto

basic alumina [Brockmann grade III basic alumina deactivated with

water (6% wt/wt)]. Puriﬁcation by ﬂash chromatography [Brock-

mann grade III basic alumina deactivated with water (6% wt/wt);

petroleum ether 40–60:ether, 6:1] gave the title enol ether 26 as

a pale yellow oil (1.07 g, 86%); R_f0.66 (petroleum ether 40–

60:ether, 6:1); ½a _D²⁰

ꢂ

¼ ꢀ22:6 (c 1.75, CHCl₃); m_max(CHCl₃)/cm^ꢀ1

1637; d_H(250 MHz; CDCl₃) 7.58–7.78 (4H, m, Ar), 7.22–7.46

(11H, m, Ar), 5.54–5.78 (2H, m, H-5, H-6), 4.65 (1H, d, J 11.5,

OCHHPh), 4.37 (1H, d, J 11.5, OCHHPh), 4.36 (1H, s, C@CHH), 4.03

(1H, s, C@CHH), 3.86–4.00 (2H, m, CHHOSi, H-9), 3.49–3.84 (2H,

m, CHHOSi, H-8), 2.54–2.71 (2H, m, H-4, H-7), 2.36–2.45 (2H, m,

2 ꢄ H-3), 1.99–2.31 (2H, m, H-7, H-4), 1.06 [9H, s, (CH₃)₃C]; d_C

(62.5 MHz; CDCl₃) 165.8, 138.2, 135.7, 135.4, 133.6, 133.5, 130.5,

129.5, 128.4, 127.8, 127.6, 126.9, 113.0, 88.6, 84.3, 78.6, 71.3,

65.5, 32.7, 27.6, 24.0, 26.8 and 19.2 [C(CH₃)₃]; m/z (CI; NH₃) 513

[(M+H)⁺, 100%]; [m/z (ES). Found: (M+H)⁺, 513.2819. C₃₃H₄₁O₃Si re-

quires M, 513.2825].

4.1.16. (2S,5Z,8S,9R)- and (2R,5Z,8S,9R)-8-Benzyloxy-9-(tert-

butyldiphenylsilanyloxy-methyl)-2-methoxy-2-phenylselanyl-

methyl-2,3,4,7,8,9-hexahydrooxonines 27b and 27a

½

a ²_D⁵

ꢂ

¼ þ63:3 (c 1.26, CHCl₃); m_max(CHCl₃)/cm^ꢀ11746; d_H

(250 MHz; CDCl₃) 9.52 (1H, s, CHO), 7.70–7.74 (2H, m, Ar), 7.57–

7.61 (2H, m, Ar), 7.18–7.43 (11H, m, Ar), 5.71–5.82 (1H, m,

CH@CH), 5.50–5.61 (1H, m, CH@CH), 4.75 (1H, d, J 11.2, OCHHPh),

4.49 (1H, d, J 11.2, OCHHPh), 4.17–4.22 (2H, m), 3.75–3.87 (2H, m),

2.80 (3H, s, OMe), 2.70–2.75 (1H, m), 2.42–2.52 (1H, m), 2.12–2.19

(1H, m), 1.82–2.08 (2H, m), 1.66–1.79 (1H, m), 1.11 [9H, s,

C(CH₃)₃]; d_C(62.5 MHz; CDCl₃) 138.6, 136.0, 135.7, 133.7, 132.2,

129.6, 128.5, 127.5, 125.4, 104.1, 75.3, 73.0, 71.3, 63.5 51.0, 30.4,

25.1, 18.6, 27.0 and 19.5 [C(CH₃)₃]; m/z (CI; NH₃) 576 [(M+NH₄)⁺,

30%], 274 (100); [m/z (ES) Found: (M+NH₄)⁺, 576.3142. C₃₄H₄₆NO_5-

Si requires M, 576.3145].

A solution of phenylselenenyl chloride (0.97 g, 5.38 mmol) in

THF (2 mL, 2 mL rinse) was added dropwise via cannula to a stir-

red solution of the enol ether 26 (1.38 g, 2.69 mmol) in

THF:MeOH (1:1, 16 mL) and NEt₃(0.75 mL) at room temperature.

After addition was complete, the reaction mixture was stirred for

1 h, whereupon a saturated aqueous solution of NaHCO₃(30 mL)

was added, followed by water (20 mL). The organic phase was

separated, and the aqueous layer was extracted with ether

(3 ꢄ 30 mL). The combined organic extracts were washed with

brine (30 mL) and dried (MgSO₄). The solvent was removed in va-

cuo and puriﬁcation by ﬂash chromatography [Brockmann grade

III basic alumina deactivated with water (6% wt/wt); (petroleum

ether 40–60:ether, 25:1] afforded a mixture of the diastereomeric

selenides 27 as a pale yellow oil (1.36 g, 72%). For characterisa-

tion purposes a pure sample of 27b was obtained by further chro-

matography. Data for 27b: R_f0.33 (petroleum ether 40–60:ether,

4.1.18. (2R,5Z,8S,9R)-8-Benzyloxy-9-(tert-butyldiphenylsilanyl-

oxymethyl)-2-methoxy-2-vinyl-2,3,4,7,8,9-hexahydrooxonine

30

NaH (36 mg of a 60% dispersion in mineral oil, 0.9 mmol) was

washed with hexane (3 ꢄ 1 mL). Anhydrous DMSO (2.5 mL) was

S. Y. Frankie Mak et al. / Tetrahedron: Asymmetry 20 (2009) 921–944

933

added and the reaction mixture was heated at 65 °C for 45 min or

until the evolution of H₂gas ceased, leaving a clear grey solution.

The mixture was allowed to cool to room temperature, before a

solution of CH₃PPh₃Br (0.536 g, 1.5 mmol) in DMSO (2 mL) was

added via cannula. The reaction mixture immediately turned yel-

low. After 10 min, a solution of aldehyde 29 (25.0 mg, 0.045 mmol)

in DMSO (1 mL, 0.5 mL rinse) was added via cannula. The reaction

mixture was allowed to stir at room temperature for 1 h, during

which the solution remained yellow. The reaction mixture was

quenched by the addition of water (5 mL) and the layers were sep-

arated. The aqueous layer was extracted with ether (3 ꢄ 15 mL).

The combined organic extracts were washed with water (15 mL),

then with brine (15 mL) and were dried (MgSO₄). The solvent

was removed in vacuo and puriﬁcation by ﬂash chromatography

(petroleum ether 40–60:ether, 6:1) gave title compound 30

(21.2 mg, 85%), which slowly crystallised on standing; mp 126–

127 °C (ether); R_f0.40 (petroleum ether 40–60:ether, 6:1);

dered molecular sieves. The reaction mixture was stirred at room

temperature for 0.5 h whereby the reaction mixture became a

black colour. The reaction mixture was ﬁltered through a plug of

silica and was washed with excess EtOAc. The solvent was re-

moved in vacuo to afford the title compound as a colourless oil

(17.9 mg, 93%), which was used immediately without further puri-

ﬁcation; R_f0.54 (petroleum ether 40–60:ether, 1:1); d_H(400 MHz;

CDCl₃) 9.73 (1H, d, J 2.8, CHO), 7.27–7.44 (5H, m, Ar), 5.84–5.92

(1H, m, CH@CH), 5.50–5.64 (3H, m, CH@CH, CH@CHH, trans

CH@CHH), 5.40 (1H, dd, J 8.6, 4.0, cis CH@CHH), 4.65 (1H, d, J

11.7, OCHHPh), 4.44 (1H, d, J 11.7, OCHHPh), 4.10 (1H, dd, J 9.9,

2.8, H-9), 3.84 (1H, ddd, J 9.9, 3.7, 2.2, H-8), 3.07 (3H, s, OMe),

2.64–2.70 (1H, m), 2.37–2.43 (1H, m), 2.00–2.07 (1H, m), 1.77–

1.86 (3H, m). NaH (24 mg of a 60% dispersion in mineral oil, 0.6

mmol) was washed with hexane (3 ꢄ 1 mL). Anhydrous DMSO

(1.5 mL) was added and the mixture was heated at 65 °C until

the evolution of H₂gas ceased, leaving a clear grey solution. The

mixture was allowed to cool to room temperature, before a solu-

tion of CH₃PPh₃Br (0.32 g, 1.5 mmol) in DMSO (1 mL) was added

via cannula. The reaction mixture immediately turned yellow in

colour and after 10 min, a solution of (2S,5Z,8S,9R)-8-benzyloxy-

2-methoxy-2-vinyl-2,3,4,7,8,9-hexahydro-oxonine-9-carbaldehyde

(27.2 mg, 0.086 mmol) in DMSO (1 mL, 0.5 mL rinse) was added via

cannula. The reaction mixture remained yellow and was allowed to

stir at room temperature for 45 min. The reaction mixture was

quenched by the addition of water (15 mL) and the layers were

separated. The aqueous layer was extracted with ether (4 ꢄ 50

mL). The combined organic extracts were washed with half satu-

rated brine (20 mL) and dried (MgSO₄). The solvent was removed

in vacuo and puriﬁcation by ﬂash chromatography (petroleum

ether 40–60:ether:CH₂Cl₂, 5:1:4) afforded title compound 31

(23.1 mg, 85%) as a colourless oil; R_f0.70 (petroleum ether 40–

½

a ²_D⁵

ꢂ

¼ þ110:4 (c 0.58, CHCl₃); m_max(CHCl₃)/cm^ꢀ12930, 2844; d_H

(500 MHz; CDCl₃) 7.71–7.73 (2H, m, Ar), 7.57–7.59 (2H, m, Ar),

7.17–7.38 (11H, m, Ar), 5.77–5.83 (1H, m, CH@CH), 5.66 (1H, dd,

J 17.1, 1.7, trans CHH@CH), 5.51–5.55 (1H, m, CH@CH), 5.49 (1H,

dd, J 10.5, 1.7, CH@CHH), 5.39 (1H, dd, J 10.5 and 1.7, cis CHH@CH),

4.73 (1H, d, J 11.2, OCHHPh), 4.45 (1H, d, J 11.2, OCHHPh), 4.20 (1H,

d, J 11.0, CHHOSi), 4.15–4.17 (1H, m, H-8), 3.79 (1H, d, J 11.0,

CHHOSi), 3.69 (1H, d, J 9.4, H-9), 2.70–2.72 (1H, m, H-7), 2.65

(3H, s, OMe), 2.39–2.43 (1H, m, H-7), 2.05–2.13 (1H, m, H-4),

1.68–1.83 (3H, m, H-4, 2 ꢄ H-3), 1.11 [9H, s, (CH₃)₃C]; d_C

(100 MHz; CDCl₃) 138.8, 136.0, 135.8, 134.1, 134.0, 133.0, 129.5,

128.3, 127.5, 127.4, 127.3, 124.9, 118.4, 104.3, 76.0, 71.7, 71.1,

63.2, 50.3, 34.2, 25.1, 19.3, 27.0 and 19.3 [C(CH₃)₃]; m/z (ES) 574

[(M+NH₄)⁺, 25%]; [m/z (ES) Found: (M+NH₄)⁺, 574.3358.

C₃₅H₄₈NO₄Si requires M, 574.3533].

60:ether, 1:1); ½a _D²⁵

ꢂ

¼ þ231:5 (c 0.4, CHCl₃); m_max(CHCl₃)/cm^ꢀ1

4.1.19. (2R,5Z,8S,9R)-8-Benzyloxy-9-hydroxymethyl-2-

2932, 2857; d_H(500 MHz; CDCl₃) 7.27–7.55 (5H, m, Ar), 5.75–

5.87 (2H, m, CH@CH, CH@CHH), 5.53–5.59 (2H, m, CH@CH,

CH⁰@CH⁰H⁰), 5.50 (1H, dd, J 17.3, 2.6, trans CH@CHH), 5.35 (1H,

dd, J 10.0, 2.6, cis CH@CHH), 5.28 (1H, dd, J 17.7, 1.5, trans

CH⁰@CH⁰H⁰), 5.21 (1H, dd, J 10.3, 1.5, cis CH⁰@CH⁰H⁰), 4.63 (1H, d, J

11.7, OCHHPh), 4.49 (1H, d, J 11.7, OCHHPh), 4.02 (1H, t, J 8.9, H-

8), 3.47–3.50 (1H, m, H-9), 3.05 (3H, s, OMe), 2.74 (1H, dd, J 12.3

and 12.3), 2.27–2.32 (1H, m), 2.05–2.11 (1H, m), 1.90–1.94 (1H,

m) and 1.74–1.82 (2H, m); d_C(100 MHz; CDCl₃) 139.1, 138.1,

133.6, 128.7, 127.7, 118.3, 117.4, 103.8, 79.5, 72.8, 71.8, 51.0,

34.5, 26.0, 19.2; m/z (CI; NH₃) 315 [(M+H)⁺, 20%], 383 (100); [m/z

(ES) Found: (M+H)⁺, 315.1964. C₂₀H₂₇O₃requires M, 315.1960].

Triene 31 was also prepared from the dialdehyde 33. To a solu-

tion of the dialdehyde 33 (10.9 mg, 0.034 mmol) in THF (1 mL) in a

Schlenk tube at room temperature, was added the Tebbe reagent

(0.17 mL of a 0.5 M solution in PhMe, 0.085 mmol). The reaction

mixture was stirred for 40 min at room temperature whereupon

a 10% aqueous NaOH solution was added dropwise to quench the

reaction. It was stirred for another 30 min at this temperature until

gas evolution and dark green precipitation ceased. Ether (5 mL)

was added to this mixture and the resultant suspension was ﬁl-

tered through a short pad of silica. The ﬁltrate was concentrated

in vacuo to give the crude product. Puriﬁcation by ﬂash column

chromatography (petroleum ether 40–60:ether:CH₂Cl₂, 5:1:4)

yielded the title compound 31 as a colourless oil (5.0 mg, 45%).

methoxy-2-vinyl-2,3,4,7,8,9-hexahydrooxonine

To a stirred solution of oxonine 30 (0.21 g, 0.37 mmol) in THF (6

mL) at 0 °C, was added a solution of TBAF (3.8 mL of a 1.0 M solu-

tion in THF, 3.8 mmol). The reaction mixture was allowed to warm

to room temperature and was then stirred for 5 days, before being

quenched by the addition of water (10 mL). The organic phase was

separated and the aqueous layer was extracted with ether (3 ꢄ 15

mL). The combined organic extracts were washed with brine (15

mL) and dried (MgSO₄). The solvent was removed in vacuo and

puriﬁcation by ﬂash chromatography (petroleum ether 40–

60:ether, 1:1) gave the title compound (0.12 g, 99%), which crystal-

lised on standing; mp 54–55 °C (ether); R_f0.26 (petroleum ether

40–60:ether, 1:1); ½a _D²⁵

¼ þ224 (c 0.36, CHCl₃); m_max(CHCl₃)/

ꢂ

cm^ꢀ13472, 3017, 2947; d_H(400 MHz; CDCl₃) 7.26–7.36 (5H, m,

Ar), 5.81–5.86 (1H, m, CH@CH), 5.54 (1H, dd, J 17.3, 9.6, CH@CHH),

5.52–5.55 (1H, m, CH@CH), 5.52 (1H, dd,

J 17.3, 3.0, trans

CH@CHH), 5.41 (1H, dd, J 9.6, 3.0, cis CH@CHH), 4.71 (1H, d, J

11.5, OCHHPh), 4.50 (1H, d, J 11.5, OCHHPh), 3.80–3.84 (2H, m),

3.68–3.79 (2H, m), 3.20 (3H, s, OMe), 2.60–2.67 (2H, m), 2.33–

2.39 (1H, m), 2.03–2.07 (1H, m), 1.90–1.95 (1H, m), 1.80–1.86

(1H, m); d_C(100 MHz; CDCl₃) 138.1, 134.7, 133.1, 128.5, 127.9,

127.8, 124.7, 118.9, 104.5, 76.5, 72.3, 71.3, 63.0, 50.5, 33.8, 25.3,

19.4; m/z (ESI) 341 [(M+Na)⁺, 100%], 336 [(M+NH₄)⁺, 20]; [m/z

(ES) Found: (M+Na)⁺, 341.1726. C₁₉H₂₆NaO₄requires M, 341.1729].

4.1.20. (2R,5Z,8S,9R)-8-Benzyloxy-2-methoxy-2-vinyl-2,3,4,7,8,

9-hexahydrooxonine-9-carbaldehyde and (2R,5Z,8S,9R)-8-benzyl-

oxy-2-methoxy-2,9-divinyl-2,3,4,7,8,9-hexahydrooxonine 31

To a stirred solution of (2S,5Z,8S,9R)-8-benzyloxy-9-hydroxy-

methyl-2-methoxy-2-vinyl-2,3,4,7,8,9-hexahydro-oxonine (19.3

mg, 0.061 mmol) in CH₂Cl₂(2.5 mL) were added TPAP (0.9 mg,

0.002 mmol), NMO (31 mg, 0.27 mmol) and activated 4 Å pow-

4.1.21. (2R,8S,9R,5Z)-2-Methoxy-2-hydroxymethyl-8-benzyloxy-

9-(tert-butyldiphenylsilanyloxymethyl)-2,3,4,7,8,9-hexahydro-

oxonine

To a solution of selenides 28 (0.657 g, 0.86 mmol) in THF at 0 °C

(10 mL) was added a solution of LiAlH₄(3.5 mL of a 1.0 M solution

in THF, 3.50 mmol). The reaction mixture was stirred at this tem-

perature for 1 h and was then quenched by addition of a saturated

934

S. Y. Frankie Mak et al. / Tetrahedron: Asymmetry 20 (2009) 921–944

solution of aqueous NH₄Cl (10 mL). The layers were separated and

the aqueous layer was extracted with ether (3 ꢄ 30 mL). The com-

bined organic extracts were dried (MgSO₄), ﬁltered and concen-

trated in vacuo to give the crude product. Puriﬁcation by ﬂash

column chromatography (petroleum ether 40–60:ether, 1:1) gave

title compound (0.407 g, 55% from 27b) as a colourless oil; R_f

3.20 (3H, s, OMe), 2.71 (1H, m), 2.20–2.24 (1H, m), 1.75–1.76

(1H, m), 1.93–1.98 (3H, m).

4.1.24. (1S,3S,4R,6R,9R)-3-Benzyloxy-6-methoxy-4,6-divinyl-

5,10-dioxabicyclo[7.1.0]decane 34

To a stirred solution of the oxonine 31 (8 mg, 0.025 mmol) in

CH₂Cl₂(1.5 mL) was added mCPBA (100%; 6 mg, 0.036 mmol) at

0 °C. The reaction mixture was stirred for 5 min at 0 °C and was

then allowed to warm to room temperature over 14 h. The reaction

mixture was quenched by the addition of water (5 mL) and the lay-

ers were separated. The aqueous layer was extracted with CH₂Cl₂

(3 ꢄ 10 mL). The combined organic extracts were washed with

brine (10 mL) and dried (MgSO₄). The solvent was removed in va-

cuo and puriﬁcation by ﬂash chromatography (petroleum ether

40–60:ether, 1:1) afforded the title epoxide 34 as a clear and col-

ourless oil (5 mg, 57%); R_f0.40 (petroleum ether 40–60:ether,

0.25 (petroleum ether 40–60:ether, 1:1); ½a _D²⁵

¼ þ5:5 (c 0.13,

ꢂ

CHCl₃); m_max(CHCl₃ﬁlm)/cm^ꢀ13432, 3016; d_H(400 MHz; CDCl₃)

7.76 (2H, d, J 7.7, Ar), 7.64 (2H, d, J 6.7, Ar), 7.26–7.41 (11H, m,

Ar), 5.85–5.92 (1H, m, CH@CH), 5.59–5.65 (1H, m, CH@CH), 4.82

(1H, d, J 11.0, OCHHPh), 4.53 (1H, d, J 11.0, OCHHPh), 4.24–4.27

(1H, m, H-9), 4.13–4.16 (1H, m, H-8), 3.70–3.95 (4H, m, CH₂OSi,

CH₂OH), 2.86 (3H, s, OMe), 2.78–2.84 (1H, m), 2.58–2.64 (1H, m),

2.01–2.35 (3H, m), 1.74–1.79 (1H, m) 1.11 [9H, s, C(CH₃)₃]; d_C

(100 MHz; CDCl₃) 138.6, 136.0, 135.7, 133.7, 133.6, 132.7, 129.6,

129.5, 128.3, 127.7, 127.6, 127.5, 127.4, 125.1, 104.3, 76.7, 72.1,

71.0, 63.2, 62.1, 49.8, 27.0, 30.8, 29.1, 25.1, 19.6; m/z (CI; NH₃)

583 [(M+H)⁺, 100%]; [m/z (ES) Found: (M+NH₄)⁺578.3302,

C₃₄H₄₈O₅NSi requires M, 578.3296].

1:1); ½a ²_D⁵

ꢂ

¼ þ129:4 (c 0.48, CHCl₃); m_max(CHCl₃)/cm^ꢀ12933; d_H

(500 MHz; CDCl₃) 7.28–7.36 (5H, m, Ar), 5.76 (1H, ddd, J 17.3,

10.0, 8.3, CH@CHH), 5.52 (1H, dd, J 17.3, 10.5, CH⁰@CH⁰H⁰), 5.40

(1H, dd, J 17.3, 1.7, trans CH@CHH), 5.30–5.34 (2H, m, trans

CH⁰@CH⁰H⁰, cis CH⁰@CH⁰H⁰), 5.27 (1H, d, J 10.0, cis CH@CHH), 4.65

(1H, d, J 11.5, OCHHPh), 4.51 (1H, d, J 11.5, OCHHPh), 4.16 (1H,

dd, J 9.0 and 9.0, H-4), 3.54–3.57 (1H, m, H-3), 3.25 [1H, dt, J

11.0, 3.5, CH(O)CH], 3.05 (3H, s, OMe), 3.00 [1H, dt, J 11.0, 4.2,

CH(O)CH], 2.39–2.43 (1H, m), 1.94–2.05 (2H, m), 1.72–1.80 (2H,

m), 1.05–1.10 (1H, m); d_C(62.5 MHz; CDCl₃) 138.8, 138.4, 138.1,

128.4, 127.9, 127.7, 118.7, 117.8, 103.5 (C-6), 78.8, 73.0, 72.3,

57.2, 52.9, 51.2, 28.8, 26.4, 20.5; m/z (CI; NH₃) 348 [(M+NH₄)⁺,

10%], 331 [(M+H)⁺, 40], 299 (100); [m/z (ES) Found: (M+H)⁺,

331.1903. C₂₀H₂₇O₄requires M, 331.1909].

4.1.22. (2R,8S,9R,5Z)-2-Methoxy-2,9-dihydroxymethyl-8-

benzyloxy-2,3,4,7,8,9-hexahydrooxonine 32

To a stirred solution of (2R,8S,9R,5Z)-2-methoxy-2-hydroxy-

methyl-8-benzyloxy-9-(tert-butyldiphenylsilanyloxymethyl)-2,3,

4,7,8,9-hexahydrooxonine (0.407 g, 0.73 mmol) in THF at 0 °C was

added TBAF (3.6 mL of a 1.0 M solution in THF, 3.6 mmol). The

reaction mixture was allowed to warm to room temperature and

was stirred for 22 h. The reaction mixture was quenched by the

addition of water (10 mL). The layers were separated and the aque-

ous layer was extracted with EtOAc (3 ꢄ 10 mL). The combined or-

ganic extracts were washed with brine (10 mL) and dried (Na₂SO₄).

The solvent was removed in vacuo and the resultant crude product

was puriﬁed by ﬂash column chromatography (petroleum ether

40–60:ether 1:1, increasing polarity by replacing the eluant with

EtOAc), furnishing the title diol 32 as a white solid (0.209 g,

4.1.25. (2R,8S,9R)-8-Benzyloxy-9-(tert-butyldiphenylsilanyloxy-

methyl)-2-methoxy-2,3,4,5,6,7,8,9-octahydrooxonine-2-

carbaldehyde 35

To a stirred solution of the aldehyde 29 (15 mg, 0.027 mmol) in

EtOAc (1.5 mL) was added PtO₂(3 mg, 0.013 mmol, 50 mol%) and

the reaction mixture was stirred for 3.5 h under a hydrogen atmo-

sphere maintained by inﬂated balloon. The reaction mixture was ﬁl-

tered through a plug of Celite^TMand was washed with EtOAc (2 ꢄ 3

mL). Thesolventwasremovedinvacuotofurnishthetitlecompound

35 as a clear and colourless oil (15 mg, 100%); R_f0.39 (petroleum

89%); R_f0.16 (ether); mp. 133–135 °C; ½a _D²⁵

¼ þ162:1 (c 0.68,

ꢂ

CHCl₃); m_max(CHCl₃ﬁlm)/cm^ꢀ13506; d_H(500 MHz; CDCl₃) 7.31–

7.74 (5H, m, Ar), 5.61–5.90 (1H, m, CH@CH), 5.56–5.61 (1H, m,

CH@CH), 4.73 (1H, d, J 11.5, OCHHPh), 4.50 (1H, d, J 11.5, OCHHPh),

3.63–3.82 (6H, m, 2 ꢄ CH₂OH, H-8, H-9), 3.36 (3H, s, OMe), 2.61

(1H, m), 2.40 (2H, m), 2.00–2.13 (1H, m), 1.59–1.74 (2H); d_C

(100 MHz; CDCl₃) 137.9, 132.9, 129.6, 129.0, 128.5, 127.9, 127.7,

124.8, 104.6, 76.0, 72.7, 71.2, 61.7, 63.1, 50.1, 30.3, 29.7, 25.1; m/

ether 40–60:ether, 10:1); ½a _D²⁵

ꢂ

¼ þ15:5 (c 0.85, CHCl₃);

m_max(neat)/

cm^ꢀ11745; d_H(250 MHz; CDCl₃) 9.46 (1H, s, CHO), 7.63–7.76 (4H,

m, Ar), 7.27–7.42 (11H, m, Ar), 4.63 (1H, d, J 11.3, OCHHPh), 4.44

(1H, d, J 11.3, OCHHPh), 4.11–4.18 (2H, m), 3.93–3.98 (2H, m), 3.80

(1H, dd, J 10.9, 2.4), 2.85 (3H, s, OMe), 1.26–2.05 (10H, m), 1.10

[9H, s, C(CH₃)₃]; d_C(62.5 MHz; CDCl₃) 201.2 (CHO), 138.9, 135.9,

135.7, 133.7, 129.6, 128.3, 127.6, 127.5, 127.4, 103.9, 72.0, 71.1,

64.5, 51.5, 28.1, 26.1, 23.1, 18.4, 18.2, 27.0 and 19.5 [C(CH₃)₃]; m/z

(CI; NH₃) 578 [(M+NH₄)⁺, 80%], 361 (100); [m/z (ES) Found:

(M+NH₄)⁺, 578.3303. C₃₄H₄₈NO₅Si requires M, 578.3302].

z

(CI; NH₃) 340 [(M+NH₄)⁺, 5%]; [m/z (ES) Found: (M+H)⁺

323.1849, C₁₈H₂₇O₅requires M, 323.1853].

4.1.23. (2S,8S,9R,5Z)-2-Methoxy-8-benzyloxy-2,3,4,7,8,9-

hexahydrooxonine-2,9-dicarbaldehyde, 33

To a solution of oxalyl chloride (32

lL, 0.36 mmol) in CH₂Cl₂(1

mL) at ꢀ50 °C in a Schlenk tube, was slowly added DMSO (52

lL,

0.73 mmol). The reaction mixture was stirred at this temperature

for 30 min, followed by the addition of diol 32 (29.4 mg, 0.094

mmol) in CH₂Cl₂(1 mL, 1 mL rinse). The reaction mixture was stir-

red for 1.5 h at this temperature, whereupon Et₃N (0.20 mL, 1.44

mmol) was added. The reaction mixture was allowed to warm to

room temperature over a period of 30 min and the solvent was re-

moved in vacuo to give the crude product. EtOAc (10 mL) was

added to give a white suspension, which was ﬁltered and the resul-

tant clear ﬁltrate was concentrated in vacuo, furnishing the unsta-

ble dialdehyde 33 as a yellow oil (26.8 mg, 92%), which was used

immediately for the preparation of triene 31 without further puri-

ﬁcation; d_H(500 MHz; CDCl₃) 9.76 (1H, d, J 2.5, CHO), 9.40 (1H, s,

CHO), 7.27–7.49 (5H, m, Ar), 5.82–5.88 (1H, m, CH@CH), 5.57–

5.60 (1H, m, CH@CH), 4.67 (1H, d, J 11.6, OCHHPh), 4.45 (1H, d, J

11.6, OCHHPh), 4.16 (1H, dd, J 9.9, 2.5, H-9), 3.93 (1H, m, H-8),

4.1.26. (2R,8S,9R)-8-Benzyloxy-9-(tert-butyldiphenylsilanyl-

oxymethyl)-2-methoxy-2-vinyl-2,3,4,5,6,7,8,9-octahydroox-

onine

At ﬁrst, NaH (30 mg of a 60% dispersion in mineral oil, 0.75

mmol) was washed with hexane (3 ꢄ 2 mL). Anhydrous DMSO

(1.7 mL) was added and the mixture was heated at 65 °C for 40

min or until the evolution of H₂gas ceased, leaving a clear grey

solution. The mixture was allowed to cool to room temperature,

before a solution of CH₃PPh₃Br (0.27 g, 0.76 mmol) in DMSO (1.5

mL) was added via cannula. The reaction mixture immediately

turned yellow in colour. After 5 min, a solution of the aldehyde

35 (59 mg, 0.11 mmol) in DMSO (1 mL, 0.5 mL rinse) was added

via cannula. The reaction mixture remained yellow and was al-

lowed to stir for 40 min at room temperature. The reaction mixture

S. Y. Frankie Mak et al. / Tetrahedron: Asymmetry 20 (2009) 921–944

935

was quenched by the addition of water (5 mL) and EtOAc (5 mL)

4.1.29. (2R,8S,9R)-8-Benzyloxy-2-methoxy-2,9-divinyl-

and the layers were separated. The aqueous layer was extracted

with EtOAc (3 ꢄ 20 mL). The combined organic extracts were

washed with half saturated brine (20 mL) and dried (MgSO₄).

The solvent was removed in vacuo and puriﬁcation by ﬂash chro-

matography (petroleum ether 40–60:EtOAc, 10:1) furnished the ti-

tle compound (31.6 mg, 54%) as a clear and colourless oil; R_f0.38

2,3,4,5,6,7,8,9-octahydrooxonine 36

At ﬁrst, NaH (18 mg of a 60% dispersion in mineral oil, 0.45 mmol)

was washed with hexane (3 ꢄ 1.5 mL). Anhydrous DMSO (1 mL) was

added and the mixture was heated at 65 °C for 40 min or until the

evolution of H₂gas ceased, leaving a clear grey solution. The mixture

was allowed to cool to room temperature and then a solution of

CH₃PPh₃Br (0.265 g, 0.74 mmol) in DMSO (1 mL) was added via can-

nula. The reaction mixture immediately turned yellow in colour.

After 10 min at room temperature, a solution of (2R,8S,9R)-8-benzyl-

oxy-2-methoxy-2-vinyl-2,3,4,5,6,7,8,9-octahydrooxonine-2-carb-

aldehyde (15.2 mg, 0.048 mmol) in DMSO (1 mL, 0.5 mL rinse) was

added via cannula. The reaction mixture was stirred for a further

40 min at room temperature and was then quenched by the addition

of water (5 mL) and EtOAc (5 mL). The organic phase was separated

and the aqueous layer was extracted with EtOAc (4 ꢄ 20 mL). The

combined organic extracts were washed with half saturated brine

(20 mL) and dried (MgSO₄). The solvent was removed in vacuo and

puriﬁcation by ﬂash chromatography (petroleum ether 40–

60:ether, 9:1) afforded the alkene 36 (14 mg, 93%) as a clear and col-

(petroleum ether 40–60:ether, 10:1); ½a _D²⁵

¼ þ35:2 (c 1.9, CHCl₃);

ꢂ

m_max(neat)/cm^ꢀ12931, 2855; d_H(250 MHz; CDCl₃) 7.64–7.77

(4H, m, Ar), 7.23–7.43 (11H, m, Ar), 5.63 (1H, dd, J 17.2, 3.3, trans

CH@CHH), 5.54 (1H, dd, J 17.2, 9.8, CH@CHH), 5.77 (1H, dd, J 9.8,

3.3, cis CHH@CH), 4.62 (1H, d, J 11.3, OCHHPh), 4.41 (1H, d, J

11.3, OCHHPh), 4.11–4.21 (2H, m, CHHOSi, H-8), 3.89–3.92 (1H,

m, CHHOSi), 3.71–3.76 (1H, m, H-9), 2.77 (3H, s, OMe), 1.37–

1.99, (10H, m), 1.12 [9H, s, (CH₃)₃C]; d_C(100 MHz; CDCl₃) 139.2,

138.1, 136.0, 135.8, 134.0, 129.5, 128.3, 127.5, 127.4, 127.2,

118.3, 104.0, 70.8, 70.7, 64.0, 50.9, 31.3, 25.8, 22.7, 19.5, 18.3,

27.0 and 19.1 [C(CH₃)₃]; m/z (ES) 581 [(M+Na)⁺, 70%]; [Found:

(M+Na)⁺, 581.3065. C₃₅H₄₆NaO₄Si requires M, 581.3065].

4.1.27. (2R,8S,9R)-8-Benzyloxy-9-hydroxymethyl-2-methoxy-2-

vinyl-2,3,4,5,6,7,8,9-octahydrooxonine

ourless oil. R_f0.25 (petroleum ether 40–60:ether, 9:1); ½a _D²³

¼ þ32:6

ꢂ

(c 0.39, CHCl₃); m_max(neat)/cm^ꢀl2930, 2855, 1645; d_H(400 MHz;

CDCl₃) 7.24–7.36 (5H, m, Ar), 5.84 (1H, ddd, J 17.4, 10.5, 7.4,

CH@CHH), 5.56 (1H, dd, J 17.4, 10.3, CH⁰@CH⁰H⁰), 5.47 (1H, dd, J

17.4, 2.6, trans-CH@CHH), 5.32 (1H, dd, J 10.5, 2.6, cis-CH@CHH),

5.29 (1H, dd, J 17.4, 2.0, trans-CH⁰@CH⁰H⁰), 5.19 (1H, dd, J 10.3, 2.0,

cis-CH⁰@CH⁰H⁰), 4.55 (1H, d, J 11.7, OCHHPh), 4.39 (1H, d, J 11.7,

OCHHPh), 4.27–4.31 (1H, m, H-9), 3.42 (1H, ddd, J 9.2, 6.7, 1.9, H-

8), 3.04 (3H, s, OMe), 1.27–1.97 (9H, m), 0.81–0.94 (1H, m); d_C

(100 MHz; CDCl₃) 139.6, 138.3, 128.5, 128.2, 127.8, 127.4, 127.4,

118.2, 116.2, 103.7, 81.6, 71.6, 71.1, 51.8, 31.7, 25.7, 23.5 18.7 18.2;

m/z (ES) 339 [(M+Na)⁺, 85%]; [Found: (M+Na)⁺, 339.1935.

C₂₀H₂₈NaO₃requires M, 339.1936].

To a stirred solution of (2R,8S,9R)-8-benzyloxy-9-(tert-butyldi-

phenylsilanyloxymethyl)-2-methoxy-2-vinyl-2,3,4,5,6,7,8,9-octa-

hydrooxonine (31.6 mg, 0.056 mmol) in THF (1.2 mL) at 0 °C was

added TBAF (0.56 mL of a 1.0 M solution in THF, 0.56 mmol). The

reaction mixture was stirred at 0 °C for 30 min and then at room tem-

perature for 18 h. The reaction mixture was quenched by the addi-

tion of water (5 mL) and ether (5 mL) and the layers were

separated. The aqueous layer was extracted with ether (3 ꢄ 10 mL)

and the combined organic extracts were washed with brine (10

mL) and dried (MgSO₄). The solvent was removed in vacuo and puri-

ﬁcation by ﬂash chromatography (petroleum ether 40–60:ether,

1:1) furnished the title compound (17.8 mg, 81%) as a clear and col-

ourless oil; R_f0.29 (petroleumether 40–60:ether, 1:1); ½a _D²⁵

ꢂ

¼ þ95:4

4.1.30. (2R,5Z,8S,9R)- and (2S,5Z,8S,9R)-8-(tert-Butyldiphenylsil-

anyloxy)-9-(tert-butyl-diphenylsilanyloxymethyl)-2-methoxy-

2-phenylselanylmethyl-2,3,4,7,8,9-hexahydrooxonines 37a and

37b

(c 0.89, CHCl₃); m_max(neat)/cm^ꢀl3462, 2935; d_H(250 MHz; CDCI₃)

7.28–7.35 (5H, m, Ar), 5.55–5.66 (1H, m, CHH@CH), 5.46 (1H, dd, J

17.4, 2.4, trans-CHH@CH), 5.37 (1H, dd, J 10.2, 2.4, cis-CHH@CH),

4.63 (1H, d, J 11.4, OCHHPh), 4.42 (1H, d, J 11.4, OCHHPh), 3.96–

4.02 (1H, m, H-9), 3.67–3.77 (3H, m, 2 ꢄ CH₂OH, H-8), 3.19 (3H, s,

OMe), 2.56–2.61 (1H, m), 1.44–1.93 (9H, m); d_C(100 MHz; CDCl₃)

138.4, 137.6, 128.4, 127.8, 118.4, 104.5, 78.0, 71.0, 70.9, 63.6, 51.1,

31.1, 26.0, 22.3, 18.5, 18.2; m/z (ES) 343 [(M+Na)⁺, 100%]; [Found:

(M+Na)⁺, 343.1875. C₁₉H₂₈NaO₄requires M, 343.1875].

To a stirred solution of enol ether 9 (0.504 g, 0.76 mmol) in

THF–MeOH (1:1; 4 mL) and NEt₃(0.17 mL, 1.22 mmol) at room

temperature was added a solution of phenylselenenyl chloride

(0.146 g, 0.76 mmol) in THF (1.5 mL) via cannula. After addition

was complete, the reaction mixture was stirred for 0.5 h, before

being quenched by the addition of a saturated aqueous solution

of NaHCO₃(20 mL) and water (10 mL). The organic phase was sep-

arated and the aqueous layer was extracted with ether (3 ꢄ 50 mL).

The combined organic extracts were washed with brine (20 mL)

and dried (MgSO₄). The solvent was removed in vacuo and puriﬁ-

cation by ﬂash chromatography [Brockmann grade III basic alu-

mina deactivated with water (6% wt/wt); (petroleum ether 40–

60:ether, 25:1)] afforded the starting material 9 (0.195 g, 38%)

and a mixture of the diastereomeric selenides 37 as a pale yellow

oil (0.287 g, 44%). Data for 37a: R_f0.32 (petroleum ether 40–

4.1.28. (2R,8S,9S)-8-Benzyloxy-2-methoxy-2-vinyl-2,3,4,5,6,7,8,9-

octahydrooxonin-2-carbaldehyde

To

a stirred solution of (2R,8S,9R)-8-benzyloxy-9-hydroxy-

methyl-2-methoxy-2-vinyl-2,3,4,5,6,7,8,9-octahydrooxonine (17.8

mg, 0.056 mol) in CH₂Cl₂(2.5 mL) were added NMO (28.6 mg,

0.24 mmol) and activated 4 Å powdered molecular sieves. The

reaction mixture was stirred for 20 min at room temperature,

and then TPAP (4 mg, 0.011 mmol, 20 mol %) was added. The reac-

tion mixture was stirred for 1 h at room temperature before being

ﬁltered through a plug of silica and was then washed with EtOAc

(excess). The solvent was removed in vacuo affording the title com-

pound as a clear and colourless oil (15.2 mg, 86%); R_f0.58 (petro-

leum ether 40–60:ether, 1:1); d_H(400 MHz; CDCl₃) 9.67 (1H, d, J

2.6, CHO), 7.27–7.35 (5H, m, Ar), 5.59 (1H, dd, J 17.4, 9.8, trans-

CH@CHH), 5.51–5.56 (1H, m, CH@CHH), 5.38 (1H, dd, J 9.8, 2.9,

cis-CHH@CH), 4.59 (1H, d, J 11.7, OCHHPh), 4.36 (1H, d, J 11.7,

OCHHPh), 4.30 (1H, dd, J 9.7, 2.6, H-9), 3.80 (1H, ddd, J 9.7, 6.9,

1.8, H-8), 3.02 (3H, s, OMe), 1.96–2.04 (1H, m), 1.83–1.89 (1H,

m), 1.38–1.80 (8H, m). The aldehyde was found to be unstable

and was used immediately without further puriﬁcation in the

preparation of the diene 36.

60:ether, 10:1); ½a _D²²

ꢂ

¼ þ68:2 (c 0.20, CHCl₃); m_max(CHCl₃)/cm^ꢀl

2930, 2856; d_H(500 MHz; CDCl₃) 7.77 (2H, d, J 6.9, Ar), 7.64–7.70

(5H, m, Ar), 7.23–7.47 (18H, m, Ar), 5.54–5.59 (1H, m, H-5),

5.10–5.15 (1H, m, H-6), 4.30–4.33 (1H, m, H-8), 4.14 (1H, dd, J

11.1, 3.3, CHHOSi), 3.97–3.99 (1H, m, CHHOSi), 3.78–3.80 (1H, m,

H-9), 3.07–3.18 (2H, m, CH₂Se), 2.78 (3H, s, OMe), 2.38 (1H, t, J

11.5, H-7), 1.96–2.06 (2H, m, H-7, H-3), 1.77–1.89 (2H, m, H-3,

H-4), 1.67–1.74 (1H, m, H-4), 1.03 [9H, s, (CH₃)₃C], 0.97 [9H, s,

(CH₃)₃C]; d_C(62.5 MHz; CDCl₃) 136.1, 136.0, 135.9, 135.6, 134.5,

134.3, 134.1, 134.0, 133.3, 132.8, 131.1, 130.7, 129.6, 129.5,

129.0, 127.6, 127.5, 126.9, 126.1, 105.3, 75.6, 70.8, 65.4, 49.8,

33.1, 32.8, 30.9, 19.5, 27.2, 19.9, [C(CH₃)₃], 27.0, 19.5 [C(CH₃)₃];

936

S. Y. Frankie Mak et al. / Tetrahedron: Asymmetry 20 (2009) 921–944

m/z (ESI) 871 [(M+Na)⁺, 100%]; [m/z (ES) Found: (M+Na)⁺,

871.3082. C₄₉H₆₀NaO₄SeSi₂requires M, 871.3093].

or until the evolution of H₂gas ceased, leaving a clear grey solu-

tion. The mixture was allowed to cool to room temperature, before

a solution of CH₃PPh₃Br (0.56 g, 1.57 mmol) in DMSO (1.5 mL) was

added via cannula. The reaction mixture immediately turned yel-

low. After 10 min, a solution of aldehyde 39a (163 mg, 0.23 mmol)

in DMSO (1 mL, 0.5 mL rinse) was added via cannula. The reaction

mixture was allowed to stir at room temperature for 1.5 h. The

reaction mixture was quenched by the addition of water (5 mL)

and the layers were separated. The aqueous layer was extracted

with EtOAc (4 ꢄ 60 mL). The combined organic extracts were

washed with half saturated brine (50 mL) and dried (MgSO₄).

The solvent was removed in vacuo and puriﬁcation by ﬂash chro-

matography (petroleum ether 40–60:EtOAc, 20:1) gave the diene

40 (124 mg, 76%) as a colourless oil; R_f0.50 (petroleum ether

4.1.31. (2R,5Z,8S,9R)- and (2S,5Z,5S,9R)-8-(tert-Butyldiphenylsil-

anyloxy)-9-(tert-butyldiphenylsilanyloxymethyl)-2-methoxy-

2,3,4,7,8,9-hexahydrooxonine-2-carbaldehydes 39a and 39b

To a stirred solution of selenides 37 (0.31 g, 0.36 mmol) in a

mixture of CH₂Cl₂(9 mL) and MeOH (18 mL) was added water

(2.5 mL) until material started to precipitate out of solution. NaH-

CO₃(40 mg, 0.48 mmol) and NaIO₄(0.254 g, 1.19 mmol) were

added and the cloudy white suspension was stirred at room tem-

perature for 2.25 h. The reaction mixture was quenched by the

addition of water (30 mL) and the layers were separated. The aque-

ous layer was extracted with CH₂Cl₂(3 ꢄ 40 mL) and the combined

organic extracts were washed with brine (20 mL) and dried

(MgSO₄). The solvent was removed in vacuo to furnish the corre-

sponding selenoxides as a yellow foam. The selenoxides were dis-

solved in THF (15 mL) and were cooled to ꢀ78 °C. NaOAc (0.112 g,

1.37 mmol) and Ac₂O (0.20 mL, 2.16 mmol) were added and the

resultant suspension was stirred at ꢀ78 °C for 5 min and was then

allowed to warm to room temperature over 0.5 h. The reaction

mixture was heated at reﬂux for 1.25 h and was then allowed to

cool to room temperature, before being quenched by the addition

of water (20 mL). The organic phase was separated and the aque-

ous layer was extracted with EtOAc (3 ꢄ 30 mL). The combined or-

ganic extracts were washed with brine (20 mL) and dried (MgSO₄).

The solvent was removed in vacuo and the resultant crude mate-

rial, the acetates 38, was dissolved in a mixture of CH₂Cl₂(2 mL)

and MeOH (5 mL). An excess of K₂CO₃(ꢃ0.4 g) was added and

the mixture was stirred for 18 h at room temperature. After this

time, water (30 mL) was added and the layers were separated.

The aqueous layer was extracted with CH₂Cl₂(3 ꢄ 30 mL) and

the combined organic extracts were washed with brine (30 mL)

and dried (MgSO₄). The solvent was removed in vacuo and puriﬁ-

cation by ﬂash chromatography (hexane–ether, 10:1) yielded the

aldehydes 39 as clear and colourless oils (0.16 g, 63%). Data for

40–60:ether, 10:1); ½a _D²⁵

¼ þ89:5 (c 1.0, CHCl₃); m_max(CHCl₃)/

ꢂ

cm^ꢀ12931, 2890, 2856; d_H(250 MHz; CDCl₃) 7.60–7.77 (8H, m,

Ar), 7.26–7.40 (12H, m, Ar), 5.38–5.70 (3H, m, H-5, H-6, CH@CHH),

5.00–5.30 (2H, m, trans-CHH@CH, cis-CHH@CH), 4.34–4.39 (1H, m,

H-8), 4.04–4.14 (2H, m, CH₂OSi), 3.81–3.85 (1H, m, H-9), 2.71 (3H,

s, OMe), 2.43–2.52 (1H, m), 1.58–2.01 (5H, m) 1.03 [9H, s, (CH₃)₃C],

0.95 [9H, s, (CH₃)₃C]; d_C(62.5 MHz; CDCl₃) 139.0, 136.1, 136.0,

135.8, 134.5, 134.2, 132.2, 129.5, 129.3, 127.5, 127.4, 125.5,

118.0, 74.7, 71.4, 65.5, 50.5, 34.0, 30.0, 27.2, 27.0, 19.5 [C(CH₃)₃];

m/z (FAB) 727 [(M+Na)⁺, 100%], 705 [(M+H)⁺, 35]; [m/z (ES) Found:

(M+H)⁺, 705.3790. C₄₄H₅₇O₄Si₂requires M, 705.3795].

4.1.33. (2S,5Z,8S,9R)-8-Hydroxy-9-hydroxy-methyl-2-methoxy-

2,3,4,7,8,9-hexahydrooxonine-2-carbaldehyde, 41 and (1R,2S,4Z,-

8R,9S)-8-methoxy-10,12-dioxabicyclo[6.3.1]-dodec-4-ene-2,9-

diol 42

To a stirred solution of aldehyde 39a (44 mg, 0.062 mmol) in THF

(3 mL) was added a solution of TBAF (0.62 mL of a 1.0 M solution in

THF, 0.62 mmol) at 0 °C. The reaction mixture was allowed to warm

to room temperature over 1 h, and was then stirred for 16 h at room

temperature. The reaction mixture was quenched by the addition of

water (15 mL) and the layers were separated. The aqueous layer

was extracted with EtOAc (3 ꢄ 20 mL) and the combined organic

extracts were washed with brine (20 mL) and dried (MgSO₄). The

solvent was removed in vacuo and puriﬁcation by ﬂash chromatog-

raphy (petroleum ether 40–60:EtOAc, 1:1, then EtOAc) furnished an

equilibrium mixture of the aldehyde 41 and the lactol 42 (8.4 mg,

59%) as a colourless oil. The lactol 42 crystallised when stored in

the freezer; mp 94–95 °C; R_f0.35 (EtOAc); m_max(neat)/cm^ꢀ13355,

3271; d_H(250 MHz; CDCl₃) 9.46 (1H⁰, s, CH⁰O), 5.71–5.87 (2H⁰, m,

H-4⁰, H-5⁰) 5.51–5.69 (2H, m, H-4, H-5), 4.73 (1H, br d, J 8.7, H-9),

3.82–4.13 (3H, m), 3.57–3.80 (2H, m), 3.34 (3H, s, OMe), 3.30 (1H,

d, J 3.7, OH), 1.62–2.84 (6H, m); d_C(62.5 MHz; CDCl₃) 132.9,

126.5, 125.5, 95.4, 93.9, 74.2, 70.3, 65.8, 64.7, 48.7, 30.8, 30.3,

28.1, 23.1, 15.3; m/z (ES) 253 [(M+Na)⁺, 100%]; [m/z (ES) Found:

(M+Na)⁺, 253.1058. C₁₁H₁₈NaO₅requires M, 253.1052].

39a: R_f0.20 (petroleum ether 40–60:ether, 9:1); ½a _D²²

¼ þ66:7(c

ꢂ

0.6, CHCl₃); m_max(CHCl₃)/cm^ꢀl2931, 2890, 2856, 1743m, 1654; d_C

(500 MHz; CDCl₃) 9.28 (1H, s, CHO), 7.60–7.70 (8H, m, Ar), 7.05–

7.41 (12H, m, Ar), 5.56–5.62 (1H, m, CH@CH), 5.19 (lH, dd, J 17.3,

10.0, CH@CH), 4.13–4.20 (2H, m), 3.97–3.99 (2H, m), 2.97 (3H, s,

OMe), 2.31–2.39 (1H, m), 1.91–2.05 (3H, m), 1.74–1.79 (2H, m),

1.04 [9H, s, C(CH₃)₃], 0.92 [9H, s, C(CH₃)₃]; d_C(62.5 MHz; CDCl₃)

199.8, 136.0, 135.8, 134.2, 134.0, 133.7, 131.2, 129.6, 129.5,

127.6, 127.5, 126.4, 103.5, 76.2, 70.7, 65.6, 51.5, 30.6, 28.8, 19.4,

27.1 and 19.4 [C(CH₃)₃], 27.0 and 18.8 [C(CH₃)₃]; m/z (FAB) 729

[(M+Na)⁺, 20%], 239 (100); [m/z (ES) Found: (M+NH₄)⁺, 724.3854.

C₄₃H₅₈NO₅Si₂requires M, 724.3854]. Data for 39b R_f0.18 (petro-

leum ether 40–60:ether, 9:1); ½a _D²²

¼ þ40:8 (c 0.73, CHCl₃); m_max

ꢂ

(CHCl₃)/cm^-l2931, 2856, 1735, 1654; d_H(500 MHz; CDCl₃) 9.60

(1H, s, CHO), 7.54–7.68 (8H, m, Ar), 7.16–7.48 (12H, m, Ar), 5.67–

5.78 (1H, m, CH@CH), 5.41–5.52 (1H, m, CH@CH), 3.84–4.00 (3H,

m), 3.47–3.54 (1H, m), 3.23 (3H, s, OMe), 2.56–2.66 (1H, m),

2.36–2.49 (1H, m), 1.78–2.08 (4H, m), 1.00 [9H, s, C(CH₃)₃], 0.88

[9H, s, C(CH₃)₃]; d_C(62.5 MHz; CDCl₃) 199.1, 135.9, 135.8, 135.7,

133.3, 132.7, 129.7, 127.7, 127.6, 126.3, 102.2, 78.5, 72.1, 66.9,

50.4, 29.9, 28.4, 18.6, 27.0 and 19.2 [C(CH₃)₃], 26.8 and 19.1

[C(CH₃)₃]; m/z (ESI) 729 [(M+Na)⁺, 85%], 716 (100); [m/z (ES)

Found: (M+Na)⁺, 729.3400. C₄₃H₅₈NaO₅Si₂requires M, 729.3408].

4.1.34. (5Z,8S,9R)-8-(tert-Butyldiphenylsilanyloxy)-2-methylene-

9-vinyl-2,3,4,7,8,9-hexahydrooxonine 44

DMAP (78 mg, 0.64 mmol) was placed in a Schlenk tube under

argon. A solution of the lactone 43³⁶(0.244 g, 0.58 mmol) in THF (5

mL, 5 mL rinse) was added via cannula. The reaction mixture was

freeze thawed and degassed three times and was then cooled to

ꢀ50 °C. A solution of the Tebbe reagent (1.16 mL of a 0.5 M solution

in toluene, 0.58 mmol) was added dropwise and the reaction mix-

ture was allowed to stir for 50 min at ꢀ50 °C. The reaction mixture

was then allowed to warm to room temperature over 1.5 h, after

which it was cooled to ꢀ20 °C, before the dropwise addition of

an aqueous solution of NaOH (2 M; 0.32 mL, 0.64 mmol). The reac-

tion mixture was allowed to warm to ꢀ10 °C over 45 min giving a

precipitate. Ether (5 mL) was added and the mixture was allowed

to warm to room temperature over 15 min. The reaction mixture

4.1.32. (2R,5Z,8S,9R)-8-(tert-Butyldiphenylsilanyloxy)-9-(tert-

butyldiphenylsilanyloxymethyl)-2-methoxy-2-vinyl-2,3,4,7,8,9-

hexahydrooxonine 40

NaH (36 mg of a 60% dispersion in mineral oil, 0.9 mmol) was

washed with hexane (3 ꢄ 1 mL). Anhydrous DMSO (2 mL) was

added and the reaction mixture was heated at 65 °C for 45 min

S. Y. Frankie Mak et al. / Tetrahedron: Asymmetry 20 (2009) 921–944

937

was then poured into a ﬂask containing Na₂SO₄. The crude product

was ﬁltered through a plug of Celite and was puriﬁed by ﬂash

tion mixture was heated at reﬂux for 1.25 h, and was then allowed

to cool to room temperature, before being quenched by the addi-

tion of water (10 mL). The organic phase was separated and the

aqueous layer was extracted with EtOAc (3 ꢄ 15 mL). The com-

bined organic extracts were washed with brine (15 mL) and dried

(MgSO₄) and the solvent was removed in vacuo. The resultant

crude material (46) was dissolved in a mixture of CH₂Cl₂(1 mL)

and MeOH (2.5 mL) and an excess of K₂CO₃(ꢃ0.20 g) was added.

The reaction mixture was stirred for 18 h at room temperature, be-

fore being quenched by the addition of water (10 mL). The organic

phase was separated and the aqueous layer was extracted with

CH₂Cl₂(3 ꢄ 10 mL). The combined organic extracts were washed

with brine (10 mL) and dried (MgSO₄). The solvent was removed

in vacuo and puriﬁcation by ﬂash chromatography (petroleum

ether 40–60:ether, 10:1) gave an inseparable mixture of the title

compounds 47 (66 mg, 78%) as a colourless oil, which was used

immediately without further puriﬁcation. R_f0.20 (petroleum ether

40–60:ether, 10:1); d_H(400 MHz; CDCl₃) 9.47 (1H, s, CH⁰O), 9.41

(1H, s, CHO), 7.64–7.74 (4H and 4H⁰, m, Ar), 7.34–7.46 (6H and

6H⁰, m, Ar), 5.77–5.84 (1H, m, CH@CH), 5.54–5.66 (2H, m, CH@CH,

CH@CHH), 5.27 (1H, dd, J 17.2, 1.5, trans CH@CHH), 5.15 (1H, d, J

10.1, cis CH@CHH), 4.07 (1H, dd, J 9.0, 9.0, H-9), 3.94–3.98 (1H,

m, H-8), 3.85 (1H, m, H-8⁰), 3.39 (3H, s, OMe⁰), 3.11 (3H, s, OMe),

2.64–2.71 (1H, m), 2.06–2.13 (1H, m), 1.76–1.96 (4H, m), 1.06

[9H, s, C(CH₃)].

TM

chromatography [Brockmann grade III basic alumina deactivated

with water (6% wt/wt); petroleum ether 40–60:ether, 20:1] to give

the title compound 44 as a colourless oil (0.210 g, 86%); (Found: C,

77.5; H, 8.2. C₂₇H₃₄O₂Si requires C, 77.5; H, 8.2); R_f0.65 (petroleum

ether 40–60:ether, 5:1);

½

a ²_D⁵

ꢂ

¼ ꢀ50:0 (c 0.47, CHCl₃); d_H

(250 MHz; CDCl₃) 7.66–7.71 (4H, m, Ar), 7.33–7.47 (6H, m, Ar),

6.05 (1H, ddd, J 17.2, 10.6, 4.6, CH₂@CH), 5.54–5.64 (2H, m, H-5,

H-6), 5.26 (1H, d, J 17.2, trans-CH@CHH), 5.13 (1H, d, J 10.6, cis-

CH@CHH), 4.12 (1H, s, C@CHH), 4.07–4.10 (1H, m, H-9), 4.01 (1H,

s, C@CHH), 3.85–3.99 (1H, m, H-8), 2.30–2.58 (3H, m), 1.88–2.27

(3H, m), 1.06 [9H, s, C(CH₃)]; d_C(62.5 MHz; CDCl₃) 186.4, 137.4,

136.1, 136.0, 134.2, 133.5, 130.7, 129.7, 127.5, 126.8, 115.5, 88.2,

86.5, 32.7, 23.7, 19.4, 27.1 and 19.4 [C(CH₃)]; m/z (CI; NH₃) 419

[(M+H)⁺, 100%]; [m/z (ES) Found: (M+H)⁺, 419.2408. C₂₇H₃₅O₂Si re-

quires M, 419.2406].

4.1.35. (2R,5Z,8S,9R)- and (2S,5Z,8S,9R)-8-(tert-Butyldiphenyl-

silanyloxy)-2-methoxy-2-phenylselanylmethyl-9-vinyl-

2,3,4,7,8,9-hexahydrooxonines 45a and 45b

To a stirred solution of enol ether 44 (87.4 mg, 0.21 mmol) in a

mixture of THF (1.5 mL), NEt₃(41

lL) and MeOH (1.5 mL) was

added a solution of phenylselenenyl chloride (44 mg, 0.23 mmol)

in THF (1 mL) via cannula. The reaction mixture was allowed to stir

for 0.5 h at room temperature, before being quenched by the addi-

tion of a saturated aqueous solution of NaHCO₃(10 mL). The organic

phase was separated and the aqueous layer was extracted with

ether (3 ꢄ 20 mL). The combined organic extracts were washed

with brine (20 mL) and dried (MgSO₄). The solvent was removed

in vacuo and puriﬁcation by ﬂash chromatography [Brockmann

grade III basic alumina deactivated with water (6% wt/wt); hexane,

then with petroleum ether 40–60:ether, 20:1] afforded the starting

material (18.7 mg, 21%) and an inseparable mixture of the selenides

45 (71.4 mg, 56%); R_f0.13 (petroleum ether 40–60:ether, 20:1); d_H

(250 MHz; CDCl₃) 7.65–7.69 (4H and 4H⁰, m, Ar), 7.32–7.51 (8H and

8H⁰, m, Ar), 7.19–7.24 (3H and 3H⁰, m, Ar), 5.73–5.84 (1H, m,

CH@CH), 5.41–5.60 (2H, m, CH@CH, CH₂@CH), 5.20 (1H, dd, J 17.2,

1.8, trans-CH@CHH), 5.10 (1H, dd, J 9.9, 1.8, cis-CH@CHH), 3.98

(1H, dd, J 8.9, 8.8, H-9), 3.70–3.79 (1H, m, H-8), 3.19–3.25 (2H, m,

CHHSePh), 3.09 (3H, s, OMe⁰), 3.05 (3H, s, OMe), 2.50–2.60 (1H,

m), 2.15–2.26 (1H, m), 1.57–1.92 (4H, m), 1.03 [9H, s, C(CH₃)]; d_C

(62.5 MHz; CDCl₃) 140.7, 138.6, 136.4, 136.1, 134.6, 133.8, 132.8,

132.3, 130.4, 129.6, 127.4, 127.3, 127.0, 126.7, 125.0, 118.6, 118.1,

105.3, 75.6, 73.6, 50.4, 32.9, 32.6, 29.7, 19.8, 27.2 and 19.5

[C(CH₃)]; m/z (CI; NH₃) 607 [(M+H)⁺, 20%], 575 (100); [m/z (ES)

Found: (M+H)⁺, 607.2148. C₃₄H₄₃O₃SeSi requires M, 607.2146].

4.1.37. (2R,5Z,8S,9R)-8-(tert-Butyldiphenylsilanyloxy)-2,9-

divinyl-2-methoxy-2,3,4,7,8,9-hexahydrooxonine 48

NaH (36 mg of a 60% dispersion in mineral oil, 0.9 mmol) was

washed with hexane (3 ꢄ 2 mL). Anhydrous DMSO (1.5 mL) was

added and the mixture was heated at 60 °C for 40 min or until

the evolution of H₂gas ceased, leaving a clear grey solution. The

mixture was allowed to cool to room temperature, before a solution

of CH₃PPh₃Br (0.53 g, 1.5 mmol) in DMSO (1 mL) was added via can-

nula. The reaction mixture immediately turned yellow in colour.

After 10 min, a solution of the aldehydes 47 (47 mg, 0.10 mmol)

in DMSO (1 mL, 0.5 mL rinse) was added via cannula. The reaction

mixture remained yellow and was allowed to stir at room temper-

ature for 15 min. The reaction mixture was quenched by the addi-

tion of water (30 mL) and the layers were separated. The aqueous

layer was extracted with EtOAc (4 ꢄ 50 mL). The combined organic

extracts were washed with half saturated brine (30 mL) and dried

(MgSO₄). The solvent was removed in vacuo and puriﬁcation by

ﬂash chromatography (petroleum ether 40–60:ether, 20:1) affor-

ded the title compound 48 (30.1 mg, 64%) as a colourless oil. Only

a trace amount of the minor diastereomer was detected by ¹H

NMR; R_f0.45 (petroleum ether 40–60:ether, 9:1); ½a _D²⁵

¼ þ197:8

ꢂ

(c 0.64, CHCl₃); m_max(neat)/cm^ꢀ12932, 2857, 1589; d_H(500 MHz;

CDCl₃) 7.67–7.70 (4H, m, Ar), 7.35–7.44 (6H, m, Ar), 5.81–5.83

(1H, m, CH@CH), 5.52–5.57 (2H, m, CH@CH, CH@CHH), 5.49 (1H,

dd, J 17.5, 10.5, CH⁰@CH⁰H⁰), 5.40 (1H, dd, J 17.5, 1.9, trans-

CH⁰@CH⁰H⁰), 5.28 (1H, dd, J 10.5, 1.9, cis-CH⁰@CH⁰H⁰), 5.22 (1H, d, J

17.0, trans-CH@CHH), 5.09 (1H, d, J 10.0, cis-CH@CHH), 4.00 (1H,

dd, J 8.9, 8.9, H-9), 3.85–3.86 (1H, m, H-8), 2.99 (3H, s, OMe),

2.59–2.64 (1H, m), 1.92–1.99 (2H, m,), 1.81–1.86 (1H, m,), 1.72–

1.76 (2H, m,), 1.04 [9H, s, C(CH₃)]; d_C(62.5 MHz; CDCl₃) 139.2,

138.9, 136.4, 136.1, 134.7, 133.9, 133.1, 129.6, 127.4, 127.3, 124.9,

118.3, 103.9, 77.2, 74.6, 73.8, 50.9, 34.6, 29.7, 19.5, 27.2 and 19.3

[C(CH₃)]; m/z (CI) 463 [(M+H)⁺, 10%] 431 (100); [(ES) Found:

(M+NH₄)⁺, 480.2929. C₂₉H₄₂NO₃Si requires M, 480.2929].

4.1.36. (2R,5Z,8S,9R)- and (2S,5Z,8S,9R)-8-(tert-Butyldiphenylsil-

anyloxy)-2-methoxy-9-vinyl-2,3,4,7,8,9-hexahydrooxonine-2-

carbaldehyde 47

To a stirred solution of the selenides 45 (0.111 g, 0.18 mmol) in

a mixture of CH₂Cl₂(4 mL) and MeOH (8.5 mL) was added water

(1.5 mL) until material started to precipitate out of solution. NaH-

CO₃(20 mg, 0.24 mmol) and NaIO₄(0.129 g, 0.6 mmol) were added

and the cloudy white suspension was stirred at room temperature

for 2 h. The reaction mixture was quenched by the addition of

water (20 mL) and the layers were separated. The aqueous layer

was extracted with CH₂Cl₂(3 ꢄ 30 mL), and the combined organic

extracts were washed with brine (30 mL) and dried (MgSO₄). The

solvent was removed in vacuo and was dried under high vacuum

for 1 h to give what were presumed to be the corresponding selen-

oxides as a yellow foam, which were dissolved in THF (8 mL) and

cooled to ꢀ78 °C. NaOAc (57 mg, 0.69 mmol) and Ac₂O (0.10 mL,

1.1 mmol) were added and the mixture was allowed to stir at

ꢀ78 °C for 5 min and then at room temperature for 0.5 h. The reac-

4.1.38. (2R/S,8S,9R,5Z)-2-Methoxy-2-[(Z)-prop-1-enyl]-8-(tert-

butyldiphenylsilanyloxy)-9-vinyl-2,3,4,7,8,9-hexahydrooxo-

nines 49a and 49b

To a stirred solution of EtPPh₃Br (56 mg, 0.151 mmol) in THF (4

mL) at ꢀ78 °C was slowly added KHMDS (0.26 mL of a 0.5 M solu-

938

S. Y. Frankie Mak et al. / Tetrahedron: Asymmetry 20 (2009) 921–944

tion in toluene, 0.13 mmol). The resultant yellow solution was al-

lowed to warm to room temperature and was stirred for 30 min. To

a stirred solution of the aldehyde 47 (35 mg, 0.075 mmol) in THF (3

mL) at ꢀ78 °C, was added the preformed ylide solution. The reac-

tion mixture was then allowed to warm to room temperature

and was stirred for 30 min, before being quenched by the addition

of a saturated solution of aqueous NH₄Cl (2 mL) and water (2 mL).

The organic phase was separated and the aqueous layer was ex-

tracted with ether (3 ꢄ 10 mL). The combined organic extracts

were washed with brine (10 mL), dried (MgSO₄), ﬁltered and con-

centrated in vacuo to give the crude product. Puriﬁcation by ﬂash

chromatography (petroleum ether 40–60:ether, 9:1) afforded the

title compound 49a (18.3 mg, 51%) and the unstable 49b (3.3 mg,

9%), both were isolated as colourless oils. Data for the more polar

component 49a: R_f0.50 (petroleum ether 40–60:ether, 9:1);

74.9, 73.0, 57.2, 52.9, 51.1, 29.8, 28.8, 20.6, 27.2 and 19.4 [C(CH₃)];

m/z (CI; NH₃) 479 [(M+H)⁺, 50%], 447 (100), 191 (100); [m/z (ES)

Found: (M+H)⁺, 479.2615. C₂₉H₃₉O₄Si requires M, 479.2617].

4.1.40. (2R,8S,9R,Z)-2-Methoxy-2-[(Z)-prop-1-enyl]-9-vinyl-

2,3,4,7,8,9-hexahydrooxonin-3-ol 50

To a stirred solution of oxonine 49a (24.0 mg, 0.186 mmol) in

THF (1 mL) at 0 °C was added TBAF (0.56 mL of a 1.0 M solution

in THF, 0.56 mmol). The reaction mixture was allowed to stir for

5 min at 0 °C, and was then warmed to room temperature and stir-

red for another 2 h. The reaction mixture was directly subjected to

column chromatography (petroleum ether 40–60:ether, 4:1) to

furnish the alcohol 50 (9.0 mg, 75%) as a colourless oil; R_f0.22

(petroleum ether 40–60:ether, 2:1); ½a _D²⁵

¼ þ121:8 (c 0.45, CHCl₃);

ꢂ

m_max(CHCl₃ﬁlm)/cm^ꢀ13478, 3018, 2924, 1655; d_H(500 MHz;

CDCl₃) 5.82–5.91 (2H, m, CH@CH, CH@CHH), 5.70 (1H, dq, J 12.0,

7.3, CH@CHMe), 5.62 (1H, dt, J 10.4, 6.1, CH@CH), 5.29–5.33 (2H,

m, CH@CHH), 5.26 (1H, dq, J 12.0, 1.8, CH@CHMe), 3.88 (1H, dd, J

9.1, 9.1, H-9), 3.60–3.64 (1H, m, H-8), 2.89–2.95 (1H, m), 2.28

(1H, ddd, J 13.5, 6.2, 4.0), 2.13–2.19 (1H, m), 2.02 (1H, ddd, J

14.1, 11.1, 1.5), 1.85–1.94 (2H, m), 1.81 (1H, dd, J 7.3, 1.8,

CH@CHCH₃); d_C(125 MHz; CDCl₃) 139.2, 134.2, 131.0, 129.1,

124.0, 118.4, 105.9, 74.4, 70.9, 50.5, 35.9, 28.6, 19.7, 13.9; m/z

(ES) 261 [(M+Na)⁺, 15%]; [m/z (ES) Found: (M+Na)⁺261.1471,

C₁₄H₂₂O₃Na requires M, 261.1467].

½

a ²_D⁵

ꢂ

¼ þ143:4 (c 0.37, CHCl₃); m_max(CHCl₃ﬁlm)/cm^ꢀ12931s,

2858s; d_H(500 MHz; CDCl₃) 7.70–7.72 (4H, m, Ar), 7.36–7.45

(6H, m, Ar), 5.85 (1H, m, CH@CH), 5.52–5.65 (3H, m, CH@CH,

CH@CHH, CH@CHMe), 5.23 (1H, dd, J 17.4, 1.6, trans-CH@CHH),

5.18 (1H, dq, J 11.9, 1.6, CH@CHMe), 5.11 (1H, dd, J 10.1, 1.6, cis-

CH@CHH), 4.00 (1H, dd, J 9.0, 9.0, H-9), 3.85 (1H, ddd, J 8.9, 4.0,

2.0, H-8), 3.01 (3H, s, OMe), 2.65–2.72 (1H, m), 1.75–2.08 (5H,

m), 1.74 (3H, dd, J 7.2, 1.6, CH@CHCH₃), 1.07 [9H, s, C(CH₃)₃]; d_C

(125 MHz; CDCl₃) 139.1, 136.4, 136.3, 136.1, 134.7, 133.9, 133.3,

131.5, 129.5, 128.6, 127.4, 127.3, 124.9, 118.1, 105.8, 74.4, 73.7,

50.6, 35.7, 29.7, 27.2,, 19.8, 19.5, 13.9; m/z (ES) 499 [(M+Na)⁺, 5%]

477 [(M+H)⁺, 5]; [m/z (ES) Found: (M+Na)⁺499.2647, C₃₀H₄₀O₃NaSi

requires M, 499.2644].

4.1.41. (1R,2Z,5S)-5-(tert-Butyldiphenylsilanyloxy)-cyclopent-

2-en-1-ol 55

Data for the less polar component 49b: R_f0.58 (petroleum ether

40–60:ether, 9:1); d_H(500 MHz; CDCl₃) 7.68–7.72 (4H, m, Ar),

7.35–7.45 (6H, m, Ar), 5.86 (1H, ddd, J 17.3, 10.5, 6.4, CH@CHH),

5.77 (1H, dt, J 10.2, 7.3 CH@CH), 5.69 (1H, dq, J 12.0, 1.8, CH@CHMe),

5.44–5.53(2H, m, CH@CH, CH@CHMe), 5.24 (1H, dd, J 17.3, 1.6, trans-

CH@CHH), 5.11 (1H, dd, J 10.5, 1.6, cis-CH@CHH), 3.84 (1H, dd, J 6.5,

6.5, H-9), 3.79 (1H, ddd, J 8.6, 4.2, 2.0, H-8), 3.24 (3H, s, OMe), 2.75–

2.80 (1H, m), 2.46–2.52 (1H, m), 1.93–1.99 (1H, m), 1.90–1.87 (2H,

m), 1.72–1.76 (1H, m), 1.72 (3H, dd, J 7.2, 1.8, CH@CHCH₃), 1.07

[9H, s, C(CH₃)₃]; The compound is very labile and readily ring opens

to give the corresponding open-chain ketone.

To a solution of the second-generation Grubbs’ catalyst 18 (1 mg,

0.002 mmol) in CH₂Cl₂(2 mL), was added a solution of oxonine 49a

(6.2 mg, 0.013 mmol) in CH₂Cl₂(2 mL). The reaction mixture was

heated at reﬂux for 2 h. The reaction mixture was cooled to room

temperature and the solvent was removed in vacuo. Puriﬁcation

by ﬂash column chromatography afforded the cyclopentenol 55

(2.3 mg, 52%) as a colourless oil; R_f0.20 (petroleum ether 40–

60:ether, 10:1); ½a _D²⁵

ꢂ

¼ þ198 (c 0.64, CHCl₃); m_max(neat)/cm^ꢀ1

3528, 3070, 2930, 2857; d_H(500 MHz; CDCl₃) 7.68–7.73 (4H, m

Ar), 7.36–7.46 (6H, m, Ar), 5.80–5.83 (2H, m, CH@CH), 4.33–4.37

(2H, m, CHOSi, CHOH), 3.10 (1H, d, J 4.4, OH), 2.28–2.32 (1H, m),

2.17–2.24 (1H, m), 1.09 [9H, s, (CH₃)₃C]; d_C(62.5 MHz; CDCl₃)

135.7, 132.6, 132.1, 130.0, 127.8, 127.7, 74.9, 73.0, 27.0 and 19.3

[C(CH₃)₃]; m/z (CI) 356 [(M+NH₄)⁺, 40%], 321 (100), 274 (100); [m/z

(ES) Found: (M+NH₄)⁺, 356.2049. C₂₁H₃₀NO₂Si requires M,

356.2046].

4.1.39. (1S,3S,4R,6R,9R)-3-(tert-Butyldiphenylsilanyloxy)-4,6-

divinyl-6-methoxy-5,10-dioxa-bicyclo[7.1.0]-decane 51

To a stirred solution of the alkene 48 (14.1 mg, 0.031 mmol) in

CH₂Cl₂(1.3 mL) at 0 °C were added mCPBA (6 mg, 0.035 mmol;

100%) and NaHCO₃(5 mg, 0.06 mmol). The reaction mixture was

stirred for a further 15 min and was then allowed to warm to room

temperature over 5 h. The reaction mixture was quenched by the

addition of a saturated aqueous solution of NaHSO₃(3 mL) and water

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

extracted with CH₂Cl₂(3 ꢄ 5 mL). The combined organic extracts

were washed with a saturated aqueous solution of NaHCO₃(10

mL) and then with brine (10 mL) and were dried (MgSO₄). The sol-

vent was removed in vacuo and puriﬁcation by ﬂash chromatogra-

phy (petroleum ether 40–60:ether, 8:1 increasing polarity to 2:1)

furnished the epoxide 51 as a clear and colourless oil (9.5 mg,

4.1.42. (3S,8S,9R,5Z)-3-Hydroxy-8-(tert-butyldiphenylsilanyloxy)-

9-vinyl-2,3,4,7,8,9-hexahydrooxonin-2(7H)-one 62

To a solution of KHMDS (76 lL of a 0.5 M solution in PhMe,

0.038 mmol) in THF (0.5 mL) at ꢀ70 °C was added (dropwise) a

solution of lactone 43 (15.3 mg, 0.036 mmol) in THF (0.5 mL).

The reaction mixture was stirred at ꢀ70 °C for 30 min before a

solution of the ( )-phenylsulfonyloxaziridine (20.0 mg, 0.077

mmol) in THF (0.5 mL) was added dropwise. The reaction mixture

was stirred at this temperature for 30 min and was then quenched

by the addition of a solution of CSA (25.4 mg, 0.108 mmol) in THF

(0.5 mL). It was then allowed to warm to room temperature over

15 min. The reaction mixture was diluted with ether (5 mL) and

a saturated solution of aqueous NaHCO₃(5 mL). The aqueous layer

was separated and extracted with ether (3 ꢄ 10 mL). The combined

organic extracts were washed with brine (10 mL), dried (MgSO₄),

ﬁltered and concentrated in vacuo to give the crude product. Puri-

ﬁcation by ﬂash chromatography (petroleum ether 40–60:ether,

1:1) furnished a mixture of hydroxy lactone 62 and the imine

PhSO₂N@CHPh. Further puriﬁcation of this mixture by column

chromatography (CH₂Cl₂) allowed the isolation of a pure sample

of the alcohol (9.3 mg, 62%) as a colourless oil; R_f0.43 (petroleum

65%); R_f0.55 (petroleum ether 40–60:ether, 1:1); ½a _D²⁵

¼ þ89 (c

ꢂ

0.3, CHCl₃); m_max(neat)/cm^ꢀ12932, 2857; d_H(500 MHz; CDCl₃)

7.67–7.69 (4H, m Ar), 7.36–7.45 (6H, m, Ar), 5.45 (1H, dd, J 17.3,

10.7, CH⁰@CH⁰H⁰), 5.38 (1H, ddd, J 17.2, 10.0, 1.5, CH@CHH), 5.29

(1H, dd, J 17.3, 1.8, trans-CH⁰@CH⁰H⁰), 5.22–5.25 (2H, m, cis-

CH⁰@CH⁰H⁰, trans-CH@CHH), 5.09 (1H, dd, J 10.0, 1.5, cis-CH@CHH),

4.09 (1H, dd, J 9.0, 9.0, H-4), 3.88–3.90 (1H, m, H-3), 3.32–3.36 (1H,

m, H-1), 3.01–3.05 (1H, m, H-9), 2.96 (3H, s, OMe), 2.03–2.07 (2H,

m), 1.93–2.01 (1H, m), 1.74–1.77 (1H, m), 1.57–1.60 (2H, m), 1.06

[9H, s, C(CH₃)]; d_C(125 MHz; CDCl₃) 138.7, 138.5, 136.4, 136.1,

134.1, 134.0, 133.5, 129.8, 129.7, 127.6, 127.4, 118.8, 118.6, 103.4,

S. Y. Frankie Mak et al. / Tetrahedron: Asymmetry 20 (2009) 921–944

939

ether 40–60:ether, 1:1) and 0.67 (CH₂Cl₂); ½a _D²⁵

ꢂ

¼ þ27:4 (c 0.12,

129.6, 129.4, 127.9, 127.6, 127.5, 115.9, 91.8, 86.8 (C-9), 73.9, 76.5,

30.5, 33.1, 27.0, 19.3, 0.31; m/z (CI; NH₃) 524 [(M+NH₄)⁺, 10%], 507

[(M+H)⁺, 100]; [m/z (ES) Found: (M+H)⁺507.2750, C₃₀H₄₃O₃Si₂re-

quires M, 507.2745].

CHCl₃); m_max(CHCl₃ﬁlm)/cm^ꢀ13438, 2927, 2861, 1742; d_H

(500 MHz; CDCl₃) 7.68–7.70 (4H, m, Ar), 7.40–7.49 (6H, m, Ar),

6.08–6.13 (1H, m, CH@CHH), 5.41 (1H, d, J 17.2, trans-CH@CHH),

5.32–5.37 (2H, m, CH@CH, CH@CH), 5.29 (1H, d, J 10.5, cis-

CH@CHH), 5.21–5.24 (1H, m, H-9), 4.36–4.38 (1H, m, CHOH),

3.85–3.88 (1H, m, H-8), 2.45–2.48 (2H, m), 2.31–2.33 (1H, m),

2.23 (1H, d, J 9.4, OH), 2.00–2.03 (1H, m); d_C(100 MHz; CDCl₃)

173.1, 136.0, 135.8, 134.7, 133.8, 132.8, 132.5, 129.9, 126.7,

127.6, 122.5, 119.3, 81.8, 74.9, 70.7, 34.9, 32.1, 26.6, 19.0; m/z

(CI; NH₃) 454 [(M+NH₄)⁺, 80%], 437 [(M+H)⁺, 40]; [m/z (ES) Found:

(M+NH₄)⁺454.2405, C₂₆H₃₆O₄NSi requires M, 454.2408].

4.1.45. (3S,8S,9R,5Z)-2-Methylene-3-hydroxy-8-(tert-butyldi-

phenylsilanyloxy)-9-vinyl-2,3,4,7,8,9-hexahydrooxonine

To a solution of the enol ether (3S,8S,9R,5Z)-2-methylene-3-tri-

methylsilanyloxy-8-(tert-butyldiphenylsilanyloxy)-9-vinyl-2,3,4,

7,8,9-hexahydrooxonine (0.627 g, 1.23 mmol) in THF (10 mL) at

ꢀ10 °C, was added TBAF (1.6 mL of a 1.0 M solution in THF, 1.60

mmol). The reaction mixture was stirred at this temperature for

15 min and was then quenched by the addition of a saturated solu-

tion of aqueous NaHCO₃(15 mL) and ether (30 mL). The aqueous

layer separated was extracted with ether (3 ꢄ 25 mL) and the com-

bined organic extracts were washed with brine (20 mL), dried

(MgSO₄), ﬁltered and concentrated in vacuo to give the crude prod-

uct. Puriﬁcation by ﬂash column chromatography (petroleum ether

40–60:ether, 3:1) gave the title hydroxy enol ether as a colourless

oil (0.409 g, 76%); R_f0.31 (petroleum ether 40–60:ether, 2:1);

4.1.43. (3S,8S,9R,5Z)-3-Trimethylsilanyloxy-8-(tert-butyldiphenyl-

silanyloxy)-9-vinyl-2,3,4,7,8,9-hexahydrooxonin-2(7H)-one 63

To a solution of the crude hydroxy lactone 62 (81.2 mg, 0.186

mmol) and triethylamine (0.31 mL, 2.224 mmol) in THF (5 mL)

was added TMSCl (0.24 mL, 1.891 mmol). The reaction mixture

was stirred at room temperature for 2 h, upon which a saturated

solution of aqueous NaHCO₃(10 mL) was added. The aqueous layer

that was separated was extracted with ether (3 ꢄ 10 mL). The com-

bined organic extracts were washed with brine (10 mL), dried

(MgSO₄) and concentrated in vacuo to give the crude product. Puri-

ﬁcation by ﬂash column chromatography (petroleum ether 40–

60:ether, 6:1) furnished the title compound 63 (67.9 mg, 54% over-

all yield from the vinyl-substituted lactone 43); R_f0.64 (petroleum

½

a ²_D⁵

ꢂ

¼ þ17:0 (c 0.10, CHCl₃); m_max(CHCl₃ﬁlm)/cm^ꢀ13382, 3073,

3012, 2927, 2861, 1638; d_H(500 MHz; CDCl₃) 7.68–7.71 (4H, m,

Ar), 7.28–7.46 (6H, m, Ar), 6.05 (1H, ddd, J 17.2, 10.7, 4.4,

CH@CHH), 5.67–5.73 (1H, m, CH@CH), 5.47–5.53 (1H, m, CH@CH),

5.29 (1H, dd, J 17.2, 1.2, trans CH@CHH), 5.17 (1H, dd, J 10.7, 1.2,

cis-CH@CHH), 4.33 (1H, s, RORC@CHH), 4.26 (1H, s, RORC@CHH),

4.18–4.20 (1H, m, CHOH), 3.96–4.00 (2H, m, H-8, H-9), 2.54–2.65

(2H, m), 2.29–2.34 (1H, m, ring CHH), 2.01–2.03 (1H, m, ring

ether 40–60:ether, 6:1); ½a _D²⁵

¼ þ33:7 (c 0.27, CHCl₃); m_max(CHCl₃

ꢂ

ﬁlm)/cm^ꢀ12957, 2921, 2855, 1732; d_H(500 MHz; CDCl₃) 7.68–

7.69 (4H, m, Ar), 7.38–7.45 (6H, m, Ar), 5.95 (1H, br m, CH@CHH),

5.44–5.48 (2H, m, CH@CH), 5.33 (1H, d, J 17.2, trans-CH@CHH),

5.18–5.23 (2H, m, cis-CH@CHH, H-9), 4.34–4.35 (1H, m, H-3),

3.97 (1H, m, H-8), 2.16–2.46 (4H, m), 1.07 [9H, s, C(CH₃)₃], 0.13

[9H, s, Si(CH₃)₃]; d_C(100 MHz; CDCl₃) 172.8, 136.0, 135.9, 134.8,

133.9, 133.0, 130.5, 129.9, 129.7, 127.7, 127.6, 124.5, 118.0, 80.0,

75.5, 72.3, 33.1, 26.9, 19.3, ꢀ0.3; m/z (CI; NH₃) 526 [(M+NH₄)⁺,

100%], 509 [(M+H)⁺, 100]; [m/z (ES) Found: (M+H)⁺509.2523,

C₂₉H₄₁O₄Si₂requires M, 509.2538].

CHH), 1.80 (1H, d,

J 5.4, CHOH), 1.09 [9H, s, C(CH₃)₃]; d_C

(100 MHz; CDCl₃) 166.3, 136.9, 136.1, 136.0, 135.9, 134.0, 133.3,

129.8, 129.7, 128.7, 127.5, 126.7, 116.0, 91.6, 87.0, 73.3, 76.3,

32.2, 29.7, 27.0, 19.4; m/z (CI; NH₃) 435 [(M+H)⁺, 60%]; [m/z (ES)

Found: (M+H)⁺435.2358, C₂₇H₃₅O₃Si requires M, 435.2350].

4.1.46. (3S,8S,9R,5Z)-2-Methylene-3-dimethylsilanyloxy-8-

(tert-butyldiphenylsilanyloxy)-9-vinyl-2,3,4,7,8,9-

hexahydrooxonine 65

The hydroxy enol ether (3S,8S,9R,5Z)-2-methylene-3-hydroxy-8-

(tert-butyldiphenylsilanyloxy)-9-vinyl-2,3,4,7,8,9-hexahydrooxonine

(63.2 mg, 0.145 mmol), 1,1,3,3-tetramethyldisilazane (0.26 mL,

1.466 mmol) and ammonium chloride (2 mg) were stirred at 60

°C under a nitrogen atmosphere overnight (18 h). The mixture

was diluted with dry hexane (10 mL) and the ammonium chloride

was then ﬁltered off. The solvent was removed in vacuo to give the

title compound 65 (71.7 mg, 100%) as a colourless oil; R_f0.29

4.1.44. (3S,8S,9R,5Z)-2-Methylene-3-trimethylsilanyloxy-8-

(tert-butyldiphenylsilanyloxy)-9-vinyl-2,3,4,7,8,9-

hexahydrooxonine

The lactone 63 (110.9 mg, 0.225 mmol) and DMAP (31 mg, 0.598

mmol) were dissolved in dry THF (2 mL). This mixture was degassed

(freeze-thaw, three cycles) and cooled to ꢀ50 °C. The Tebbe reagent

(0.48 mL of a 0.5 M solution in PhMe, 0.240 mmol) was then added

and the temperature was maintained at ꢀ45 to ꢀ40 °C for 30 min.

The solution was allowed to warm to room temperature and was

stirred for 1.5 h. The reaction mixture was then cooled to ꢀ10 °C

andwasquenchedbytheadditionof a10%solutionofaqueousNaOH

(ca. 0.5 mL). The resultant suspension was warmed to room temper-

atureover30minandwasthendilutedwithether(5mL). Anhydrous

Na₂SO₄was added to this mixture, which was then ﬁltered through a

(petroleum ether 40–60:ether, 1:1); ½a _D²⁵

¼ þ16:8 (c 0.22, CHCl₃);

ꢂ

m_max(CHCl₃ﬁlm)/cm^ꢀ12928, 2857, 2116, 1637; d_H(500 MHz;

CDCl₃) 7.68–7.71 (4H, m, Ar), 7.37–7.46 (6H, m, Ar), 6.05 (1H,

ddd, J 17.2, 10.6, 4.6, CH@CHH), 5.76–5.78 (1H, m, CH@CH),

5.46–5.52 (1H, m, CH@CH), 5.30 (1H, dd, J 17.2, 1.4, trans-

CH@CHH), 5.15 (1H, dd, J 10.6, cis-CH@CHH), 4.66 (1H, sp, J 2.8,

Si-H), 4.34 (1H, s, RORC@CHH), 4.19–4.23 (2H, m, RORC@CHH, H-

8/H-9), 4.01–4.05 (1H, m, H-3/H-8/H-9), 3.92–3.94 (1H, m, H-3/

H-8/H-9), 2.64–2.77 (2H, m), 2.19–2.24 (1H, m), 1.94–1.97 (1H,

TM

short pad of Celite . The solvent was removed in vacuo and the res-

iduewaspuriﬁedbyﬂashcolumnchromatography(petroleumether

40–60:ether, 10:1) to give the title enol ether (99.5 mg, 89%) as a col-

m), 1.09 [9H, s, C(CH₃)₃], 0.22 [6H, d,

J 2.8, Si(CH₃)₂]; d_C

ourless oil; R_f0.76 (petroleum ether 40–60:ether, 9:1); ½a _D²⁵

ꢂ

¼ þ10:9

(100 MHz; CDCl₃) 165.8, 136.9, 136.0, 135.9, 135.8, 134.1, 133.3,

129.7, 128.1, 127.6, 127.5, 127.4, 115.9, 92.3, 86.8, 76.5, 75.5,

32.7, 29.7, 26.9, 19.3, ꢀ0.92; m/z (CI; NH₃) 510 [(M+NH₄)⁺, 50%],

493 [(M+H)⁺, 50]; [m/z (ES) Found: (M+H)⁺493.2588 C₂₉H₄₁O₃Si₂

requires M, 493.2589].

(c 0.32, CHCl₃); m_max(CHCl₃ﬁlm)/cm^ꢀ12962, 2931, 2855, 1936,

1469; d_H(500 MHz; CDCl₃) 7.67–7.70 (4H, m, Ar), 7.36–7.45 (6H,

m, Ar), 6.04 (1H, ddd, J 17.2, 10.6 4.7, CH@CHH), 5.74–5.78 (1H, m,

CH@CH), 5.46–5.52 (1H, m, CH@CH), 5.29 (1H, dd, J 17.2, 1.5 trans-

CH@CHH), 5.15 (1H, dd, J 10.6, 1.5, cis-CH@CHH), 4.30 (1H, s,

RORC@CHH), 4.19 (1H, dd, J 9.7, 6.1, CHOTMS), 4.16 (1H, s,

RORC@CHH), 4.01–4.04 (1H, m, H-8/H-9), 3.90–3.92 (1H, m, H-8/

H-9), 2.73–2.77 (1H, m), 2.62–2.68 (1H, m), 2.12–2.17 (1H, m),

1.92–1.95 (1H, m), 1.08 [9H, s, C(CH₃)₃], 0.14 [9H, s, Si(CH₃)₃]; d_C

(100 MHz; CDCl₃) 166.6, 137.0, 136.0, 135.9, 134.0, 133.3, 129.7,

4.1.47. (2R/S,3S,8S,9R,5Z)-2-Hydroxymethyl-3-hydroxy-8-(tert-

butyldiphenylsilanyloxy)-9-vinyl-2,3,4,7,8,9-hexahydro-

oxonines 66b and 66a

To a solution of the enol ether 65 (56.0 mg, 0.114 mmol) and

(HSiMe₂)₂NH (20 lL, 0.112 mmol) in PhMe (3 mL) at room temper-

940

S. Y. Frankie Mak et al. / Tetrahedron: Asymmetry 20 (2009) 921–944

ature under

a

CaCl₂drying tube, was added

L of a 0.11 M solution in xylenes,

mol). The reaction mixture was stirred for 18 h and was ﬁl-

a

solution of

ic extracts were washed with brine (5 mL), dried (MgSO₄), ﬁltered

and concentrated in vacuo to give the crude product. Puriﬁcation

by ﬂash chromatography (hexane–ether, 4:1) furnished the cis-

PMP acetal 67b (0.224 g, 42%) and trans-PMP acetal 67a (0.209 g,

39%) as separate components.

Pt[(CH₂@CHSiMe₂)₂O]₂(31

3.41

l

TM

tered through a short pad of Florosil . The ﬁltrate was concentrated

in vacuo and was then dried under high vacuum for 30 min. The

resultant crude residue was dissolved in MeOH (1 mL) and THF

Data for the cis-PMP acetal 67b: R_f0.29 (hexane–ether, 4:1);

(1 mL), whereupon a solution of KOH (72

lL of a 15% aqueous solu-

½

a ²_D⁴

ꢂ

¼ þ115:6 (c 0.30, CHCl₃); m_max(CHCl₃ﬁlm)/cm^ꢀ12959,

tion, 0.192 mmol) and a solution of H₂O₂(0.11 mL of a 27.5% aque-

ous solution, 0.880 mmol) were added. The reaction mixture

turned into a white suspension and was stirred for 2 h at room

temperature, whereupon it was quenched by the addition of anhy-

drous sodium thiosulfate (ca. 10 mg). The reaction mixture was

stirred for 30 min and anhydrous MgSO₄was then added. Subse-

quent ﬁltration and solvent removal furnished the crude product.

Puriﬁcation by column chromatography (5% MeOH in CH₂Cl₂) fur-

nished the diols 66 (35.8 mg, 70%) as an inseparable mixture. They

were subsequently prepared as separate entities for full character-

isation as described below. Preparation of the trans-diol 66a: To a

solution of the trans-PMP acetal 67a (24.0 mg, 0.042 mmol) in

MeOH (2 mL), was added PTSAꢁH₂O (10.2 mg, 0.052 mmol). The

reaction mixture was stirred at room temperature for 4 h. The sol-

vent was then removed in vacuo and puriﬁcation by column chro-

matography (5% MeOH in CH₂Cl₂) furnished the trans-diol 66a as a

colourless oil (19 mg, 100%); R_f0.34 (5% MeOH in CH₂Cl₂);

2931, 2897, 2856, 1684; d_H(500 MHz; CDCl₃) 7.65–7.69 (4H, m,

Ar), 7.35–7.45 (8H, m, Ar), 6.84–6.86 (2H, m, Ar), 5.93 (1H, dt, J

11.0, 5.2, CH@CH), 5.84 (1H, ddd, J 17.2, 10.4, 7.5, CH@CHH), 5.57

(1H, dt, J 11.0, 5.3, CH@CH), 5.45 (1H, s, H-2), 5.33 (1H, d, J 17.2,

trans-CH@CHH), 5.10 (1H, d, J 10.4, cis CH@CHH), 4.35 (1H, dd, J

12.5, 1.0, H-4_eq) 4.11 (1H, ddd, J 10.0, 6.3, 2.2, CHO), 4.03 (1H,

ddd, J 8.4, 3.2, 3.2, H-7), 3.94 (1H, dd, J 12.5, 1.8, H-4_ax), 3.79 (3H,

s, OMe), 3.49 (1H, dd, J 7.5, 7.5, CHO), 3.15 (1H, br s, H-4a), 2.80–

2.87 (2H, m), 2.26–2.31 (1H, m), 1.93–1.95 (1H, m), 1.06 [9H, s,

C(CH₃)₃]; d_C(100 MHz; CDCl₃) 159.8, 138.9, 136.1, 135.9, 134.3,

133.4, 130.8, 130.0, 129.7, 129.6, 127.6, 127.5, 127.4, 126.0,

117.1, 113.4, 100.7, 88.8, 77.9, 76.3, 71.0, 55.2, 29.8, 29.7, 27.1,

19.3; m/z (CI; NH₃) 571 [(M+H)⁺, 100%], [m/z (ES) Found: (M+H)⁺

571.2877, C₃₅H₄₃O₅Si requires M, 571.2874].

Data for the trans-PMP acetal 67a: (Found: C, 73.6; H 7.4

C₃₅H₄₂O₅Si requires C, 73.6; H, 7.4%); R_f0.39 (hexane–ether, 4:1);

½

a ²_D⁴

ꢂ

¼ þ36:3 (c 0.34, CHCl₃); m_max(CHCl₃ﬁlm)/cm^ꢀ12931, 2857,

½

a ²_D⁵

ꢂ

¼ þ27:3 (c 0.17, CHCl₃); m_max(CHCl₃ﬁlm)/cm^ꢀ13389, 2930,

1615; d_H(500 MHz; C₆D₆at 340 K) 7.84–7.88 (4H, m, Ar), 7.60–

7.62 (2H, m, Ar), 7.31–7.34 (6H, m, Ar), 6.90–6.92 (2H, m, Ar),

5.95 (1H, ddd, J 17.2, 10.3, 7.4, CH@CHH), 5.78–5.84 (1H, m,

CH@CH), 5.53–5.58 (1H, m, CH@CH), 5.40 (1H, s, H-2), 5.34 (1H,

d, J 17.2, trans-CH@CHH), 5.13 (1H, d, J 10.4, cis-CH@CHH), 4.32–

4.34 (1H, m), 4.10–4.14 (1H, m), 4.02–4.05 (1H, m), 3.71–3.80

(3H, m), 3.44 (3H, s, OMe), 2.68–2.72 (1H, m), 2.52–2.57 (3H, m),

1.25 (9H, s, C(CH₃)₃); d_C(125 MHz; C₆D₆at 340K) 160.3, 139.7,

136.2 136.1, 134.6, 134.0, 131.3, 129.7, 128.2, 129.0, 127.9, 127.8,

127.6, 118.5, 113.7, 113.6, 101.6, 79.8, 19.6, 75.1, 73.7, 71.2, 54.5,

31.6, 30.1, 27.1, 19.3; m/z (CI; NH₃) 571 [(M+H)⁺, 100%]; [m/z (ES)

Found: (M+H)⁺571.2881, C₃₅H₄₃O₅Si requires M, 571.2874].

2857; d_H(500 MHz; CDCl₃) 7.66–7.69 (4H, m, Ar), 7.36–7.47 (6H,

m, Ar), 5.84 (1H, ddd, J 17.4, 10.2, 8.3, CH@CHH), 5.68–5.72 (1H,

m, CH@CH), 5.36–5.41 (1H, m, CH@CH), 5.34 (1H, dd, J 10.2, 0.8,

cis-CH@CHH), 5.22 (1H, dd, J 17.4, 0.8, trans-CH@CHH), 3.81–3.87

(3H, m), 3.74–3.78 (2H, m), 3.40–3.42 (1H, m, H-8), 2.54–2.55

(1H, m), 2.43–2.47 (1H, m), 2.30–2.35 (1H, m), 2.23–2.26 (1H,

m), 1.04 [9H, s, C(CH₃)₃]; d_C(125 MHz; CDCl₃) 139.6, 136.2,

136.0, 134.2, 133.4, 130.5, 130.4, 129.7, 128.7, 128.6, 127.5,

119.6, 73.9, 70.5, 63.0, 32.9, 31.1, 27.0, 19.3; m/z (CI; NH₃) 470

[(M+NH₄)⁺, 20%]; [m/z (ES) Found: (M+NH₄)⁺470.2717, C₂₇H₄₀O₄N-

Si requires M, 470.2721].

Preparation of the cis-diol 66b: To a solution of the cis-PMP acetal

67b (15.6 mg, 0.027 mmol) in MeOH (1.5 mL), was added

PTSAꢁH₂O (6.5 mg, 0.034 mmol). The reaction mixture was stirred

at room temperature for 4 h. The solvent was then removed in va-

cuo and puriﬁcation by column chromatography (5% MeOH in

CH₂Cl₂) afforded the cis-diol 66b as a colourless oil (4.1 mg, 33%);

4.1.49. (2S,3S,8S,9R,5Z)-2-Hydroxymethyl-3-(4-methoxybenzyloxy)-

8-(tert-butyldiphenylsilanyloxy)-9-vinyl-2,3,4,7,8,9-

hexahydrooxonine 68

To a stirred solution of cis-PMP acetal 67b (31.2 mg, 0.055 mmol)

in CH₂Cl₂(3.0 mL) at ꢀ78 °C, was added a solution of DIBAL-H (0.18

mL of a 1.5 M solution in PhMe, 0.270 mmol). The reaction mixture

was stirred at this temperature for 10 min, and was then warmed

to ꢀ10 °C. Stirring was continued at this temperature for another

hour. It was recooled to ꢀ78 °C and quenched by the addition of

MeOH (1.5 mL), a saturated solution of aqueous NH₄Cl (1.5 mL)

and water (3 mL). The reaction mixture was warmed to room tem-

perature and the separated aqueous layer was extracted with ether

(3 ꢄ 5 mL). The combined organic extracts were washed with brine

(5 mL), dried (MgSO₄), ﬁltered and concentrated in vacuo to give the

crude product. Puriﬁcation by ﬂash chromatography (hexane–ether,

1:1) afforded the title alcohol 68 (19.0 mg, 61%) as a colourless oil; R_f

R_f0.34 (5% MeOH in CH₂Cl₂); ½a _D²⁴

¼ þ63:6 (c 0.06, CHCl₃); m_max

ꢂ

(CHCl₃ﬁlm)/cm^ꢀ13366, 2924, 2855; d_H(500 MHz; CDCl₃) 7.66–

7.69 (4H, m, Ar), 7.36–7.46 (6H, m, Ar), 5.87 (1H, ddd, J 17.3,

10.5, 6.9, CH@CHH), 5.77–5.83 (1H, m, CH@CH), 5.60 (1H, dt, J

10.8, 6.0, CH@CH), 5.33 (1H, d, J 17.3, trans-CH@CHH), 5.15 (1H,

d, J 10.5, cis-CH@CHH), 4.02–4.06 (1H, m), 3.90–3.93 (1H, m),

3.80–3.82 (2H, m), 3.59–3.62 (1H, m), 3.45–3.49 (1H, m), 2.69–

2.74 (1H, m), 2.59–2.63 (1H, m), 2.30–2.35 (1H, m), 2.14–2.25

(2H, m), 2.00–2.05 (1H, m), 1.06 [9H, s, C(CH₃)₃]; d_H(125 MHz;

CDCl₃) 139.6, 136.1, 135.9, 134.2, 133.2, 129.7, 129.6, 129.2,

127.5, 126.7, 117.1, 88.2, 85.3, 76.2, 72.9, 64.0, 32.8, 29.7, 27.0,

19.3; m/z (ES) 475 [(M+Na)⁺, 50%], 453 [(M+H)⁺, 40]; [m/z (ES)

Found: (M+H)⁺453.2453, C₂₇H₃₇O₄Si requires M, 453.2461].

0.23 (hexane–ether, 1:1); ½a _D²⁴

ꢂ

¼ þ88:2 (c 0.38, CHCl₃);

m_max(CHCl₃

ﬁlm)/cm^ꢀ13468, 2931, 2856, 1613; d_H(500 MHz; CDCl₃) 7.65–

7.69 (4H, m, Ar), 7.35–7.45 (6H, m, Ar), 7.23–7.24 (2H, d, J 8.4, Ar),

6.86–6.88 (2H, d, J 8.4, Ar), 5.83–5.90 (2H, m, CH@CH, CH@CHH),

5.58 (1H, dt, J 10.9, 6.1, CH@CH), 5.35 (1H, d, J 17.2, trans-CH@CHH),

5.15 (1H, d, J 10.4, cis-CH@CHH), 4.62 (1H, d, J 11.7, OCHHAr), 4.34

(1H, d, J 11.7, OCHHAr), 3.92–3.94 (1H, m, H-8), 3.81 (3H, s, OMe),

3.70–3.76 (2H, m, H-2, H-3), 3.60–3.66 (1H, m, CHHOH), 3.49–3.54

(1H, m, H-9), 3.44–3.47 (1H, m, CHHOH), 2.74–2.77 (1H, m), 2.64–

2.71 (1H, m), 2.32–2.37 (1H, m), 2.26–2.29 (1H, m, CH₂OH), 1.95–

1.97 (1H, m), 1.07 [9H, s, C(CH)₃]; d_C(125 MHz; CDCl₃) 159.3,

139.6, 136.1, 135.9, 134.3, 133.3, 129.8, 129.7, 129.6, 129.5, 128.7,

127.5, 127.4, 117.4, 113.9, 113.8, 63.9, 70.6, 55.2, 29.7, 28.6, 27.0,

4.1.48. (2R,4aR/S,6R,7S,11aS,Z)-7-tert-Butyldiphenylsilyloxy -2-

(4-methoxyphenyl)-6-vinyl-4a,6,7,8,11,11a-hexahydro-4H-

[1,3]dioxino[5,4-b]oxonines 67a and 67b

To a stirred solution of a mixture of the diols 66 (0.424 g, 0.938

mmol) in PhMe (16 mL), were added PPTS (0.047 g, 0.186 mmol)

and p-anisaldehyde dimethyl acetal (0.19 mL, 1.49 mmol). The

reaction mixture was heated at 90 °C for 18 h and was quenched

by the addition of saturated solution of aqueous NaHCO₃(2 mL)

and water (2 mL). The organic layer was separated and the aqueous

layer was extracted with CH₂Cl₂(3 ꢄ 25 mL). The combined organ-

S. Y. Frankie Mak et al. / Tetrahedron: Asymmetry 20 (2009) 921–944

941

19.3; m/z (CI; NH₃) 590 [(M+NH₄)⁺, 30%], 573 [(M+H)⁺, 5]; [m/z (ES)

Found: (M+NH₄)⁺590.3295, C₃₅H₄₈O₅NSi requires M, 590.3296].

4.1.52. (1S,2S,7S,8R,4Z,9Z)-2-(4-Methoxybenzyloxy)-7-(tert-buty-

ldiphenylsilanyloxy)-11-oxa-bicyclo[6.2.1]undeca-4,9-diene 72

and (1S,2R)-3-tert-butyldiphenylsilanyloxy-2-((1S,5S)-5-(4-meth-

oxybenzyloxy)cyclopent-2-enyloxy)cyclopent-3-ene 71

4.1.50. (2R,3S,8S,9R,5Z)-3-(4-methoxybenzyloxy)-8-(tert-butyldi-

phenylsilanyloxy)-9-vinyl-2,3,4,7,8,9-hexahydrooxonine-2-

carbaldehyde 69

To a stirred solution of the alcohol 68 (20.1 mg, 0.035 mmol)

in CH₂Cl₂(2 mL) were added NMO (18.0 mg, 0.154 mmol) and

activated 4 Å powdered molecular sieves. The reaction mixture

was stirred at room temperature for 0.5 h, followed by the addi-

To a solution of the second-generation Grubbs’ catalyst 18

(6.5 mg, 0.007 mmol) in CH₂Cl₂(2 mL), was added a solution of

the oxonine 70 (10.0 mg, 0.017 mmol) in CH₂Cl₂(2 mL). The reac-

tion mixture was heated at reﬂux for 5 h. The reaction mixture was

cooled to room temperature and the solvent was removed in va-

cuo. Puriﬁcation by ﬂash column chromatography (hexane–ether,

4:1) furnished the title compounds 71 and 72 (8.8 mg, 88%) as a

ca. 1:1 inseparable mixture; R_f0.65 (hexane–ether, 2:1); m/z (CI;

NH₃) 558 [(M+NH₄)⁺, 100%]; [m/z (ES) Found: (M+NH₄)⁺

558.3040, C₃₄H₄₄O₄NSi requires M, 558.3034].

tion of TPAP (1.0 mg, 2.8

lmol). The reaction mixture was stir-

red for 1 h, whereby the resulting black solution was ﬁltered

through a plug of silica and was washed with excess EtOAc.

The solvent was removed in vacuo to furnish the aldehyde 69

as a colourless oil (20.0 mg, 100%); R_f0.63 (hexane–ether, 1:1);

½

a ²_D⁴

ꢂ

¼ þ19:2 (c 0.18, CHCl₃); m_max(CHCl₃ﬁlm)/cm^ꢀ12931,

4.1.53. (1R,2S,7S,8R,4Z,9Z)-7-(4-Methoxybenzyloxy)-11-oxa-

bicyclo[6.2.1]undeca-4,9-dien-2-ol 74 and (1S,2R)-2-((1S,5S)-5-

(4-methoxybenzyloxy)cyclopent-2-enyloxy)cyclopent-3-enol 73

To a solutionof themixture of 71and 72 (24.4 mg, 0.037 mmol) in

THF (1 mL) at 0 °C, was added a solution of TBAF (0.2 mL of a 1.0 M

solution in THF, 0.200 mmol). The reaction mixture was then

warmed to room temperature and was stirred at this temperature

for 2 h. The reaction mixture was subjected to column chromatogra-

phy directly (petroleum ether 40–60:ether, 1:1 increasing the polar-

ity to neat ether) to give the alcohol 74 (4.6 mg, 48%) and the bis-

cyclopentene 73 (4.2 mg, 43%). Data for 74; R_f0.04 (petroleum ether

2858, 1731; d_H(500 MHz; CDCl₃) 9.70 (1H, s, CHO), 7.65–7.69

(4H, m, Ar), 7.36–7.45 (6H, m, Ar), 7.15 (2H, d, J 8.5, Ar), 6.85

(2H, d, J 8.5, Ar), 5.87–5.90 (1H, m, CH@CH), 5.75 (1H, ddd, J

17.5, 10.2, 8.0, CH@CHH), 5.55 (1H, dt, J 11.0, 5.8, CH@CH),

5.22 (1H, d, J 17.5, trans-CH@CHH), 5.13 (1H, d, J 10.2, cis-

CH@CHH), 4.47 (1H, d, J 11.5, OCHHAr), 4.32 (1H, d, J 11.5, OCH-

HAr), 3.92–4.10 (2H, m, CHOSi, CHOPMB), 3.80 (3H, s, OMe), 3.67

(1H, d, J 3.3, H-2), 3.38–3.41 (1H, m, H-9), 2.68–2.70 (1H, m),

2.79–2.82 (1H, m), 2.32–2.37 (1H, m), 1.97–2.00 (1H, br m),

1.07 [9H, s, C(CH)₃]; d_C(125 MHz; CDCl₃) 205.6, 159.2, 137.2,

136.2, 135.9, 129.8, 129.7, 129.6, 129.5, 129.4, 127.5, 126.6,

118.6, 113.7, 90.3, 89.7, 78.9, 75.5, 71.3, 55.2, 29.7, 28.9, 27.0,

19.3; m/z (CI; NH₃) 588 [(M+NH₄)⁺, 40%], 571 [(M+H)⁺, 10];

[m/z (ES) Found: (M+NH₄)⁺588.3133, C₃₅H₄₆O₅NSi requires M,

588.3140].

40–60:ether, 1:1); ½a _D²⁴

¼ ꢀ27:8 (c 0.11, CHCl₃); m_max(CHCl₃ﬁlm)/

ꢂ

cm^ꢀ13430, 2921, 2853; d_H(500 MHz; CDCl₃) 7.27 (2H, d, J 8.5, Ar),

6.90 (2H, d, J 8.5, Ar), 6.11–6.13 (1H, m, H-9/H-10) 5.88–5.90 (1H,

m, H-9/H-10), 5.58–5.66 (2H, m, H-4, H-5), 5.12–5.17 (2H, m, H-1,

H-8), 4.62 (1H, d, J 11.6, OCHHAr), 4.49 (1H, d, J 11.6, OCHHAr),

3.83 (3H, s, OMe), 3.73–3.76 (1H, m, H-2), 3.52–3.55 (1H, m, H-7),

2.58–2.70 (2H, m, H-3, H-6), 2.19–2.27 (1H, m, H-3⁰), 2.11–2.15

(1H, m, H-6⁰), 2.03 (1H, d, J 10.3, OH); d_C(125 MHz; CDCl₃) 159.2,

130.34, 130.28, 129.2, 128.90, 128.89, 126.4, 113.8, 92.7, 88.3,

74.1, 69.4, 71.2, 55.3, 28.8, 27.4; m/z (ES) 325 [(M+Na)⁺, 100%]; [m/

z (ES) Found: (M+Na)⁺325.1395, C₁₈H₂₂O₄Na requires M, 325.1416].

Data for the bis-cyclopentenol 73: R_f0.25 (petroleum ether 40–

4.1.51. (2S,3S,8S,9R,5Z)-3-(4-Methoxybenzyloxy)-8-(tert-

butyldiphenylsilanyloxy)-2,9-divinyl-2,3,4,7,8,9-

hexahydrooxonine 70

To a stirred solution of CH₃PPh₃Br (94.6 mg, 0.263 mmol) in THF

(3.5 mL) at ꢀ78 °C, was added a solution of KHMDS (0.44 mL of a

0.5 M solution in PhMe, 0.220 mmol). The resultant yellow solution

was allowed warm to room temperature and was stirred for 30

min. To a stirred solution of the aldehyde 69 (75.0 mg, 0.035 mmol)

in THF (3.5 mL) at ꢀ78 °C, was added the preformed ylide solution.

The reaction mixture was then allowed to warm to room temper-

ature and was stirred for 30 min, before being quenched by the

addition of a saturated solution of aqueous NH₄Cl (5 mL) and water

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

was extracted with ether (3 ꢄ 20 mL). The combined organic ex-

tracts were washed with brine (20 mL), dried (MgSO₄), ﬁltered

and concentrated in vacuo to give the crude product. Puriﬁcation

by ﬂash chromatography (hexane–ether, 2:1) afforded the title

compound 70 (64.3 mg, 86%) as a clear and colourless oil; R_f0.74

60: ether, 1:1); ½a _D²⁴

¼ þ25:7 (c 0.14, CHCl₃); m_max(CHCl₃ﬁlm)/

ꢂ

cm^ꢀl3509, 3006, 2918; d_H(500 MHz; CDCl₃) 7.28–7.31 (2H, m,

Ar), 6.89–6.91 (2H, m, Ar), 5.94–5.96 (1H, m, CH@CH), 5.89–5.91

(1H, m, CH⁰@CH⁰), 5.78–5.82 (2H, m, CH@CH, CH⁰@CH⁰), 4.74–

4.75 (1H, m, H-1⁰), 4.54 (2H, d, J 11.3, OCH₂Ar), 4.48–4.50 (1H,

m, H-2), 4.33 (1H, ddd, J 11.5, 5.7, 3.1, H-1), 4.19 (1H, dt, J 9.1,

4.4, H-5⁰), 3.82 (3H, s, OMe), 3.02 (1H, d, J 5.7, CHOH), 2.73–2.78

(1H, m, H-4⁰), 2.52–2.57 (1H, m, H-5), 2.37–2.42 (1H, m, H-5),

2.28–2.34 (1H, m, H-4⁰); d_C(125 MHz; CDCl₃) 159.3, 133.4,

132.6, 130.0, 129.9, 129.7, 129.4, 113.8, 89.4, 84.9, 82.3, 70.3,

71.5, 55.3, 39.9, 37.1; m/z (ES) 325 [(M+Na)⁺, 100%], 303

[(M+H)⁺, 5]; [m/z (ES) Found: (M+Na)⁺325.1413, C₁₈H₂₂O₄Na

requires M, 325.1416].

(hexane–ether, 2:1); ½a _D²⁴

¼ þ70:7 (c 0.60, CHCl₃); m_max(CHCl₃

ꢂ

ﬁlm)/cm^ꢀ12931, 2857s 1612; d_H(500 MHz; CDCl₃) 7.65–7.69

(4H, m, Ar), 7.35–7.45 (6H, m, Ar), 7.23–7.25 (2H, m, Ar), 6.84–

6.87 (2H, m, Ar), 5.99 (1H, ddd, J 17.4, 10.4, 7.0, CH@CHH), 5.72–

5.80 (1H, m, CH@CH), 5.70 (1H, ddd, J 17.2, 10.3, 6.9, CH⁰@CH⁰H⁰),

5.60 (1H, dt, J 10.9, 6.2, CH@CH), 5.10–5.16 (3H, m, trans-CH@CHH,

trans-CH⁰@CH⁰H⁰, cis-CH⁰@CH⁰H⁰), 5.04 (1H, dd, J 10.4, 0.9, cis-

CH@CHH), 4.54 (1H, d, J 11.8, OCHHAr), 4.43 (1H, d, J 11.8, OCH-

HAr), 3.91–3.96 (2H, m, H-2, H-3), 3.81 (3H, s, OMe), 3.54–3.59

(2H, m, H-8, H-9), 2.70–2.75 (2H, m), 2.13–2.18 (1H, m), 1.91–

1.93 (1H, m), 1.06 [9H, s, C(CH₃)₃]; d_C(125 MHz; CDCl₃) 159.1,

138.1, 137.3, 136.2, 136.0, 134.4, 133.6, 130.7, 129.6, 129.5,

129.3, 128.6, 127.5, 127.4, 117.0, 115.7, 113.7, 113.6, 79.8, 79.6,

76.2, 74.1, 71.4, 55.3, 29.2, 27.1, 19.4; m/z (CI; NH₃) 586

[(M+NH₄)⁺, 20%]; [m/z (ES) Found: (M+NH₄)⁺586.3360, C₃₆H₄₈O₄N-

Si requires M, 586.3347].

4.1.54. (1S,2S,7S,8R,4Z,9Z)-2-Hydroxy-7-(tert-butyldiphenylsi-

lanyloxy)-11-oxa-bicyclo[6.2.1]undeca-4,9-diene 76

To a solution of a mixture of 71 and 72 (20.1 mg, 0.037 mmol) in

CH₂Cl₂(2 mL) at 0 °C, was added a solution of BCl₃ꢁSMe₂(74

lL of

2.0 M solution in CH₂Cl₂, 0.148 mmol). The reaction mixture was

then warmed to room temperature before being quenched by the

addition of a saturated solution of aqueous NaHCO₃(2 mL). The

layers were separated and the aqueous layer was extracted with

ether (3 ꢄ 5 mL). The combined organic extracts were dried

(MgSO₄), ﬁltered and concentrated in vacuo to give the crude prod-

uct. Puriﬁcation by column chromatography (hexane–ether 2:1)

furnished the alcohol 76 (8.0 mg, 51%) as a colourless oil; R_f0.19

(hexane–ether, 1:1); ½a _D²⁴

¼ þ7:2 (c 0.19, CHCl₃); m_max(CHCl₃,

ꢂ

ﬁlm)/cm^ꢀ13410, 2918, 2852; d_H(500 MHz; CDCl₃) 7.73–7.75

942

S. Y. Frankie Mak et al. / Tetrahedron: Asymmetry 20 (2009) 921–944

(4H, m, Ar), 7.30–7.47 (6H, m, Ar), 6.04 (1H, br m, H-9/H-10), 5.81

(1H, br m, H-4/H-5), 5.65 (1H, br m, H-9/H-10), 5.55–5.58 (1H, br

m, H-4/H-5), 5.12–5.14 (2H, br m, H-1, H-8), 4.00–4.02 (1H, br m,

H-2/H-7), 3.76 (1H, d, J 7.0, H-2/H-7), 2.67–2.69 (1H, br m), 2.42

(1H, br m), 1.99 (1H, br m), 1.86 (1H, br m), 1.12 [9H, s, C(CH₃)₃];

d_C(125 MHz; CDCl₃) 135.9, 134.1, 133.8, 130.1, 129.7, 129.6,

128.6, 127.7, 127.6, 127.5, 126.5, 125.5, 93.1, 90.1, 71.2, 68.0,

32.1, 29.7, 27.1, 19.4; m/z (CI; NH₃) 438 [(M+NH₄)⁺, 100%], 421

[(M+H)⁺, 5]; [m/z (ES) Found: (M+NH₄)⁺438.2465, C₂₆H₃₆O₃NSi re-

quires M, 438.2459].

(5 mL) and water (5 mL). The reaction mixture was warmed to

room temperature and the separated aqueous layer was extracted

with ether (3 ꢄ 25 mL). The combined organic extracts were

washed with brine (20 mL), dried (MgSO₄), ﬁltered and concen-

trated in vacuo to give the crude product. Puriﬁcation by ﬂash

chromatography (hexane–ether, 1:1) furnished the title alcohol

as a colourless oil (215 mg, 93%); R_f0.23 (hexane–ether, 1:1);

½

a ²_D⁴

ꢂ

¼ þ71:0 (c 0.46, CHCl₃); m_max(CHCl₃ﬁlm)/cm^ꢀ13570, 3071,

3014, 2931, 2857; d_H(500 MHz; CDCl₃) 7.65–7.69 (4H, m, Ar),

7.36–7.46 (6H, m, Ar), 7.24–7.28 (2H, m, Ar), 6.82–6.90 (2H, m,

Ar), 5.85 (1H, ddd, J 17.5, 10.1, 8.1, CH@CHH), 5.62–5.66 (1H, m,

CH@CH), 5.42–5.44 (1H, m, CH@CH), 5.35 (1H, d, J 17.5, trans-

CH@CHH), 5.22 (1H, d, J 10.1, cis-CH@CHH), 4.60 (1H, d, J 11.0,

OCHHAr), 4.37 (1H, d, J 11.0, OCHHAr), 3.80–3.83 (4H, m, OMe,

H-9), 3.74–3.76 (1H, m, H-8), 3.69–3.61 (2H, m, CH₂OH), 3.49–

3.51 (2H, m, H-2, H-3), 2.61 (1H, m), 2.51 (1H, br m), 2.30–2.35

(1H, m), 2.20 (1H, m), 2.02 (1H, t, J 6.8, CH₂OH), 1.05 [9H, s,

C(CH)₃]; d_C(100 MHz; CDCl₃) 159.3, 139.8, 139.6, 136.1, 136.0,

135.9, 134.2, 133.4, 129.8, 129.7, 129.6, 129.5, 127.5, 127.0,

119.4, 113.9, 76.8, 74.0, 71.0, 62.9, 55.3, 30.8, 28.6, 27.0, 19.4; m/

z (CI; NH₃) 590 [(M+NH₄)⁺, 30%], 573 [(M+H)⁺, 20]; [m/z (ES)

Found: (M+NH₄)⁺590.3293, C₃₅H₄₈O₅NSi requires M, 590.3296].

4.1.55. (1S,7S,8R,4Z,9Z)-7-(tert-Butyldiphenylsilanyloxy)-11-

oxabicyclo[6.2.1]undeca-4,9-dien-2-one 77

To a stirred solution of the alcohol 76 (15.1 mg, 0.036 mmol) in

CH₂Cl₂(2 mL)wereaddedNMO(19.0 mg, 0.154mmol)andactivated

4 Å powdered molecular sieves. The reaction mixture was stirred at

room temperature for 0.5 h, followed by the addition of TPAP

(1.2 mg, 3.4

lmol). The reaction mixture was stirred for another

hour, whereby the resulting black solution was ﬁltered through a

plug of silica and was washed with excess EtOAc. The solvent was re-

moved in vacuo to furnish the ketone 77 as a colourless oil (13.4 mg,

89%); R_f0.63 (hexane–ether, 1:1); ½a _D²⁴

¼ þ126:4 (c 0.22 in CHCl₃);

ꢂ

m

_max(CHCl₃ﬁlm)/cm^ꢀ12956, 2929, 2857, 1713;d_H(500 MHz;CDCl₃)

7.71–7.72 (4H, m, Ar), 7.40–7.46 (6H, m, Ar), 5.77 (1H, ddd, J 5.9, 2.7,

1.9, H-1), 5.23–5.29 (4H, m, alkene protons), 5.01–5.03 (1H, m, H-8),

4.44 (1H, dd, J 9.9, 9.9, H-7), 3.86 (1H, dd, J 10.7, 3.7, H-3), 3.48 (1H,

dd, J 10.7, 10.7, H-3⁰), 2.65–2.68 (1H, m, H-6), 2.17–2.19 (1H, m, H-

6⁰), 1.13 [9H, s, C(CH₃)₃]; d_C(125 MHz; CDCl₃) 207.5, 135.83,

135.82, 134.8, 133.7, 131.4, 130.4, 130.3, 129.8, 127.74, 127.69,

124.6, 95.5, 92.9, 69.8, 40.4, 32.6, 26.9, 19.1; m/z (CI; NH₃) 436

[(M+NH)₄⁺, 100%], 417 [(M+H)⁺, 10]; [m/z (ES) Found: (M+NH₄)⁺

436.2297, C₂₈H₄₀O₃SiN requires M, 436.2302].

4.1.58. (2S,3S,8S,9R,5Z)-3-(4-Methoxybenzyloxy)-8-(tert-butyldi-

phenylsilanyloxy)-9-vinyl-2,3,4,7,8,9-hexahydrooxonine-2-

carbaldehyde 78

To a stirred solution of (2R,3S,8S,9R,5Z)-2-hydroxymethyl-8-

(tert-butyldiphenylsilanyloxy)-3-(4-methoxybenzyloxy)-9-vinyl-

2,3,4,7,8,9-hexahydrooxonine (34 mg, 0.035 mmol) in CH₂Cl₂(2

mL) were added NMO (31 mg, 0.265 mmol) and activated 4 Å pow-

dered molecular sieves. The reaction mixture was stirred at room

temperature for 0.5 h, followed by the addition of TPAP (1.3 mg,

0.004 mmol). The reaction mixture was stirred for 1 h, whereby

the resultant black solution was ﬁltered through a plug of silica

and was washed with excess EtOAc. The solvent was removed in

vacuo to furnish the aldehyde 78 as a colourless oil (31.6 mg,

4.1.56. (1R,7S,8S,4Z,9Z)-7-(4-Methoxybenzyloxy)-11-oxa-

bicyclo[6.2.1]undeca-4,9-dien-2-one 75

To a stirred solution of the alcohol 74 (5.4 mg, 0.036 mmol) in

CH₂Cl₂(1.5 mL) were added NMO (9.4 mg, 0.080 mmol) and acti-

vated 4 Å powdered molecular sieves. The reaction mixture was stir-

red at room temperature for 0.5 h, followed by the addition of TPAP

93%); R_f0.63 (hexane–ether, 1:1); ½a _D²⁴

¼ þ21:6 (c 0.49, CHCl₃);

ꢂ

m_max(CHCl₃ﬁlm)/cm^ꢀ12932, 1713; d_H(500 MHz; CDCl₃) 9.62

(1H, d, J 1.9, CHO), 7.64–7.59 (4H, m, Ar), 7.37–7.47 (6H, m, Ar),

7.18–7.20 (2H, m, Ar), 6.84–6.87 (2H, m, Ar), 5.65 (1H, ddd, J

17.1, 10.2, 8.2, CH@CHH), 5.45–5.51 (1H, m, CH@CH), 5.30 (1H, d,

J 17.1, trans-CH@CHH), 5.27 (1H, d, J 10.2, cis-CH@CHH), 5.13–

5.24 (1H, m, CH@CH), 4.53 (1H, d, J 10.8, OCHHAr), 4.37 (1H, d, J

10.8, OCHHAr), 3.96–4.03 (1H, m, H-9), 3.80 (3H, s, OMe), 3.66–

3.86 (3H, m, H-8, H-3, H-2), 2.30–2.64 (3H, m), 2.15–2.26 (1H,

m); d_C(125 MHz; CDCl₃) 202.0, 159.4, 137.0, 136.1, 136.0, 134.2,

133.2, 132.0, 129.8, 129.6, 129.5, 127.7, 127.6, 122.1, 114.3,

113.8, 113.7, 74.7, 73.4, 71.2, 55.3, 29.7, 28.9, 27.1; m/z (ES) 588

[(M+NH₄)⁺, 40%]; [m/z (ES) Found: (M+NH₄)⁺588.3133, C₃₅H₄₆O₅N-

Si requires M, 588.3140].

(1.0 mg, 2.8

lmol). The reaction mixture was stirred for another

hour, whereby the resulting black solution was ﬁltered through a

plug of silica and was washed with excess EtOAc. The solvent was re-

moved in vacuo to afford the ketone 75 as a colourless oil (3.3 mg,

66%); R_f0.47 (petroleum ether 40–60:ether, 1:1); ½a _D²⁴

¼ þ82:7 (c

ꢂ

0.15, CHCl₃); m_max(CHCl₃ﬁlm)/cm^ꢀ12924, 1707, 1612; d_H

(500 MHz; CDCl₃) 7.28–7.29 (2H, m, Ar), 6.90–6.92 (2H, m, Ar),

6.18 (1H, ddd, J 6.1, 2.4, 1.6, H-9/H-10), 5.92–5.94 (1H, m, H-9/H-

10), 5.64–5.69 (1H, m, H-4/H-5), 5.45–5.51 (1H, m, H-4/H-5), 5.33–

5.36 (1H, m, H-1/H-8), 5.05–5.07 (1H, m, H-1/H-8), 3.83–3.86 (1H,

m, H-7), 3.84 (3H, s, OMe), 3.56 (1H, dd, J 11.0, 9.2, H-3), 3.25 (1H,

1H, dd, J 11.0, 7.9, H-3⁰), 2.77–2.87 (1H, m, H-6), 2.58–2.64 (1H, m,

H-6⁰); d_C(125 MHz; CDCl₃) 206.1, 159.3, 131.1, 130.4, 130.3, 129.1,

127.7, 124.4, 113.8, 94.2, 89.5, 73.9, 71.4, 55.3, 40.0, 28.6; m/z (ES)

323 [(M+Na)⁺, 100%], 301 [(M+H)⁺, 5]; [m/z (ES) Found: (M+Na)⁺

323.1245, C₁₈H₂₀O₄Na requires M, 323.1254].

4.1.59. (2R,3S,8S,9R,5Z)-3-(4-Methoxybenzyloxy)-8-(tert-butyldi-

phenylsilanyloxy)-2,9-divinyl-2,3,4,7,8,9-hexahydro oxonine 79

To a stirred solution of CH₃PPh₃Br (39.6 mg, 0.111 mmol) in THF

(2 mL) at ꢀ78 °C, was added a solution of KHMDS (0.18 mL of a 0.5

M solution in PhMe, 0.090 mmol). The resultant yellow solution

was allowed to warm room temperature and was stirred for 30

min. To a stirred solution of the aldehyde 78 (31.6 mg, 0.055

mmol) in THF (1.5 mL) at ꢀ78 °C, was added the preformed ylide

solution. The reaction mixture was then allowed to warm to room

temperature and was stirred for 30 min, before being quenched by

the addition of a saturated solution of aqueous NH₄Cl (1 mL) and

water (2 mL). The organic phase was separated and the aqueous

layer was extracted with ether (3 ꢄ 15 mL). The combined organic

extracts were washed with brine (20 mL) and dried (MgSO₄). The

solvent was removed in vacuo and puriﬁcation by ﬂash chromatog-

4.1.57. (2R,3S,8S,9R,5Z)-2-Hydroxymethyl-8-(tert-butyldi-

phenylsilanyloxy)-3-(4-methoxybenzyloxy)-9-vinyl-2,3,4,7,8,9-

hexahydrooxonine

To a stirred solution of the trans-PMP acetal 67a (231 mg, 0.406

mmol) in CH₂Cl₂(5 mL) at ꢀ78 °C, was added a solution of DIBAL-H

(1.3 mL of a 1.5 M solution in PhMe, 1.95 mmol). The reaction mix-

ture was stirred at this temperature for 10 min and was then

warmed to ꢀ10 °C. Stirring was continued for another hour at this

temperature. It was recooled to ꢀ78 °C and was quenched by the

addition of MeOH (5 mL), a saturated solution of aqueous NH₄Cl

S. Y. Frankie Mak et al. / Tetrahedron: Asymmetry 20 (2009) 921–944

943

raphy (hexane–ether, 2:1) furnished the oxonine 79 (26.4 mg, 84%)

233 [(M+Na)⁺, 100%]; [m/z (ES) Found: (M+Na)⁺233.1148,

C₁₂H₁₈O₃Na requires M, 233.1156].

as

a clear and colourless oil; R_f0.74 (hexane–ether, 2:1);

½

a ²_D⁴

ꢂ

¼ þ36:6 (c 0.25, CHCl₃); m_max(CHCl₃)/cm^ꢀ12960, 2931,

1631; d_H(500 MHz; CDCl₃) 7.67–7.71 (4H, m, Ar), 7.36–7.46 (6H,

m, Ar), 7.22–7.24 (2H, m, Ar), 6.86–6.88 (2H, m, Ar), 5.88–5.95

(1H, m, CH@CHH), 5.76–5.83 (1H, m, CH⁰@CH⁰H⁰), 5.54–5.58 (1H,

m, CH@CH), 5.27–5.31 (1H, m, CH@CH), 5.10–5.22 (4H, m,

2 ꢄ CH@CH₂and 2 ꢄ CH⁰@CH⁰₂), 4.52 (1H, d, J 11.2, OCHHAr),

4.37 (1H, d, J 11.2, OCHHAr), 3.93–3.96 (1H, m), 3.81–3.84 (4H,

m, OMe, OCH), 3.75–3.77 (1H, m), 3.37–3.39 (1H, m), 2.25–2.48

(4H, m, 2 ꢄ ring CH₂), 1.05 [9H, s, C(CH₃)₃]; d_C(125 MHz; CDCl₃)

159.2, 139.0, 136.2, 136.0, 134.5, 133.6, 130.4, 129.7, 129.6,

129.5, 129.3, 127.9, 127.5, 118.5, 117.1, 113.7, 113.6, 79.8, 74.1,

71.4, 55.3, 30.4, 27.1, 19.4; m/z (CI; NH₃) 586 [(M+NH₄)⁺, 20%];

[m/z (ES) Found: (M+NH₄)⁺586.3344, C₃₆H₄₈O₄NSi requires M,

586.3347].

4.1.62. ((1S,2R)-3-tert-Butyldiphenylsilanyloxy-2-((1R,5S)-5-(4-

methoxybenzyloxy)cyclopent-2-enyloxy)cyclopent-3-ene 81

To a solution of the second-generation Grubbs’ catalyst 18

(2.1 mg, 2.5

lmol) in CH₂Cl₂(2 mL), was added a solution of

the oxonine 79 (7.9 mg, 0.014 mmol) in CH₂Cl₂(2 mL). The reac-

tion mixture was heated to reﬂux for 4 h. TLC analysis at this

stage indicated that starting material remained largely un-

touched. Another portion of the catalyst solution (2.5 mg in 1

mL of CH₂Cl₂) was added to the mixture and the reﬂux was con-

tinued for another 0.5 h. The reaction mixture was then left to stir

at room temperature for 18 h before the solvent was removed in

vacuo. Puriﬁcation by column chromatography (hexane–ether,

1:1) recovered the majority of starting material 79 (5.9 mg,

75%), along with the title compound 81 (1.2 mg, 13%); R_f0.32

4.1.60. (2R,3S,8S,9R,5Z)-3-Hydroxy-8-(tert-butyldiphenylsil-

anyloxy)-2,9-divinyl-2,3,4,7,8,9-hexahydrooxonine

(hexane–ether, 2:1); ½a _D²⁴

¼ þ76:7 (c 0.06, CHCl₃); m_max(CHCl₃

ꢂ

ﬁlm)/cm^ꢀ12930, 2856; d_H(500 MHz; CDCl₃) 7.75–7.77 (4H, m,

Ar), 7.31–7.45 (8H, m, Ar), 6.88–6.89 (2H, m, Ar), 5.95–5.97 (1H,

m, CH@CH), 5.91–5.93 (1H, m, CH@CH), 5.81–5.82 (1H, m,

CH⁰@CH⁰), 5.74–5.76 (1H, m, CH⁰@CH⁰), 4.69–4.70 (1H, m, H-1/

H-1⁰), 4.55 (1H, d, J 11.4, CHHOAr), 4.50 (1H, d, J 11.4, CHHOAr),

4.28–4.31 (2H, m, H-5/H-5⁰, H-1/H-1⁰), 4.03 (1H, dd, J 12.0, 5.5,

H-5/H-5⁰), 3.82 (3H, s, OMe), 2.52–2.57 (1H, m), 2.41–2.47 (2H,

m), 1.93–1.99 (1H, m), 1.09 [9H, s, C(CH₃)₃]; d_C(125 MHz; CDCl₃)

158.9, 135.8, 135.7, 134.4, 134.0, 133.9, 132.6, 131.0, 130.9, 130.5,

129.6, 129.5, 129.1, 127.6, 127.5, 113.6, 81.1, 81.0, 78.2, 74.6,

71.0, 55.2, 37.9, 36.0, 26.9, 19.2; m/z (CI; NH₃) 558 [(M+NH₄)⁺,

30%]; [m/z (ES) Found: (M+NH₄)⁺558.3040, C₃₄H₄₄O₄NSi requires

M, 558.3034].

To a solution of the oxonine 79 (18 mg, 0.032 mmol) in wet

CH₂Cl₂(2 mL + 1 drop of water), was added DDQ (14 mg, 0.062

mmol). The reaction mixture was stirred at room temperature

for 1 h. It was then diluted with CH₂Cl₂(5 mL) and was washed

with a saturated solution of aqueous NaHCO₃(2 ꢄ 5 mL). The

aqueous wash was extracted with CH₂Cl₂(3 ꢄ 5 mL). The com-

bined organic extracts were washed with water (10 mL), dried

(MgSO₄), ﬁltered and concentrated in vacuo to give the crude

product. Puriﬁcation by ﬂash column chromatography (hexane–

ether, 1:1) furnished the title compound as a colourless oil

(13 mg, 91%); R_f0.63 (hexane–ether, 1:1); ½a _D²⁴

¼ þ30:1 (c 0.17,

ꢂ

CHCl₃); m_max(CHCl₃ﬁlm)/cm^ꢀ13437, 2931, 2858; d_H(500 MHz;

CDCl₃) 7.67–7.71 (4H, m, Ar), 7.36–7.45 (6H, m, Ar), 5.90 (1H,

ddd, J 18.0, 10.3, 8.1, CH@CHH), 5.83 (1H, ddd, J 18.0, 10.3, 8.1,

CH⁰@CH⁰H⁰), 5.55–5.61 (1H, m, CH@CH), 5.22–5.29 (1H, m,

4.1.63. (2R,3S,5Z,8Z)-3-(tert-Butyldiphenylsilanyloxy)-9-[(Z)-

prop-1-enyl]-2-vinyl-2,3,4,7-tetrahydrooxonine 82

CH@CH), 5.17–5.26 (3H, m), 5.14 (1H, dd,

J

10.3, 0.9, cis-

To a stirred solution of EtPPh₃Br (137.5 mg, 0.370 mmol) in THF

(3 mL) at –78 °C, was added a solution of KHMDS (0.63 mL of a 0.5

M solution in PhMe, 0.315 mmol). The resultant yellow solution

was allowed to warm to room temperature and was stirred for

30 min. To a stirred solution of a mixture of aldehydes 69, 78

and (2Z,5Z,8S,9R)-8-(tert-butyldiphenylsilyloxy)-9-vinyl-4,7,8,9-

tetrahydrooxonine-2-carbaldehyde formed from exposure of the

aldehyde 78 to pyrrolidine and PPTS, (ca. 1:2.8:4, 73.3 mg) in

THF (3 mL) at ꢀ78 °C, was added the preformed ylide solution.

The reaction mixture was then allowed to warm to room temper-

ature over 30 min, before being quenched by the addition of a sat-

urated solution of aqueous NH₄Cl (5 mL) and water (5 mL). The

organic phase was separated and the aqueous layer was extracted

with ether (3 ꢄ 20 mL). The combined organic extracts were

washed with brine (20 mL) dried (MgSO₄), ﬁltered and concen-

trated in vacuo to give the crude product. Puriﬁcation by ﬂash

chromatography (petroleum ether 40–60:ether, 20:1) furnished

the 2,9-trans adduct (12.3 mg, 15%), the 2,9-cis adduct (27.0 mg,

32%) and the enol ether 82 (15.7 mg, 23%); R_f0.76 (petroleum ether

CH@CHH), 3.99 (1H, dd, J 8.1, 8.1, H-2/H-9), 3.79–3.84 (1H, m,

H-3/H-8), 3.66 (1H, dd, J 8.1, H-2/H-9), 3.53–3.55 (1H, m, H-3/

H-8), 2.57–2.59 (1H, m), 2.48–2.50 (1H, m,), 2.35–2.38 (1H m),

2.25–2.30 (1H, m), 1.46 (1H, d,

J 2.3, CHOH), 1.05 [9H, s,

C(CH₃)₃]; d_C(125 MHz; CDCl₃) 136.7, 136.2, 136.1, 136.0, 135.9,

134.4, 133.5, 129.8, 129.7, 129.6, 127.7, 127.5, 118.9, 118.2,

73.9, 71.0, 27.0, 19.2; m/z (CI; NH₃) 466 [(M+NH)₄⁺, 100%], 449

[(M+H)⁺, 20]; [m/z (ES) Found: (M+NH₄)⁺466.2774, C₂₈H₄₀O₃SiN

requires M, 466.2772].

4.1.61. (2R,3S,8S,9R,5Z)-2,9-Divinyl-2,3,4,7,8,9-hexahydrooxonin-

3,8-diol 80

To a solution of the alcohol (2R,3S,8S,9R,5Z)-3-hydroxy-8-(tert-

butyldiphenylsilanyloxy)-2,9-divinyl-2,3,4,7,8,9-hexahydrooxonine

(18.2 mg, 0.041 mmol) in THF (1 mL) at 0 °C, was added a solution

of TBAF (0.15 mL of a 1.0 M solution in THF, 0.150 mmol). The reac-

tion mixture was then warmed to room temperature and was stir-

red at this temperature for 18 h. The reaction mixture was

subjected to column chromatography directly (ether) to give the

diol 80 as white crystalline solid (5.6 mg, 66%); R_f0.56 (ether);

40–60:ether, 9:1); ½a _D²⁴

¼ þ36:6 (c 0.25, CHCl₃); m_max(CHCl₃ﬁlm)/

ꢂ

cm^ꢀ12960, 2929, 2856, 1639; d_H(500 MHz; CDCl₃) 7.68–7.72 (4H,

m, Ar), 7.36–7.46 (6H, m, Ar), 5.61–5.81 (4H, m, alkene), 5.50–5.55

(1H, m, alkene), 5.18–5.21 (2H, m, trans-CH@CHH, alkene), 5.12

(1H, dd, J 10.3, 1.7, cis-CH@CHH), 4.00–4.04 (1H, m, H-2), 3.79

(1H, dd, J 8.0, 8.0, H-3), 3.29–3.35 (1H, m), 3.05 (1H, ddd, J 13.6,

5.1, 3.5), 2.19–2.25 (1H, m), 1.99 (1H, ddd, J 13.6, 5.1, 3.5), 1.79

mp 92–95 °C (from CH₂Cl₂); ½a _D²⁴

¼ þ155:0 (c 0.20, CHCl₃); m_max

ꢂ

(CHCl₃ﬁlm)/cm^ꢀ13376, 3078, 3016, 2924; d_H(500 MHz; CDCl₃)

5.93–6.00 (1H, m, CH@CHH), 5.79–5.81 (1H, m, CH@CH), 5.28–

5.31 (2H, m, CH@CH₂), 3.80 (1H, dd, J 8.6, 8.6, H-2/H-9), 3.59–

3.63 (1H, m, CHOH), 2.58 (2H, br s), 1.56 (1H, d, J 3.1, CHOH); d_C

(125 MHz; CDCl₃) 138.6, 127.8, 119.0, 80.8, 71.1, 30.4; m/z (ES)

(3H, dd,

J 7.8, 1.8, CH@CH₂CH₃), 1.06 [9H, s, C(CH₃)₃]; d_C

(125 MHz; CDCl₃) 154.4, 138.5, 136.3, 136.0, 134.5, 133.6, 131.3,

129.6, 127.5, 127.4, 127.0, 125.5, 124.6, 118.5, 116.3, 86.9, 84.9,

75.2, 30.3, 23.4, 27.1, 19.4, 15.3; m/z (ES) 445 [(M+H)⁺, 100%];

[m/z (ES) Found: (M+H)⁺445.2581, C₂₉H₃₇O₂Si requires M,

445.2663].

Due to conformational mobility of the diol 80, the ¹³C NMR signals either were

broadened or appeared as multiplets. The reported data above were the averaged

ﬁgure taken from these broadened signals and multiplets.

944

S. Y. Frankie Mak et al. / Tetrahedron: Asymmetry 20 (2009) 921–944

18. Davidson, J. E. P.; Gilmour, R.; Ducki, S.; Davies, J. E.; Green, R.; Burton, J. W.;

Holmes, A. B. Synlett 2004, 1434–1436.

19. Petasis, N. A.; Bzowej, E. I. J. Am. Chem. Soc. 1990, 112, 6392–6394.

20. Petasis, N. A.; Lu, S. P.; Bzowej, E. I.; Fu, D. K.; Staszewski, J. P.;

AkritopoulouZanze, I.; Patane, M. A.; Hu, Y. H. Pure Appl. Chem. 1996, 68,

667–670.

21. Crystallographic data (excluding structure factors) for the structures in this

paper have been deposited with the Cambridge Crystallographic Data Centre as

supplementary publication numbers CCDC 720022 (9), 720025 (19b), 720024

(30), 720023 (42). Copies of the data can be obtained, free of charge, on

application to CCDC, 12 Union Road, Cambridge CB2 lEZ, UK [fax: +44(0)-1223-

336033 or e-mail:deposit@ccdc.cam.ac.uk].

22. Burton, J. W.; Clark, J. S.; Derrer, S.; Stork, T. C.; Bendall, J. G.; Holmes, A. B. J. Am.

Chem. Soc. 1997, 119, 7483–7498.

23. Carling, R. W.; Clark, J. S.; Holmes, A. B. J. Chem. Soc., Perkin Trans. 1 1992, 83–

94.

24. Carling, R. W.; Curtis, N. R.; Holmes, A. B. Tetrahedron Lett. 1989, 30, 6081–

6084.

25. Frigerio, M.; Santagostino, M. Tetrahedron Lett. 1994, 35, 8019–8022.

26. Schwab, P.; France, M. B.; Ziller, J. W.; Grubbs, R. H. Angew. Chem., Int. Ed. 1995,

34, 2039–2041.

4.1.64. (1R,2S,4Z,6Z,9Z)-2-(tert-Butyldiphenylsilanyloxy)-11-

oxa-bicyclo[4.4.1]undeca-4,6,9-triene 83

To a solution of the second-generation Grubbs’ catalyst 18

(8.0 mg, 9.4 lmol) in CH₂Cl₂(3 mL), was added a solution of the enol

ether82(7.3 mg, 0.016mmol)inCH₂Cl₂(3mL). Thereactionmixture

was heated at reﬂux for 2 hours. The reaction mixture was cooled to

room temperature and the solvent was removed in vacuo. Puriﬁca-

tion by ﬂash column chromatography (petroleum ether 40–

60:ether, 20:1) furnished the title compound 83 (5.4 mg, 76%) as

colourless oil; R_f0.56 (petroleum ether 40–60:ether, 9:1);

½

a ²_D⁴

ꢂ

¼ þ17:0 (c 0.27, CHCl₃); m_max(CHCl₃ﬁlm)/cm^ꢀ12928, 2856,

1665; d_H(500 MHz; CDCl₃) 7.65–7.69 (4H, m, Ar), 7.36–7.46 (6H,

m, Ar), 5.95 (1H, dd, J 10.8, 3.3, H-5), 5.75 (1H, dt, J 11.6, 3.1, H-10),

5.55–5.60 (1H, m, H-9), 5.37 (1H, ddd, J 10.8, 8.6, 2.6, H-4), 5.33

(1H, dd, J 8.0, 4.2, H-7), 4.37–4.41 (1H, m, H-1), 4.07 (1H, ddd, J

10.4, 8.6, 1.6, H-2), 3.36–3.40 (1H, m, H-8), 2.74–2.80 (1H, m, H-3),

2.25 (1H, dt, J 17.2, 8.1, H-8⁰), 2.08 (1H, ddd, J 16.5, 8.6, 1.6, H-3⁰),

1.06 [9H, s, C(CH₃)₃]; d_C(125 MHz; CDCl₃) 153.4 (C-6), 135.79,

135.78, 134.3, 133.5, 129.7, 129.6, 129.4, 128.2, 127.9, 127.6,

127.5, 126.4, 117.8, 79.4, 77.5, 36.7, 24.0, 26.9, 19.3; m/z (ES) 425

[(M+Na)⁺, 80%]; [m/z (ES) Found: (M+Na)⁺425.1896, C₂₆H₃₀O₂SiNa

requires M, 425.1907].

27. Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1, 953–956.

28. Sharpless, K. B.; Umbreit, M. A.; Nieh, M. T.; Flood, T. C. J. Am. Chem. Soc. 1972,

94, 6538–6540.

29. For studies on the effect of allylic and homoallylic oxygen substituents on RCM

for the synthesis of a number of eluthesides see: Caggiano, L.; Castoldi, D.;

Beumer, R.; Bayon, P.; Tesler, J.; Gennari, C. Tetrahedron Lett. 2003, 44, 7913–

7919.

30. Hoye, T. R.; Zhao, H. Org. Lett. 1999, 1, 1123–1125.

31. Maishal, T. K.; Sinha-Mahapatra, D. K.; Paranjape, K.; Sarkar, A. Tetrahedron Lett.

2002, 43, 2263–2267.

Acknowledgements

32. Burton, J. W.; Anderson, E. A.; O’Sullivan, P. T.; Collins, I.; Davies, J. E.; Bond, A.

D.; Feeder, N.; Holmes, A. B. Org. Biomol. Chem. 2008, 6, 693–702.

33. Mancuso, A. J.; Huang, S. L.; Swern, D. J. Org. Chem. 1978, 43, 2480–2482.

34. (a) Ireland, R. E.; Smith, R. G. J. Am. Chem. Soc. 1988, 110, 854–860; (b) Freeman,

P. J.; Hutchinson, L. L. J. Org. Chem. 1980, 45, 1924–1930.

35. Mak, S. Y. F.; Curtis, N. R.; Payne, A. N.; Congreve, M. S.; Wildsmith, A. J.;

Francis, C. L.; Davies, J. E.; Pascu, S. I.; Burton, J. W.; Holmes, A. B. Chem. Eur.

J. 2008, 14, 2867–2885.

36. Wakamatsu, H.; Blechert, S. Angew. Chem., Int. Ed. 2002, 41, 794–796.

37. Fürstner, A.; Langemann, K. J. Am. Chem. Soc. 1997, 119, 9130–9136.

38. For recent studies on bridgehead enolates see: Giblin, G. M. P.; Kirk, D. T.;

Mitchell, L.; Simpkins, N. S. Org. Lett. 2003, 5, 1673–1675; Blake, A. J.; Giblin,

G. M. P.; Kirk, D. T.; Simpkins, N. S.; Wilson, C. Chem. Commun. 2001, 2668–

2669.

We thank the Royal Society for the award of a University Re-

search Fellowship (J.W.B.), Universities UK and the Cambridge

Commonwealth Trust (studentship to S.Y.F.M.), GSK (studentship

to J.E.P.), British Biotech (studentship to G.C.H.C.) and the EPSRC

for generous ﬁnancial support, including ﬁnancial assistance to-

wards the purchase of the Nonius CCD diffractometer, and provi-

sion of the Swansea National Mass Spectrometry Service. We

thank the ARC (Grant No. FF0348471), VESKI and CSIRO for support.

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Synthesis of simplified analogues of eleutherobin via a Claisen rearrangement/RCM strategy

DOI: 10.1016/j.tetasy.2009.03.010

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