A stereoselective cyclisation cascade mediated by SmI2-H 2O: Synthetic studies towards stolonidiol

Tetrahedron: Asymmetry 21 (2010) 1246–1261

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Tetrahedron: Asymmetry

journal homepage: w ww.elsevier.com/locate/tetasy

A stereoselective cyclisation cascade mediated by SmI₂–H₂O: synthetic

studies towards stolonidiol

*

Thomas M. Baker, Lisa A. Sloan, Lokman H. Choudhury, Masahito Murai, David J. Procter

School of Chemistry, University of Manchester, Oxford Road, Manchester, M13 9PL, UK

a r t i c l e i n f o

a b s t r a c t

Article history:

A cascade reaction involving sequential conjugate reduction, stereoselective aldol cyclisation and chemo-

selective lactone reduction mediated by SmI₂–H₂O provides access to a cyclopentanol bearing two vicinal

quaternary stereocentres with good stereocontrol. The functionalised cyclopentanol product has been

converted to a key intermediate in ongoing asymmetric studies towards stolonidiol.

Received 8 February 2010

Accepted 4 March 2010

Available online 11 May 2010

Dedicated to Professor Henri Kagan on the

occassion of his 80th birthday

1. Introduction

proach was successful in forming the challenging cyclopentanol

motif, the lack of stereocontrol and unwanted retro-aldol path-

Since its introduction by Kagan,¹the electron transfer reagent,

samarium(II) iodide (SmI₂) has become one of the most important

reducing agents in organic synthesis.²The versatile reagent has

been used to mediate many processes, ranging from functional

group interconversions to complex carbon–carbon bond-forming

sequences.²Cyclisation reactions are arguably the most useful

transformations mediated by SmI₂, and these have been used

extensively in natural product synthesis.^2f,h

ways observed necessitated a revision of our synthetic strategy.

Herein, we report a diastereoselective cascade approach to a cyclo-

pentanol bearing two vicinal quaternary stereocentres. The func-

tionalised cyclopentanol product has been converted to a key

intermediate in our ongoing asymmetric studies on stolonidiol.

2. Results and discussion

The diterpenoid stolonidiol 1 was isolated in 1987 by Yamada

from a Japanese soft coral.³Preliminary assays showed it to possess

strong cytotoxic activity against P388 leukaemia cells in vitro (IC₅₀

The second generation cyclisation substrate 5 was designed to

address a number of problems encountered in our previous ap-

proach.⁷Firstly, we proposed that replacement of the tertiary alco-

hol-bearing side chain with a protected methylene hydroxy group

would disfavour retro-aldol fragmentation. In addition, we be-

lieved that judicious choice of the protecting group would result

in improved diastereoselectivity in the spirocyclisation by coordi-

nation of the group to Sm(III). We decided to use an acetate pro-

tecting group in 5 after carrying out cyclisation studies on model

substrates. The model substrates were prepared from ketoester 6

that was ﬁrst converted to b-hydroxyketone 7. The introduction

of a range of protecting groups then gave intermediates 8 which

were converted to substrates 10 by ozonolysis and Wittig reaction

with phosphorane 9.⁸For three substrates (R = TBS, Bz and MEM) it

proved more efﬁcient to proceed via intermediate 11 (Scheme 3).

Upon treatment with SmI₂in THF and MeOH at 0 °C, substrates

10a–f underwent cyclisation to give spirolactones 12a–f and 13a–f

in moderate to good yields. Only with the acetate 10b was moder-

ate selectivity for the desired all-syn isomer observed (Scheme 4).

We proposed that the use of a six-membered lactone substrate,

rather than the ﬁve-membered lactone system explored in our pre-

liminary studies, would allow the initial product 14 to be reduced

to triol 4 using the selective Sm(II)-mediated lactone reduction re-

cently discovered in our group.⁹In this way, the unprecedented

0.015 l

g mL^À1). More recently, stolonidiol has been shown to dis-

play potent choline acetyltransferase (ChAT) inducible activity,

suggesting that it may act as a neurotrophic factor-like agent on

the cholinergic nervous system.⁴Agents with neurotrophic fac-

tor-like activity are potential therapeutics for dementia and disor-

ders such as Alzheimer’s disease. To date, Yamada has reported the

only synthesis of stolonidiol.⁵The cyclopentane ring in stolonidiol,

bearing three contiguous stereocentres, including two vicinal, qua-

ternary stereocentres, presents a major challenge in any approach

to the natural product. We have chosen to address this problem by

adapting and extending a reaction previously developed by our

group.⁶Our planned synthesis proceeds through the allylic carbon-

ates 2 and 3, obtained by manipulation of triol 4, the anticipated

product of a SmI₂–H₂O-mediated cyclisation cascade of unsatu-

rated keto-lactone 5 (Scheme 1).

We have previously reported the use of a Sm(II)-mediated spi-

rocyclisation in a ﬁrst generation approach to the functionalised

cyclopentanol motif of stolonidiol (Scheme 2).⁷Although this ap-

* Corresponding author.

E-mail address: david.j.procter@manchester.ac.uk (D.J. Procter).

doi:10.1016/j.tetasy.2010.03.047

T. M. Baker et al. / Tetrahedron: Asymmetry 21 (2010) 1246–1261

1247

O

TBSO

O

OR

O

R = TBS, 12a:13a, 1:1

R = Ac, 12b:13b, 2:1

R = C(O)OEt, 12c:13c, 1.5:1

R = C(O)PhMe–4, 12d:13d, 1.6:1

R = Bz, 12e:13e, 1:1

R = MEM, 12f:13f, 1.3:1

R

OH

SmI₂

OH

RO

O

12a–f

13a–f

O

1

2 (R = Me)

3 (R = H)

THF, MeOH

O

stolonidiol

O

OH

0 ºC

50–84%

O

OH

BnO

OAc

O

10a–f

HO

OH

RO

O

BnO

OH

OAc

O

5

4

Scheme 4. Model cyclisation studies.

Scheme 1. Retrosynthetic analysis of stolonidiol 1.

The synthesis of the cyclisation substrate 5 began with a boron–

mediated asymmetric aldol reaction¹⁰between known imide 15¹¹

and aldehyde 16¹²to give adduct 17 in 82% yield as a single diaste-

reoisomer. The auxiliary was reductively removed with NaBH₄fol-

lowed by selective mono-acetylation of the resulting primary

alcohol. The secondary hydroxyl group was subsequently oxidised

to the corresponding ketone using the TPAP/NMO system¹³to give

ketone 18. A two-step oxidative cleavage of the alkene moiety then

gave the corresponding aldehyde. Subsequent Wittig reaction of

the aldehyde with phosphorane 19 gave the cyclisation substrate

5 in good overall yield and as a single double bond isomer

(Scheme 6).

Upon treatment of substrate 5 with SmI₂in THF and H₂O, we

found that the sequential reaction proceeded as planned, giving

the highly functionalised cyclopentanol 4 in 86% yield and as a

6:1 mixture of diastereoisomers in favour of the desired all-syn-

isomer (Scheme 7).

O

BnO

OH

BnO

OH

BnO

OH

SmI₂

51% (1:1)

33%

THF–MeOH

O

0 ºC

O

BnO

OH

Scheme 2. A ﬁrst generation Sm(II)-mediated approach to the cyclopentanol motif

in stolonidiol.

The cascade begins with the conjugate reduction of the elec-

tron-deﬁcient oleﬁn, generating a Sm(III)-enolate¹⁴which then

undergoes a diastereoselective aldol cyclisation onto the pendant

ketone, generating the spirocyclic cyclopentanol intermediate

14.⁶The spirocyclic lactone was then selectively reduced to triol

4, in the presence of the primary acetate.⁹The stereochemistry of

the major isomer of 4 is consistent with the proposed transition

structure in which both carbonyl groups complex to Sm(III) in

the Sm(III)-enolate intermediate. The use of less SmI₂prevents

the ﬁnal stage of the cascade taking place, allowing isolation of

the major spirocyclic lactone intermediate 14. Subsequent depro-

tection of the benzyl ether (20 mol % Pd(OH)₂/C, H₂, EtOH, 45%)

provided crystalline diol 20 suitable for X-ray analysis,¹⁵unambig-

uously conﬁrming the stereochemistry of the spirocycle and the

major triol product (Fig. 1).

O

OEt

6

1. p–TsOH, ethylene glycol

benzene, 95%

2. LiAlH₄, Et₂O, 95%

3. p–TsOH, acetone

O

OH

1. O₃, CH₂Cl₂

O

OH

DMS

2. CH₂Cl₂

O

Ph₃P

O

7

11

O

Having successfully secured a route to the functionalised cyclo-

pentanol 4, we focussed on its conversion to allylic carbonates 2

and 3, strategically important intermediates in our proposed ap-

O

9

see

Experimental

R = TBS, Bz, MEM

R = Ac, C(O)OEt,

OC(O)PhMe–4

O

1. O₃, CH₂Cl₂

O

OR

O

OR

Sm^III

O

BnO

OAc

DMS

O

10a R = TBS

10b R = Ac

O

2. CH₂Cl₂

OBn

10c R = C(O)OEt

O

10d R = C(O)PhMe–4

10e R = Bz

8

Ph₃P

5

O

10f R = MEM

9

O

OH

Scheme 3. Preparation of model cyclisation studies.

HO

BnO

OH

14

Scheme 5. Proposed stereoselective cyclisation cascade.

OAc

OH

three-stage reaction cascade, carried out in a one-pot reaction

using one reagent, would allow rapid access to a key intermediate

in our approach to the target (Scheme 5).

OAc

4

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T. M. Baker et al. / Tetrahedron: Asymmetry 21 (2010) 1246–1261

O

We initially anticipated the introduction of the gem-dimethyl

group, forming the tertiary alcohol side chain, at this stage in the

synthesis. To this end, hydrolysis of the primary acetate in 22 pre-

ceeded a two-step oxidation of the alcohol to the corresponding

carboxylic acid, which was converted to the methyl ester 23. Treat-

ment with MeMgBr led to the desired tertiary alcohol 24 in a quan-

titative yield (Scheme 9). Unfortunately, attempts to form the

corresponding cyclic carbonate from 24 proved unsuccessful using

carbonyldiimidazole and triphosgene. Debenzylation of the pri-

mary benzyl-ether in 24 and elimination under Grieco’s condi-

tions¹⁷afforded diol 25. Unfortunately, conversion of 25 to the

corresponding cyclic carbonate or the bis-acetate could not be

achieved. As a result, it was concluded that a late stage installation

of the two methyl groups would be more amenable to the contin-

uation of the synthesis.

BnO

H 16

n-Bu₂BOTf

O

OH

O

NEt₃

N

O

BnO

N

O

CH₂Cl₂

82%

15

17

Bn

1.NaBH₄, THF/H₂O

2. Ac₂O, NEt₃, CH₂Cl₂

0 ºC

3. TPAP, NMO, CH₂Cl₂

68% (3 steps)

1. OsO₄, tBuOH

Et₂O, H₂O

pyridine K₂CO₃

K₃[Fe(CN)₆]

O

5

2. NaIO₄, THF, H₂O

BnO

OAc

18

3. CH₂Cl₂,

O

Ph₃P

O

1. K₂CO₃, MeOH, 40 ºC, 97%

2. DMP, CH₂Cl₂

19

TBSO

22

85% (3 steps)

3. NaClO₂, NaH₂PO₄

2-methyl-2-butene, t-BuOH

4. TMSCHN₂, MeOH

toluene, 75% (3 steps)

BnO

OH

MeO

23

Scheme 6. Asymmetric synthesis of cyclisation substrate 5.

O

MeMgBr

Et₂O

O

OH

100%

SmI₂

BnO

OAc

THF-H₂O

HO

BnO

1. Pd/C, H₂

MeOH, 89%

TBSO

BnO

0 °C to rt

86%

O

OH

OAc

5

4

2. 2-NO₂PhSeCN

OH

O

OH

major, 6:1 dr

25

24

n-Bu₃P, THF

OH

then H₂O₂, 72%

Scheme 7. SmI₂–H₂O-mediated cyclization cascade.

Scheme 9. An unsuccessful approach to allylic carbonate 2.

As such, compound 22 was debenzylated and subjected to elim-

ination conditions, forming the allylic alcohol 26. Upon removal of

the primary acetate, treatment of the resulting diol 27 with tri-

phosgene led to the isolation of the desired allylic carbonate 3 in

an excellent yield (Scheme 10).

1. Pd/C, H₂

MeOH, 97%

TBSO

22

2. 2-NO₂PhSeCN

n-Bu₃P, THF

then H₂O₂

86%

OH

26

OAc

K₂CO₃, MeOH

40 ºC, 100%

Figure 1. X-ray crystal structure of 20.

(Cl₃CO)₂C=O

pyridine

TBSO

proach to stolonidiol. After protection of the distal primary hydro-

xyl group as the TBS ether, deoxygenation of the remaining free hy-

droxyl in 21 was achieved in two steps by conversion to the

thiocarbonate and treatment with n-Bu₃SnH (Scheme 8).¹⁶

O

CH₂Cl₂

100%

3

OH

27

O

Scheme 10. Formation of allylic carbonate 3.

With this versatile intermediate, constituting the right-hand

fragment of stolonidiol, completed, elaboration of the left-hand

11-membered ring can be approached in a number of ways, giving

a degree of ﬂexibility to the completion of the synthesis.

One strategy for extending the carbon framework involves the

addition of a suitable organometallic to an aldehyde derived from

3. A preliminary study has shown that ozonolysis of the allylic car-

bonate proceeds uneventfully to give the corresponding aldehyde

28 in an excellent yield.¹⁸Treatment of this aldehyde with 2-ben-

zyloxymethyl-3-bromopropene and indium powder¹⁹in 1:1 THF–

H₂O gave the desired Barbier adduct 29 in 48% yield as a 3:1

mixture of diastereoisomers in addition to a diastereoisomeric

mixture of adducts in which the primary TBS group had been lost.

OH

TBSCl

imidazole

HO

BnO

TBSO

BnO

CH₂Cl₂

82%

OH

4

21

OAc

1. ClC(S)OPh

2. n-Bu₃SnH

AIBN, toluene

95 ºC, 72%

DMAP, pyridine

CH₂Cl₂, 90%

TBSO

BnO

OH

22

OAc

Scheme 8. Selective deoxygenation of triol 4.

T. M. Baker et al. / Tetrahedron: Asymmetry 21 (2010) 1246–1261

1249

Protection of the primary hydroxyl group in 29 as the TBS ether

and subsequent cyclic carbonate formation gave the advanced

intermediate 30 (Scheme 11).

0.2 mm thickness. Plates were viewed using a 254 nm ultraviolet

lamp and dipped in aqueous potassium permanganate or p-

anisaldehyde.

4.2. Preparation of model substrates 10a–f

1. O₃, CH₂Cl₂

4.2.1. Ethyl 2-acetylpent-4-enoate 6²⁰

TBSO

BnO

Br

-78 ºC

O

28

A solution of sodium ethoxide was prepared by the slow, por-

tion-wise addition of sodium metal (1.41 g, 61.3 mmol, 1.0 equiv)

to a stirred solution of EtOH (40 ml) at room temperature and

the resultant solution stirred for 0.5 h. Neat ethylacetoacetate

(7.7 g, 61.3 mmol, 1.0 equiv) was then added dropwise and the

solution stirred for 20 min before the addition of potassium iodide

(1.01 g, 6.13 mmol, 0.1 equiv) and neat allylbromide (6.89 ml,

79.7 mmol, 1.3 equiv). The resultant solution was stirred at reﬂux

for 17 h. The reaction mixture was cooled to room temperature

and poured into a beaker of water (30 mL) and the aqueous layer

was separated and extracted with Et₂O (4 Â 15 ml). The combined

organic phases were dried (MgSO₄), ﬁltered and concentrated in

vacuo to give the crude product. Puriﬁcation by column chroma-

tography (eluting with 10% EtOAc in petroleum ether (40–60 °C))

gave 6 (6.03 g, 32.02 mmol, 52%) as a clear oil. m_max(ATR)/cm^À1

2978 m, 2336 m, 1713br s (ketone and ester C(O)), 1438 m,

1331 m, 1183 m, 1024 m, 919 m; d_H(500 MHz, CDCl₃) 1.32 (3H,

t, J 7.1, (CH₃CH₂O), 2.28 (3H, s, C(O)CH₃), 2.64 (2H, apparent t, J

7.4, CH₂CH@CH₂), 3.57 (1H, t, J 7.3, CH), 4.25 (2H, q, J 7.1,

OCH₂CH₃), 5.07–5.18 (2H, m, CH@CH₂), 5.72–5.86 (1H, m,

CH@CH₂); d_C(100 MHz, CDCl₃) 14.4 (CH₃CH₂), 29.4 (CH₃C(O)),

32.4 (CH₂CH@CH₂), 59.5 (CH), 61.7 (OCH₂), 117.7 (CH₂@CH),

134.5 (CH@CH₂), 169.5 (ester C(O))_,202.8 (ketone C(O)); MS: m/z

(CI⁺) 188 (100%) [M⁺NH₄], 171 (15%) [M⁺H], HRMS Calcd for

C₉H₁₈O₃N ([M⁺NH₄]): 188.1281. Found 188.1278.

3

O

In

2. DMS

95%

(1:1) THF/H₂O

O

1. TBSCl

imidazole

TBSO

HO

TBSO

CH₂Cl₂, 67%

RO

2. triphosgene

pyridine

CH₂Cl₂, 68%

OR

OH

HO

OTBS

OBn

30

29

R = R = C(O)

48% major, 3:1 dr

(+ 20%–TBS)

O

3.3%

OTBS

O

BnO

H

OTBS

nOe study on 30

Scheme 11. Preliminary studies on the elaboration of allylic carbonate 3.

The stereochemistry of 30 and 29 was conﬁrmed by NOE stud-

ies on 30 (Scheme 11). Thus, our preliminary studies show the va-

lue of the allylic carbonate 3 as an intermediate in an asymmetric

approach to stolonidiol.

4.2.2. Ethyl-2-(2-methyl-[1,3]dioxolan-2-yl)-pent-4-enoate

To a stirred solution of 6 (5.6 g, 32.9 mmol, 1 equiv) and p-tolu-

enesulfonic acid (20 mg) in benzene (112 ml) at room temperature

was added ethylene glycol (5.0 ml, 91.5 mmol, 2.7 equiv) and the

resultant solution was stirred at reﬂux for 18 h under Dean Stark

conditions. The reaction mixture was cooled to room temperature

and concentrated in vacuo to give the crude product. The residue

was puriﬁed by column chromatography (eluting with 10% EtOAc

in petroleum ether (40–60 °C)) giving ethyl-2-(2-methyl-

[1,3]dioxolan-2-yl)-pent-4-enoate (7.18 g, 31.3 mmol, 95%) as a

clear oil. m_max(ATR)/cm^À13075 m, 2980 m, 1714s (ester C@O),

1440 m, 1359 m, 1279 m, 12020, 1141 m, 1007 m; ¹H NMR d

1.27 (3H, t, J = 7 Hz, OCH₂CH₃), 1.42 (3H, s, CH₃C^q), 2.35–2.41

(1H, m, 1H from CH₂CH@CH₂), 2.47–2.53 (1H, m, 1H from

CH₂CH@CH₂), 2.75 (1H, dd, J = 11.4 Hz, 3.8, CHCH₂CH@CH₂),

3.94–4.06 (4H, m, OCH₂CH₂O), 4.17 (2H, q, J = 6 Hz, OCH₂CH₃),

5.0–5.11 (2H, m, CH@CH₂); ¹³C NMR d 14.3 (CH₃CH₂), 21.6 (CH₃),

32.4 (CH₂CH@CH₂), 60.5 (CHCH₂CH@C), 64.8 (OCH₂CH₂O), 64.9

(OCH₂CH₂O), 109.4 (C^q), 116.6 (CH₂@CH), 135.3 (CH₂@CH), 172.1

(C@O). MS: m/z (CI⁺) 223 [M+NH₄]⁺(40%), 215 [M+H]⁺(100%), 87

(15%), HRMS Calcd for C₁₁H₁₈O₄: 214.1200. Found: 214.1199.

3. Conclusion

In conclusion, we have developed a cyclisation cascade medi-

ated by SmI₂–H₂O for the rapid, stereoselective synthesis of highly

substituted cyclopentanols. The cascade features a reductive aldol-

cyclisation followed by lactone reduction and allows two vicinal,

fully substituted stereocentres to be constructed with good stereo-

control. The product of the cascade has been converted to a key

intermediate in our ongoing studies towards the asymmetric syn-

thesis of stolonidiol.

4. Experimental

4.1. General

All experiments were performed under an atmosphere of nitro-

gen, using anhydrous solvents, unless stated otherwise. THF was

distilled from sodium/benzophenone, and when used in conjunc-

tion with SmI₂, deoxygenated by bubbling with N₂for 15 min.

Dichloromethane was distilled from CaH₂, and methanol was dis-

tilled from the corresponding magnesium alkoxide and stored un-

der argon. Water was distilled before deoxygenation by the

bubbling through of N₂. ¹H NMR and ¹³C NMR were recorded using

300, 400 and 500 MHz spectrometers, with chemical shift values

being reported in ppm relative to residual chloroform (d_H= 7.27

or d_C= 77.2) as internal standards. All coupling constants (J) are re-

ported in Hertz (Hz). Mass spectra were obtained using positive

and negative electrospray (ES ) or gas chromatography (GC) meth-

odology. Infra-red spectra were recorded as evaporated ﬁlms or

neat using a FT/IR spectrometer. Column chromatography was car-

4.2.3. 2-(2-Methyl-[1,3]dioxolan-2-yl)-pent-4-en-1-ol

To a suspension of lithium aluminium hydride (3.0 g, 50.3 mmol,

1.5 equiv) in Et₂O (175 ml) was added a solution of ethyl-2-(2-

methyl-[1,3]dioxolan-2-yl)-pent-4-enoate (7.18 g, 31.3 mmol

1 equiv) in Et₂O (51 ml) dropwise. The resultant solution was stirred

at reﬂux for 4 h and allowed to cool to room temperature before

being quenched by the addition of a water/NaOH solution (40 ml).

The reaction was ﬁltered and the ﬁltrate dried (MgSO₄), ﬁltered

and concentrated in vacuo. The crude product was puriﬁed by col-

umn chromatography (eluting with 20% EtOAc in petroleum ether

(40–60 °C)) giving 2-(2-methyl-[1,3]dioxolan-2-yl)-pent-4-en-1-ol

ried out using 35–70

carried out on aluminium sheets coated with Silica Gel 60 F254,

l, 60A silica gel. Routine TLC analysis was

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T. M. Baker et al. / Tetrahedron: Asymmetry 21 (2010) 1246–1261

(5.5 g, 31.9 mmol, 95%) as a clear oil. m_max(ATR)/cm^À13413s,

2887 m, 1706 m, 1641 m, 1435 m, 1212 m, 1039 m, 864 m; ¹H

NMR d 1.26 (3H, s, CH₃C^q), 1.80–1.89 (2H, m, 1H from CH₂CH@CH₂,

CHCH₂OH), 2.23–2.28 (1H, m, 1H from CH₂CH@CH₂), 3.54–3.60

(2H, m, CH₂OH), 3.90–3.94 (4H, m, OCH₂CH₂O), 4.96–5.02 (2H, m,

CH@CH₂), 5.70–5.77 (1H, m, CH@CH₂); ¹³C NMR d 20.8 (CH₃), 31.5

(CH₂CH@CH₂), 47.6 (CHCH₂CH@), 62.3 (CH₂OH), 64.4 (OCH₂CH₂O),

64.6 (OCH₂CH₂O), 112.5 (C^q), 116.4 (CH₂@CH), 136.8 (CH@CH₂);

MS: m/z (CI)⁺190 (40%), 173 (100%) [M+H]⁺, 87 (35%), HRMS Calcd

for C₉H₁₅O₃: 171.1016. Found: 171.1014.

carbonic acid 2-acetyl-pent-4-enyl ester ethyl ester (115 mg,

0.57 mmol, 74%) as a pale yellow oil which was used directly with-

out puriﬁcation. m_max(thin ﬁlm)/cm^À12982w, 2933w, 2362w,

2337w, 1748s (C@O), 1718s (C@O), 1368w, 1261s, 1173w, 1010w,

922w, 791w; ¹H NMR (500 MHz, CDCl₃) d 1.30 (3H, t, J = 7.0 Hz,

OCH₂CH₃), 2.22 (3H, s, CH₃C@O), 2.23–2.27 (1H, m, 1H from

CH₂CH@CH₂), 2.38–2.44 (1H, m, 1H from CH₂CH@CH₂), 2.93–2.98

(1H, m, CH₃C(O)CH), 4.19 (2H, q, J = 7.0 Hz, OCH₂CH₃), 4.21 (1H,

dd, J = 11.0, 5.5 Hz, 1H from CH₂OC(O)O), 4.31 (1H, dd, J = 11.0,

8.0 Hz, 1H from CH₂OC(O)O), 5.08–5.12 (2H, m, CH@CH₂), 5.72

(1H, ddt, J = 17.0, 10.0, 7.0 Hz, CH@CH₂); ¹³C NMR (125 MHz, CDCl₃)

4.2.4. 3-(Hydroxymethyl)hex-5-en-2-one 7

d 14.1 (OCH₂CH₃), 30.1 (CH₃C@O), 32.4 (CH₂CH@CH₂), 50.9

To a stirred solution 2-(2-methyl-1,3-dioxolan-2-yl)pent-4-en-

1-ol (956 mg, 5.55 mmol, 1.0 equiv) in acetone (9.37 ml) at room

temperature was added p-toluene sulfonic acid (20 mg, catalytic)

and the resultant solution stirred at reﬂux for 2 h. The reaction mix-

ture was cooled to room temperature and concentrated in vacuo to

give the crude product. Puriﬁcation by column chromatography

(eluting with 30% EtOAc in petroleum ether (40–60 °C)) gave 7

(685 mg, 5.35 mmol, 96%) as a clear oil. m_max(ATR)/cm^À13405s,

2928 m, 2888 m, 1704s (ketone C(O)), 1642 m, 1424 m, 1037 m,

917 m; d_H(500 MHz, CDCl₃) 2.15 (3H, s, CH₃C(O)), 2.19–2.24 (1H,

m, 1H of CH₂CH@CH₂) 2.29–2.36 (1H, m, 1H of CH₂CH@CH₂), 2.69–

2.74 (1H, m, CHCH₂CH@CH₂), 3.67 (1H, dd J 11.4, 4.1, AB system

1H of CH₂OH), 3.73 (1H, dd J 11.6, 7.3, AB system 1H of CH₂OH),

5.00–5.06 (2H, m, CH@CH₂), 5.67 (1H , ddt J 17.0, 10.1, 6.9, CH@CH₂);

d_C(100 MHz, CDCl₃) 30.0 (CH₃C(O)), 32.4 (CH₂CH@CH₂), 53.8

(CHCH₂OH), 62.4 (CH₂OH), 117.5 (CH₂@CH), 134.8 (CH@CH₂),

212.0 (ketone C(O)); MS: m/z (CI⁺) 146 (100%) [M+NH₄]⁺, 129

(63%) [M+H]⁺_,HRMS Calcd for C₇H₁₁O₂: 127.0754. Found: 127.0752.

(CHCH₂O), 64.2 (OCH₂CH₃), 66.9 (CH₂OC@O), 118. (CH@CH₂),

133.9 (CH@CH₂), 154.9 (OC(O)O), 208.4 (CH₃C@O); MS: m/z (ES+

mode) 223 (100%) [M+Na]⁺, 218 (40%) [M+NH₄]⁺, 201 (63%)

[M+H]⁺; HRMS Calcd for C₁₀H₁₆O₄Na: 223.0941. Found: 223.0937.

4.2.7. 4-Methoxy-benzoic acid 2-acetyl-pent-4-enyl ester 8

(R = C(O)PhMe-4)

To a stirred solution of 3-(hydroxymethyl)hex-5-en-2-one 7

(100 mg, 0.78 mmol, 1.0 equiv) in CH₂Cl₂(3.1 mL) at 0 °C was added

pyridine (0.11 mL, 1.40 mmol, 1.8 equiv) dropwise. After 5 min, p-

anisoyl chloride (0.16 mL, 1.17 mmol, 1.5 equiv) and DMAP

(4.8 mg, 0.04 mmol, 5 mol %) were added in one portion. The reac-

tion was stirred at 0 °C for 10 min before being warmed to room

temperature and stirred for an additional 2 h. The reaction was

quenched by the addition of saturated aqueous NaHCO₃solution

(4 mL). The aqueous phase was extracted with CH₂Cl₂(4 Â 5 mL)

and the combined organic phases dried (MgSO₄), ﬁltered and con-

centrated in vacuo. The residue was puriﬁed by column chromatog-

raphy (eluting with 30% EtOAc in petroleum ether (40–60 °C)) to

4.2.5. 3-(Acetoxymethyl)hex-5-en-2-one 8 (R = Ac)

give 4-methoxy-benzoic acid 2-acetyl-pent-4-enyl ester

8

To a stirred solution of 3-(hydroxymethyl)hex-5-en-2-one 7

(100 mg, 0.78 mmol) in CH₂Cl₂(15 ml) at room temperature was

added pyridine (0.44 ml, 5.46 mmol, 7 equiv), acetic anhydride

(0.37 ml, 3.90 mmol, 5 equiv) and DMAP (19.5 mg, 0.16 mmol,

0.2 equiv) sequentially, and the reaction stirred for 14 h. The reac-

tion was quenched by the addition of saturated, aqueous NaHCO₃

solution (15 ml). The aqueous phase was extracted with CH₂Cl₂

(4 Â 20 ml) and the combined organics were dried (MgSO₄), ﬁl-

tered and concentrated in vacuo to give the desired acetate 3-

(acetoxymethyl)hex-5-en-2-one 8 (R = Ac) (133 mg, 0.78 mmol,

100%) as a yellow oil. m_max(thin ﬁlm)/cm^À12913w, 2367w,

2333w, 1743s (C@O), 1718s (C@O), 1636w, 1560w, 1367m,

1236s, 1036m; ¹H NMR (500 MHz, CDCl₃) d 2.04 (3H, s, CH₃C(O)O),

2.18–2.27 (1H, m, 1H from CH₂CH@CH₂), 2.20 (3H, s, CH₃C@O),

2.35–2.44 (1H, m, 1H from CH₂CH@CH₂), 2.90 (1H, p, J = 7.0 Hz,

CH₃C(O)CH), 4.21 (2H, d, J = 6.5 Hz, CH₂OC(O)CH₃), 5.07–5.18 (2H,

m, CH@CH₂), 5.71 (1H, qt, J = 10.0, 7.0 Hz, CH@CH₂); ¹³C NMR

(R = C(O)PhMe–4) (199 mg, 0.76 mmol, 98%) as a colourless oil. m_max

(thin ﬁlm)/cm^À13077w, 2953w, 2918w, 1839w, 2357w, 2337w,

1713s (C@O), 1606s, (C@O), 1511m, 1419w, 1273m,1256s, 1167s,

1102m, 1028m, 848w, 770m; ¹H NMR (500 MHz, CDCl₃) d 2.25

(3H, s, CH₃C@O), 2.30–2.35 (1H, m, 1H from H₂C@CHCH₂), 2.45–

2.51 (1H, m, 1H from H₂C@CHCH₂), 3.02–3.07 (1H, m, CH₃C(O)CH),

3.86 (3H, s, OCH₃), 4.43 (1H, dd, J = 11, 8 Hz, 1H from CH₂OC(O)),

4.47 (1H, dd, J = 11, 5 Hz, 1H from CH₂OC(O)), 5.08–5.14 (2H, m,

H₂C@CH), 5.77 (1H, tdd, J = 14, 10.5, 7 Hz, CH₂@CH), 6.92 (2H, d,

J = 9 Hz, CHCOCH₃), 7.95 (2H, d, J = 9 Hz, CHCHCOCH₃); ¹³C NMR

(125 MHz, CDCl₃) d 30.0 (CH₃C@O), 32.6 (CH₂CH@CH₂), 51.2

(C(O)CHCH₂), 55.5 (OCH₃), 64.1 (CH₂OC@O), 113.7 (2 Â ArCH),

117.9 (CH@CH₂), 122.1 (ArC), 131.6 (2 Â ArCH), 134.2 (CH@CH₂),

163.5 (ArC), 166.0 (OC@O), 208.9 (H₃CC@O); MS: m/z (ES+ mode)

285 (100%) [M+Na]⁺, 263 (88%) [M+H]⁺, HRMS Calcd for C₁₅H₁₉O₄:

263.1278. Found: 263.1267.

(125 MHz, CDCl₃)

d 20.7 (OC(O)CH₃), 29.9 (CH₃C@O), 32.5

4.3. General procedure 1. Oxidative cleavage and Wittig

oleﬁnation

(CH₂CH@CH₂), 51.0 (CHCH₂OC@O), 63.9 (CH₂OC@O), 117.9

(CH@CH₂), 134.1 (CH@CH₂), 170.7 (OC(O)CH₃), 208.7 (CH₃CO);

MS: m/z (ES+ mode), 249 (12%), 193 (100%) [M+Na]⁺; HRMS Calcd

for C₉H₁₄O₃Na: 193.0835. Found: 193.0826

A solution of keto-alkene in CH₂Cl₂was degassed with N₂then

O₂for 5 min at À78 °C. Then O₃was bubbled through the solution

until a persistent blue colour was observed. The reaction was de-

gassed with N₂until the blue colour had discipated and DMS added

dropwise. The reaction was warmed to room temperature and stir-

red overnight. The reaction was quenched by the addition of satu-

rated aqueous NaHCO₃solution and the aqueous phase extracted

with CH₂Cl₂. The combined organics were dried (MgSO₄), ﬁltered

and concentrated in vacuo to give the crude aldehyde. The crude

aldehyde was dissolved in CH₂Cl₂at room temperature. Phosphor-

ane 9 was added and the reaction stirred. The reaction mixture was

concentrated in vacuo and puriﬁed by column chromatography to

give the cyclisation substrate.

4.2.6. Carbonic acid 2-acetyl-pent-4-enyl ethyl ester 8

(R = C(O)OEt)

To a stirred solution of 3-(hydroxymethyl)hex-5-en-2-one 7

(100 mg, 0.78 mmol) in CH₂Cl₂(4 ml) at À50 °C was added pyridine

(0.16 ml, 1.95 mmol, 2.5 equiv) dropwise. After 5 min, ethyl chloro-

formate (0.082 ml, 0.86 mmol, 1.1 equiv) was added slowly over

30 min. The reaction was slowly warmed to room temperature

and stirred for 2 h. The reaction mixture was diluted with CH₂Cl₂

(40 ml) and washed with saturated, aqueous citric acid solution

(2 Â 20 ml), H₂O (20 ml) and brine (20 ml). The organic phase was

dried (MgSO₄), ﬁltered and concentrated in vacuo giving carbonate

T. M. Baker et al. / Tetrahedron: Asymmetry 21 (2010) 1246–1261

1251

4.3.1. 3-(3-Hydroxymethyl-4-oxo-pentylidene)-dihydro-furan-

2-one 11

CH₂O), 64.5 (CH₃CH₂O), 65.5 (CH₃CH₂OC@O), 66.8 (CH₂OC(O)O),

128.2 (C(O)C@CH), 135.6 (C(O)C@CH), 154.7 (OC(O)O), 170.7

(OC(O)C@CH), 207.2 (CH₃C@O); MS: m/z (ES+ mode) 562 (40%),

438 (37%), 293 (100%) [M+Na]⁺; HRMS Calcd for C₁₃H₁₈O₆Na:

293.0996. Found: 293.1008.

As described in general procedure 1. Ozonolysis performed on

3-hydroxymethyl-hex-5-en-2-one 7 (1.0 g, 7.81 mmol 1.0 equiv)

in CH₂Cl₂(75 mL) and DMS (12 mL) gave the corresponding alde-

hyde (917 mg, 7.04 mmol, 90%). Subsequent Wittig oleﬁnation per-

formed using phosphorane 9 (2.92 g, 8.46 mmol, 1.2 equiv) in

CH₂Cl₂(46 mL), stirring for 20 h, gave 3-(3-hydroxymethyl-4-

oxo-pentylidene)-dihydro-furan-2-one 11 (334 mg, 1.87 mmol,

24%) after column chromatography (eluting with 60% EtOAc in

petroleum ether (40–60 °C)).m_max(ATR)/cm^À13438s, 2923 m,

1740s (ketone C@O), 1706s (ester C@O), 1213 m, 1030 m; ¹H

NMR d 2.20 (3H, s, CH₃C@O), 2.35–2.41 (1H, m, 1H from CH₂CH@C),

2.40–2.54 (1H, m, 1H from CH₂CH@CH₂), 2.80–2.85 (1H, m, 1H

from CHCH₂CH@C), 2.86–2.90 (2H, m, CH₂CH₂O), 3.68–3.71 (1H,

m, 1H from CH₂OH), 3.79–3.82 (1H, m, 1H from CH₂OH), 4.34

(2H, t, J = 7.3 Hz, CH₂OC@O), 6.58–6,62 (1H, m, CH@C); ¹³C NMR

4.3.4. 3-(3-(4-Methoxy)benzoyloxymethyl-4-oxo-pentylidene)-

dihydro-furan-2-one 10d

As described in general procedure 1. Ozonolysis performed on 8

(R = C(O)PhMe-4) (186 mg, 0.71 mmol, 1.0 equiv) in CH₂Cl₂(7.0 mL)

and DMS (1.21 mL) gave the corresponding aldehyde (170 mg,

0.64 mmol, 91%). Wittig oleﬁnation performed using phosphorane 9

(436 mg, 1.29 mmol, 2 equiv) in CH₂Cl₂(8.5 mL), stirring for 24 h,

gave the cyclisation substrate 10d (154 mg, 0.46 mmol, 75%) after

column chromatography (eluting with 60% EtOAc in petroleum ether

(40–60 °C)). m_max(thin ﬁlm)/cm^À12958w, 2917w, 2839w, 2357w,

2337w, 1759s (C@O), 1711s (C@O), 1606s (C@O), 1580w, 1512m,

1420w, 1358w, 1317w, 1256s, 1192w, 1168m, 1102m, 1028m,

963w, 849w,770m;¹HNMR(500 MHz, CDCl₃)d2.28(3H, s, H₃CC@O),

2.39–2.45 (1H, m, 1H from C@CHCH₂), 2.63–2.67 (1H, m, 1H from

C@CHCH₂), 2.83–2.94 (2H, m, CH₂@CCH₂), 3.13 (1H, quint, J = 6 Hz,

CH₃C(O)CH), 3.85 (3H, s, OCH₃), 4.33–4.36 (2H, m, CH₂@CCH₂CH₂),

4.46–4.49 (2H, m, CHCH₂OC(O)), 6.63–6.68 (1H, m, CH₂@C), 6.91

d

25.1 (CH₂CH₂O), 28.3 (CH₂CH₂@C), 30.2 (CH₃C@O), 52.8

(CHCH₂CH@C), 62.3 (CH₂OH), 65.6 (OCH₂CH₂), 127.8 (C^q), 136.6

(CH@C), 171.0 (ester C@O), 210.5 (ketone C@O), MS: m/z (CI)⁺

216 (M+NH₄)⁺(100%), 199 (M+H)⁺(33%) 186 (100%), 169 (30%);

HRMS Calcd for C₁₀H₁₃O₄: 197.0808. Found: 197.0806.

4.3.2. 3-(3-Acetoxymethyl-4-oxo-pentylidene)-dihydro-furan-

2-one 10b

(2H, d, J = 8.5 Hz, H₃COCCH), 7.92 (2H, d, J = 7.5 Hz, H₃COCHCH); ¹³

C

NMR (125 MHz, CDCl₃) d 25.1 (CH₂CH₂OC@O), 28.7 (CH₂CH@C),

30.0 (CH₃C@O), 50.6 (CHCH₂OC@O), 55.5(OCH₃), 64.0(CHCH₂OC@O),

65.5 (CH₂CH₂OC@O), 113.7 (2 Â ArCH), 121.6 (ArC), 127.9

(C(O)C@CH), 131.7 (2 Â ArCH), 136.2 (CH₂CH@C), 163.7 (ArC), 165.8

(PhC@O), 170.8 (CH₂CH₂OC@O), 207.5 (H₃CC@O); MS: m/z (ES+

mode) 355 (56%) [M+Na]⁺, 350 (100%) [M+NH₄]⁺, HRMS Calcd for

As described in general procedure 1. Ozonolysis performed on 8

(R = Ac) (140 mg, 0.823 mmol 1.0 equiv) in CH₂Cl₂(8.0 mL) and

DMS (1.4 mL) gave the corresponding aldehyde (113 mg,

0.66 mmol, 80%). Wittig oleﬁnation performed using phosphorane

9 (440 mg, 1.30 mmol, 2 equiv) in CH₂Cl₂(8.5 mL), stirring for 24 h,

gave the cyclisation substrate 10b (106 mg, 0.44 mmol, 68%) after

column chromatography (eluting with 30% EtOAc in petroleum

ether (40–60 °C)). m_max(thin ﬁlm)/cm^À12928w, 1743s (C@O),

1716s (C@O), 1673m, 1431m, 1367m, 1224m, 1039m, 712w; ¹H

NMR (500 MHz, CDCl₃) d 2.06 (3H, s, OC(O)CH₃), 2.24 (3H, s,

CH₃C@O), 2.31–2.37 (1H, m, 1H from CH₂CH@C), 2.55–2.61 (1H,

m, 1H from CH₂CH@C), 2.85–2.96 (2H, m, CH₂CH₂OC@O), 3.01

(1H, p, J = 6.3 Hz, CHCH₂CH@C), 4.23 (1H, dd, J = 11.0, 6.3 Hz, 1H

from CH₂OC(O)CH₃), 4.28 (1H, dd, J = 11.0, 5.4 Hz, 1H from CH₂O-

C(O)CH₃), 4.39 (2H, apparent t, J = 7.6 Hz, CH₂CH₂OC@O), 6.59–

6.64 (1H, m, CH@C); ¹³C NMR (125 MHz, CDCl₃) d 20.7 (CH₃C(O)O),

25.1 (CH@CCH₂CH₂), 28.7 (CH₂CH@C), 30.1 (CH₃C@O), 50.4

(CHCH₂O), 63.8 (CHCH₂O), 65.4 (CH₂CH₂OC@O), 128.0 (CH@C),

135.9 (CH@C), 170.5 (OC(O)CH₃), 207.4 (CH₃C@O); MS: m/z (ES+

mode) 263 (100%) [M+Na]⁺; HRMS Calcd for C₁₂H₁₆O₅Na:

236.0890. Found: 236.0898.

C₁₈H₂₀O₆Na: 355.1152. Found: 355.1146.

4.3.5. 3-(3-Benzoyloxymethyl-4-oxo-pentylidene)-dihydro-

furan-2-one 10e

To a stirred solution of 11 (76 mg, 0.38 mmol) in CH₂Cl₂(2.6 ml)

at 0 °C was added triethylamine (0.06 ml, 0.42 mmol, 1.1 equiv),

benzoyl chloride (0.05 ml, 0.42 mmol, 1.1 equiv) and DMAP

(51.3 mg, 0.42 mmol, 1.1 equiv) dropwise. After 90 min, the solu-

tion was diluted with CH₂Cl₂(20 mL), and washed with saturated

aqueous NaCl solution (10 mL). The organic layer was dried

(MgSO₄), ﬁltered and concentrated in vacuo. The crude residue

was puriﬁed by chromatography (silica gel, 40% EtOAc in petro-

leum ether (40–60 °C)) to give 10e (21 mg, 0.07 mmol, 18%). 10e

was found to be unstable thus preventing full characterisation.

¹H NMR (500 MHz, CDCl₃) d 2.30 (3H, s, CH₃C@O), 2.44 (1H, p AB

system, J = 7.9 Hz, 1H from CH₂CH@C), 2.68 (1H, p AB system,

J = 7.9 Hz, 1H from CH₂CH@C), 2.84–2.98 (2H, m, CH₂CH₂OC@O),

3.12–3.19 (1H, m, CH₃C(O)CH), 4.36 (2H, t, J = 7.6 Hz,

CH₂CH₂OC@O), 4.52 (2H, t, J = 5.4 Hz, CHCH₂OC@O), 4.65–4.69

(1H, m, CH₂CH@C), 7.45 (2H, t, J = 7.9 Hz, 2 Â ArCH), 7.59 (1H, t,

J = 7.6 Hz, ArCH), 7.98 (2H, d, J = 7.6 Hz, 2 Â ArCH).

4.3.3. Carbonic acid ethyl ester 3-oxo-2-[2-(2-oxo-dihydro-

furan-3-ylidene)-ethyl]-butyl ester 10c

As described in general procedure 1. Ozonolysis performed on 8

(R = C(O)Et) (115 mg, 0.57 mmol, 1.0 equiv) in CH₂Cl₂(5.6 mL) and

DMS (1.0 mL) gave the corresponding aldehyde (118 mg,

0.58 mmol, 100%). Wittig oleﬁnation performed using phosphor-

ane 9 (396 mg, 1.17 mmol, 2 equiv) in CH₂Cl₂(7.6 mL), stirring

for 24 h, gave the cyclisation substrate 10c (125 mg, 0.46 mmol,

80%) after column chromatography (eluting with 30% EtOAc in

petroleum ether (40–60 °C)). m_max(thin ﬁlm)/cm^À12988w,

2913w, 1748s (C@O), 1718s (C@O), 1676 m, 1382w, 1367w,

1258s, 1194w, 1031w, 1011m, 962w, 7891w; ¹H NMR (500 MHz,

CDCl₃) d 1.30 (3H, t, J = 7.0 Hz, OCH₂CH₃), 2.25 (3H, s, CH₃C@O),

2.34–2.40 (1H, m, 1H from CH₂CH@CH₂), 2.57–2.62 (1H, m, 1H

from CH₂CH@CH₂), 2.85–2.96 (2H, m, CH@CCH₂), 3.05 (1H, p,

J = 6.5 Hz, CH₃C(O)CH), 4.19 (2H, q, J = 7 Hz, OCH₂CH₃), 4.29 (2H,

t, J = 5.5 Hz, CHCH₂O), 4.38 (2H, t, J = 7.5 Hz, CH@CCH₂CH₂), 6.58–

6.62 (1H, m, CH@C); ¹³C NMR (125 MHz, CDCl₃) d 14.2 (CH₃CH₂O),

25.1 (CH@CCH₂), 28.5 (CH₂CH@C), 30.2 (CH₃C@O), 50.3 (C(O)CH-

4.3.6. 3-[3-(2-Methoxy-ethoxymethoxymethyl)-4-oxo-

pentylidene]-dihydro-furan-2-one 10f

To a stirred solution of 11 (100 mg, 0.5 mmol, 1 equiv) in CH₂Cl₂

(0.5 mL) was added diisopropylethylamine (1.05 mL, 6 mmol,

12 equiv) and the mixture stirred for 10 min at room temperature.

MEMCl (0.34 mL, 3 mmol, 6 equiv) was added dropwise and the

reaction stirred for 13 h. Et₂O (10 mL) and HCl (10 mL) were added

and the aqueous phase extracted with Et₂O (3 Â 10 mL). The com-

bined organic phases were dried (MgSO₄), ﬁltered and concen-

trated in vacuo to give the crude product which was puriﬁed by

column chromatography (eluting with 50% EtOAc in petroleum

ether (40–60 °C)) to give the desired MEM ether 10f (76.4 mg,

54%) as a clear oil. m_max(thin ﬁlm)/cm^À12899 m, 1754s (lactone

C@O), 1714s (ketone C@O), 1032m; ¹H NMR d 2.16 (3H, s,

1252

T. M. Baker et al. / Tetrahedron: Asymmetry 21 (2010) 1246–1261

CH₃C@O), 2.23–2.30 (1H, m, 1H from C@CHCH₂), 2.47–2.54 (1H, m,

1H from C@CHCH₂), 2.77–2.91 (3H, m, C(O)CH, CH₂CH₂OC@O),

3.33 (3H, s, OCH₃), 3.47–3.49 (2H, m, OCH₂CH₂O), 3.55–3.62 (2H,

m, OCH₂CH₂O), 3.63–3.69 (2H, m, C(O)CHCH₂), 4.31 (2H, t,

J = 7.5 Hz, CH₂OC@O), 4.61 (2H, s, OCH₂O), 6.54–6.58 (1H, m,

C@CHCH₂); ¹³C NMR d 25.10 (CH₂CH₂OC@O), 28.66 (C@CHCH₂),

30.29 (CH₃C@O), 51.38 (CH₃C(O)CH), 59.10 (OCH₃), 65.49 (C(O)CH-

CH₂O), 67.13 (OCH₂CH₂O), 67.94 (CH₂OC@O), 71.66 (OCH₂CH₂O),

95.63 (OCH₂O), 136.80 (C@CHCH₂), (C@O) and (C(O)O) not ob-

served; MS: m/z (ESI)⁺332 (100%) [M+Na]⁺; HRMS Calcd for

25.93 (SiC(CH₃)), 30.90 (CH₂CHCH₂OSi), 31.01 (CH₂CH₂OC@O),

47.35 (CHCH₂OSi), 56.28 (C^q), 63.90 (CH₂OSi), 65.51 (CH₂OC@O),

81.80 (C^q), 180.98 (C@O); MS: m/z (CI)⁺332 (10%) [M+NH₄]⁺, 315

(45%) [M+H]⁺, 182 (55%), 79 (100%); HRMS Calcd for C₁₆H₃₁O₄Si:

315.1986. Found: 315.2000.

4.4.2. rac-(5S,6S,7R)-7-(Acetoxymethyl)-6-hydroxy-6-methyl-2-

oxa-spiro[4.4]nonan-1-one 12b and rac-(5S,6S,7S)-7-

(acetoxymethyl)-6-hydroxy-6-methyl-2-oxa-spiro[4.4]nonan-

1-one 13b

C₁₄H₂₂O₆Na: 309.1309. Found: 309.1305.

To a stirred solution of SmI₂(0.1 M in THF, 6.24 ml, 0.624 mmol,

3 equiv) and MeOH (1.63 ml) at 0 °C was added a solution of lactone

10b (50 mg, 0.208 mmol) in THF (0.35 ml) and the reaction stirred for

1 h. Air was introduced into the reaction vessel and the reaction

quenched by the addition of saturated, aqueous NH₄Cl solution

(ꢀ20 ml). The aqueous phase was extracted with EtOAc (4 Â 20 ml).

The combined organic phases were dried over MgSO₄ﬁltered and

concentrated in vacuo. The crude residue was puriﬁed by chromatog-

raphy (silica gel, 30% EtOAc in petroleum ether (40–60 °C)) to give the

two spirocylic compounds 12b (17.0 mg, 0.071 mmol, 34%) and 13b

(8.9 mg, 0.037 mmol, 18%)ascolourlessoils. For the allsyn compound

12b: m_max(thin ﬁlm)/cm^À13469w (OH), 2953w, 2918w, 2362w,

2342w, 1736s (C@O), 1464w, 1370 m, 1238s, 1147w, 1029 m; ¹H

NMR (500 MHz, CDCl₃) d 1.34 (3H, s, CH₃COH), 1.72–1.80 (2H, m,

1H from CH₂CH₂CH, 1H from CH₂CH₂CH), 1.94–2.02 (2H, m, 1H from

CH₂CH₂OC@O, 1H from CH₂CH₂CH), 2.05 (3H, s, CH₃C(O)O), 2.09 (1H,

q, J = 7.5 Hz, CHCH₂OC(O)CH₃), 2.25–2.31 (2H, m, 1H from

CH₂CH₂OC@O, 1H from CH₂CH₂CH), 4.16–4.26 (3H, m, 1H from

CH₂CH₂OC@O, 1H from CH₂OC(O)CH₃, OH), 4.32–4.37 (2H, m, 1H

from CH₂CH₂OC@O, 1H from CH₂OC(O)CH₃); ¹³C NMR (125 MHz,

CDCl₃) d 21.0 (CH₃C@O), 21.8 (OHCCH₃), 25.6 (CH₂CH₂CH), 32.2

(CH₂CH₂CH), 32,5 (CH₂CH₂OC@O), 46.8 (CHCH₂OC@O), 55.4 (CH₂O-

C(O)C), 63.9 (CHCH₂OC@O), 65.4 (CH₂CH₂OC@O), 81.7 (HOCCH₃),

171.1 (CH₃C@O), 181.6 (C@O); MS: m/z (ES+ mode) 507 (18%), 265

(100%) [M+Na]⁺; HRMS Calcd for C₁₂H₁₈O₅Na: 265.1046. Found:

265.1049. For the syn, anti compound 13b: m_max(thin ﬁlm)/cm^À1

3469w (OH), 2958w, 2918w, 2362w, 1736s (C@O), 1466w, 1370 m,

1244s, 1157w, 1029 m; ¹H NMR (500 MHz, CDCl₃) d 1.16 (3H, s,

CH₃COH), 1.38–1.46 (1H, m, 1H from CH₂CH₂CH), 1.70 (1H, ddd,

J = 15.0, 11.0, 4.0 Hz, 1H from CH₂CH₂CH), 1.99 (1H, ddd, J = 12.5,

6.5, 4.0 Hz, 1H from CH₂CH₂OC@O), 2.06 (3H, s, CH₃C@O), 2.06–2.13

(1H, m, 1H from CH₂CH₂CH), 2.20 (1H, ddd, J = 14.0, 10.0, 6.5 Hz, 1H

from CH₂CH₂CH), 2.50 (1H, dt, J = 12.5, 8.0 Hz, 1H from

CH₂CH₂OC@O), 2.78 (1H, s, OH), 2.98 (1H, tt, J = 10.0, 7.0 Hz, CHCH₂O-

C(O)CH₃), 4.11 (1H, dd, J = 11.5, 7.5 Hz, 1H from CH₂OC(O)CH₃), 4.16–

4.22 (2H, m, 1HfromCH₂OC(O)CH₃, 1H fromCH₂CH₂OC@O), 4.35 (1H,

apparent dt, J = 8.5, 4.5 Hz, 1H from CH₂CH₂OC@O); ¹³C NMR

(125 MHz, CDCl₃) d 18.6 (OHCCH₃), 20.9 (CH₃C@O), 24.1 (CH₂CH₂CH),

31.1 (CH₂CH₂CH), 31.4 (CH₂CH₂OC@O), 46.2 (CHCH₂OC@O), 56.0

(CH₂OC(O)C), 64.7 (CHCH₂OC@O), 65.7 (CH₂CH₂OC@O), 80.9

(HOCCH₃), 171.0 (CH₃C@O), 180.6 (C@O); MS: m/z (ES+ mode) 507

(12%), 265 (100%) [M+Na]⁺; HRMS Calcd for C₁₂H₁₈O₅Na: 265.1046.

Found: 265.1047.

4.4. Cyclisation of model substrates 10a–f

4.4.1. rac-(5S,6S,7R)-7-(tert-Butyl-dimethyl-silanyloxymethyl)-

6-hydroxy-6-methyl-2-oxa-spiro[4.4]nonan-1-one 12a and rac-

(5S,6S,7S)-7-(tert-butyl-dimethyl-silanyloxymethyl)-6-hydroxy-

6-methyl-2-oxa-spiro[4.4]nonan-1-one 13a

To a stirred solution of 11 (100 mg, 0.50 mmol, 1.0 equiv) in

DMF (1.0 mL) at room temperature was added imidazole

(171 mg, 2.5 mmol, 5.0 equiv) the TBSCl (226 mg, 1.5 equiv mmol,

3.0 equiv) and the reaction stirred overnight. The reaction was

quenched by the addition of saturated aqueous NaHCO₃solution

(15 mL) and the aqueous phase extracted in CH₂Cl₂(3 Â 20 mL).

The combined organic phases were washed with H₂O

(3 Â 20 mL), dried (MgSO₄), ﬁltered and concentrated in vacuo to

give the TBS protected cyclisation substrate 10a (156 mg,

0.50 mmol, 100%) which was used without further puriﬁcation.

To a stirred solution of SmI₂, (20 mL, 0.1 M in THF, 2.0 mmol,

4.0 equiv) at 0 °C was added dry MeOH (4.68 mL) and the solution

stirred for 10 min. TBDMS protected cyclisation substrate 10a

(156 mg, 0.5 mmol, 1 equiv) in THF (3.4 mL) was added and the

reaction stirred for 30 min. The reaction was quenched by expo-

sure to air followed by addition of saturated aqueous NaCl solution

(10 mL). The aqueous phase was extracted with EtOAc and the

combined organic extracts dried (MgSO₄) and concentrated to give

the crude product. Puriﬁcation by column chromatography (silica

gel, 10% i-PrOH in petroleum ether (40–60 °C)) gave the all syn

(46.2 mg, 29%) and syn, anti (43 mg, 27%) spirocycles 12a and

13a, respectively, as clear crystalline solids. For the all syn spirocy-

cle 12a: mp 70.7–71.2 °C; m_max(thin ﬁlm)/cm^À12950m, 2362m,

1742s (C@O), 1150s; ¹H NMR d 0.00 (6H, s, Si(CH₃)₂), 0.83 (9H, s,

SiC(CH₃)₃), 1.27 (3H, s, C^qC(OH)CH₃), 1.61–1.70 (2H, m, 1H from

C^qCH₂CH₂CH, 1H from CH₂CHCH₂OSi), 1.81–1.95 (3H, m, 1H from

CH₂CH₂O, 1H from C^qCH₂CH₂CH, CH₂CHCH₂OSi), 2.16–2.26 (2H,

m, 1H from CH₂CH₂O, 1H from CH₂CHCH₂OSi), 3.59 (1H, dd,

J = 10, 6 Hz, 1H from CH₂OSi), 3.88 (1H, dd, J = 10, 6 Hz, 1H from

CH₂OSi), 4.13–4.18 (1H, m, 1H from CH₂OC@O), 4.25 (1H, dt,

J = 9, 4 Hz, 1H from CH₂OC@O); ¹³C NMR d À5.45 (SiCH₃), À5.27

(SiCH₃), 21.06 (CqC(OH)CH₃), 25.53 (C^q), 25.93 (SiC(CH₃)₃), 32.51

(CH₂CHCH₂OSi), 32.69 (CH₂CH₂OC@O), 50.28 (CHCH₂OSi), 55.80

(C^q), 62.74 (CH₂OSi), 65.33 (CH₂OC@O), 81.99 (C^q), 181.40 (C@O);

MS: m/z (CI)⁺315 (100%) [M+H]⁺, 79 (35%); HRMS Calcd for

C

₁₆H₃₁O₄Si: 315.1986. Found: 315.1979. For the syn, anti spirocycle

13a: mp 65.7–66.2 °C;

m

_max(thin ﬁlm)/cm^À12929 m, 1761s (C@O),

1375 m, 1254s, 1100s, 838s; ¹H NMR d 0.00 (3H, s, Si(CH₃)₂), 0.01

(3H, s, Si(CH₃)₂), 0.82 (9H, s, SiC(CH₃)₃), 1.17 (3H, s, C^qC(OH)CH₃),

1.53 (1H, ddd, J = 14, 11, 4 Hz, 1H from C^qCH₂CH₂CH), 1.81–1.89

(1H, m, CH₂CHCH₂OSi), 1.98–2.11 (2H, m, 1H from CH₂CH₂O, 1H

from C^qCH₂CH₂CH), 2.43 (1H, ddd, J = 13.5, 6.5, 4 Hz, 1H from

CH₂CH₂O), 2.85–2.92 (1H, m, CH₂CHCH₂OSi), 3.59 (1H, t,

J = 9.5 Hz, 1H, from CH₂OSi), 3.73 (1H, dd, J = 10, 5.5 Hz, 1H from

CH₂OSi), 4.10–4.14 (1H, m, 1H from CH₂OC@O), 4.23–4.28 (1H,

m, 1H from CH₂OC@O); ¹³C NMR d -5.71 (SiCH₃), -5.56 (SiCH₃),

18.79 (CqC(OH)CH₃), 22.58 (C^q), 25.78 (SiC(CH₃)), 25.88 (SiC(CH₃)),

4.4.3. rac-(5S,6S,7R)-7-(Methylenecarbonate-ethyl ester)-6-

hydroxy-6-methyl-2-oxa-spiro[4.4]nonan-1-one 12c and rac-

(5S,6S,7S)-7-(methylenecarbonate-ethyl ester)-6-hydroxy-6-

methyl-2-oxa-spiro[4.4]nonan-1-one 13c

To a stirred solution of SmI₂(0.1 M in THF, 5.6 ml, 0.560 mmol,

3 equiv) and MeOH (1.5 ml) at 0 °C was added a solution of lactone

10c (50 mg, 0.185 mmol) in THF (0.322 ml) and the reaction stirred

for 90 min. Air was introduced into the reaction vessel and the reac-

tion quenched with saturated, aqueous NH₄Cl solution. The aqueous

T. M. Baker et al. / Tetrahedron: Asymmetry 21 (2010) 1246–1261

1253

layer was extracted with EtOAc (4 Â 25 ml). The combined organic

layers were dried over MgSO₄, ﬁltered and concentrated in vacuo.

The crude residue was puriﬁed by chromatography (silica gel, 40%

EtOAc in petroleum ether (40–60 °C)) to give the two spirocycles

12c (19.4 mg, 0.071 mmol, 39%) and 13c (14.1 mg, 0.052 mmol,

28%) as colourless oils. For the all syn compound 12c: m_max(thin

ﬁlm)/cm^À13469w (OH), 2923w, 2853w, 2357w, 1738s (C@O),

1463w, 1370m, 1258s, 1026m, 789w; ¹H NMR (500 MHz, CDCl₃) d

1.31 (3H, t, J = 7.0 Hz, CH₃CH₂O), 1.35 (3H, s, CH₃COH), 1.74–1.82

(2H, m, 1H from CH₂CH₂CH, 1H from CH₂CH₂CH), 1.96 (1H, ddd,

J = 13.0, 7.0, 2.5 Hz, 1H from CH₂CH₂CH), 2.00–2.06 (1H, m, 1H from

CH₂CH₂OC@O), 2.13 (1H, p, J = 9 Hz, CHCH₂OC(O)O), 2.25–2.33 (2H,

m, 1H from CH₂CH₂OC@O, 1H from CH₂CH₂CH), 4.17–4.26 (4H, m,

2H from CH₃CH₂C@O, 1H from CH₂CH₂OC@O, 1H from CHCH₂O-

C(O)O), 4.35 (1H, dt, J = 9.0, 2.5 Hz, 1H from CH₂CH₂OC@O), 4.55

(1H, dd, J = 10.5, 6.5 Hz, 1H from CHCH₂OC(O)O); ¹³C NMR

(125 MHz, CDCl₃) d 14.3 (CH₃CH₂OC@O), 21.7 (CH₃COH), 25.7

(CH₂CH₂CH), 32.2 (CH₂CH₂CH), 32.5 (CH₂CH₂OC@O), 47.0

(CHCH₂OC@O), 55.3 (CH₂OC(O)C), 63.9 (CH₃CH₂OC@O), 65.4

(CH₂CH₂OC@O), 67.5 (CHCH₂OC@O), 81.7 (CH₃COH), 155.2 (OC(O)O),

181.5 (CH₂OC@O); MS: m/z (ES+ mode) 567 (22%), 295 (100%)

[M+Na]⁺; HRMS Calcd for C₁₃H₂₁O₆: 273.1333. Found: 273.1335.

For the syn-anti compound 13c: m_max(thin ﬁlm)/cm^À13469w (OH),

2972w, 2923w, 1743s (C@O), 1466w, 1370 m, 1261s, 1029 m,

791w; ¹H NMR (500 MHz, CDCl₃) d 1.17 (3H, s, CH₃COH), 1.31 (3H,

t, J = 7.0 Hz, CH₃CH₂OC@O), 1.41–1.49 (1H, m, 1H from CH₂CH₂CH),

1.70 (1H, ddd, J = 14.5, 11.0, 4.0 Hz, 1H from CH₂CH₂CH), 1.99 (1H,

ddd, J = 13.0, 6.5, 4.0 Hz, 1 H from CH₂CH₂OC@O), 2.08–2.22 (2H, m,

1H from CH₂CH₂CH, 1H from CH₂CH₂CH), 2.49 (1H, dt, J = 17.0,

8.5 Hz, 1H from CH₂CH₂OC@O), 2.84 (1H, s, OH), 3.01 (1H, tt,

J = 19.0, 9.5, 7.0 Hz, CHCH₂OC(O)O), 4.14–4.23 (4H, m, 2H from

CH₃CH₂OC@O, 1H from CH₂CH₂OC@O, 1H from CHCH₂OC(O)O),

4.27 (1H, dd, J = 10.5, 6.5 Hz, 1H from CHCH₂OC(O)O), 4.35 (1H,

apparent dt, J = 8.5, 4.0 Hz, 1H from CH₂CH₂OC@O); ¹³C NMR

(125 MHz, CDCl₃) d 14.3 (CH₃CH₂OC@O), 18.7 (CH₃COH), 23.9

(CH₂CH₂CH), 31.1 (CH₂CH₂CH), 31.3 (CH₂CH₂OC@O), 46.3

(CHCH₂OC@O), 56.0 (CH₂OC(O)C), 64.1 (CH₃CH₂OC@O), 65.7

(CH₂CH₂OC@O), 67.9 (CHCH₂OC@O), 80.9 (CH₃COH), 155.1 (OC(O)O),

180.6 (CH₂OC@O); MS: m/z (ES+ mode) 567 (18%), 295 (100%)

[M+Na]⁺; HRMS Calcd for C₁₃H₂₁O₆: 273.1333. Found: 273.1341.

(1H, dt, J = 9.5, 2.5 Hz, 1H from CH₂CH₂OC@O), 4.39–4.42 (1H, m,

CHCH₂OC@O), 4.56 (1H, dd, J = 10.5, 8 Hz, CHCH₂OC@O), 6.91 (2H,

d, J = 8.5 Hz, 2 Â CHCHCOCH₃), 7.98 (2H, d, J = 9 Hz, 2 Â CHCHC-

OCH₃); ¹³C NMR (125 MHz, CDCl₃)

d 22.0 (HOCCH₃), 25.5

(CH₂CH₂CH), 32.2 (CH₂CH₂CH), 32.6 (CH₂CH₂OC@O), 47.1

(CHCH₂OC@O), 55.5 (CH₂CH₂OC(O)C), 55.5 (OCH₃), 63.8

(CHCH₂OC@O), 65.4 (CH₂CH₂OC@O), 81.7 (CH₃COH), 113.6

(2 Â ArCH), 122.7 (ArC), 131.6 (2 Â ArCH), 163.3 (ArC), 166.3

(CHCH₂OC@O), 181.7 (CH₂CH₂OC@O); MS: m/z (ES+ mode) 357

(88%) [M+Na]⁺, 352 (45%) [M+NH₄]⁺, 335 (94%) [M+H]⁺, HRMS Calcd

for C₁₈H₂₂O₆Na: 357.1309. Found: 357.1303. For the syn-anti isomer

13d: m_max(thin ﬁlm)/cm^À13481w (OH), 2964w, 1757 m, 1707s,

1606s, 1512 m, 1465w, 1419w, 1375w, 1317w, 1277s, 1256s,

1168s, 1104 m, 1027 m, 962w, 849w, 771 m; ¹H NMR (500 MHz,

CDCl₃) d 1.22 (3H, s, HOCCH₃), 1.47–1.55 (1H, m, 1H from CH₂CH₂CH),

1.73 (1H, ddd, J = 13, 11, 4 Hz, 1H from CH₂CH₂CH), 2.01 (1H, ddd,

J = 13, 5.4, 4 Hz, 1H from CH₂CH₂CH), 2.12–2.25 (2H, m, 1H from

CH₂CH₂CH, 1H from CH₂CH₂OC@O), 2.52 (1H, dt, J = 13, 8.5 Hz, 1H

from CH₂CH₂OC@O), 3.12 (1H, m, CH₂CH₂CH), 3.85 (3H, s, OCH₃),

4.20 (1H, dt, J = 8.5, 6.5 Hz, 1H from CH₂CH₂OC@O), 4.30–4.41 (3H,

m, 1H from CH₂CH₂OC@O, CHCH₂OC@O), 6.91 (2H, d, J = 9 Hz,

2 Â CHCHCOCH₃), 7.97 (2H, d, J = 9 Hz, 2 Â CHCHCOCH₃); ¹³C NMR

(125 MHz, CDCl₃)

d 18.7 (HOCCH₃), 24.2 (CH₂CH₂CH), 31.2

(CH₂CH₂CH), 31.4 (CH₂CH₂OC@O), 46.5 (CHCH₂OC@O), 55.5

(CH₂CH₂OC(O)C), 56.1 (OCH₃), 64.8 (CHCH₂OC@O), 65.7

(CH₂CH₂OC@O), 81.1 (CH₃COH), 113.7 (2 Â ArCH), 122.4 (ArC),

131.6 (2 Â ArCH), 163.4 (ArC), 166.3 (CHCH₂OC@O), 180.7

(CH₂CH₂OC@O); MS: m/z (ES+ mode) 357 (56%) [M+Na]⁺, 352

(100%) [M+NH₄]⁺, HRMS Calcd for C₁₈H₂₂O₆Na: 357.1309. Found:

357.1312.

4.4.5. rac-(5S,6S,7R)-7-(Methylenebenzoate)-6-hydroxy-6-

methyl-2-oxa-spiro[4.4]nonan-1-one 12e and rac-(5S,6S,7S)-7-

(methylenebenzoate)-6-hydroxy-6-methyl-2-oxa-

spiro[4.4]nonan-1-one 13e

To a stirred solution of SmI₂(0.1 M in THF, 1.98 ml, 0.198 mmol,

3 equiv) and MeOH (0.52 ml) at 0 °C was added a solution of ben-

zoate ester 10e (20 mg, 0.066 mmol) in THF (0.11 ml) and the reac-

tion mixture stirred for 45 min. Air was introduced into the

reaction vessel and the reaction quenched with saturated NH₄Cl

solution (10 ml). The aqueous phase was separated and extracted

with EtOAc (5 Â 10 ml). The combined organics were dried over

MgSO₄, ﬁltered and concentrated in vacuo. The crude residue

was puriﬁed by chromatography (silica gel, 50% EtOAc in petro-

leum ether (40–60 °C)) to give the two spirocycles 12e (5.7 mg,

0.019 mmol, 28%) and 13e (5.1 mg, 0.017 mmol, 25%) as clear oils.

For the all-syn isomer 12e: m_max(thin ﬁlm)/cm^À13478w, 2913w,

2849w, 2362w, 1740s (C@O), 1716 (C@O), 1370w, 1273w,

1204 m, 1115w, 1024 m, 709 m; ¹H NMR (500 MHz, CDCl₃) d

1.41 (3H, s, CH₃COH), 1.79–1.89 (2H, m, 1H from CH₂CH₂CH, 1H

from CH₂CH₂CH), 1.99 (1H, ddd, J = 12.9, 6.9, 2.8 Hz, 1H from

CH₂CH₂OC@O), 2.04–2.11 (1H m, 1H from CH₂CH₂CH), 2.23–2.37

(3H, m, 1H from CH₂CH₂OC@O, 1H from CH₂CH₂CH, 1H from

CH₂CH₂CH), 4.26 (1H, apparent dt, J = 9.5, 6.7 Hz, 1H from

CH₂CH₂OC@O), 4.34 (1H, d, J = 1.3 Hz, OH), 4.37 (1H, apparent dt,

J = 9.2, 2.9 Hz, 1H from CH₂CH₂OC@O), 4.46 (1H, dd, J = 11.0,

6.6 Hz, 1H from CHCH₂OC@O), 4.62 (1H dd, J = 11.0, 7.6 Hz, 1H

from CHCH₂CO@O), 7.45 (2H, apparent t, J = 8.2 Hz, 2 Â ArH),

7.57 (1H, tt, J = 7.6, 1.3 Hz, ArH), 8.05 (2H, dd, J = 8.2, 1.3 Hz,

4.4.4. rac-((1R,2S,5R)-2-(4-Methoxy)benzyloxymethyl-1-

methyl-1-hydroxy-6-oxo-7-oxaspiro[4.4]nonane) 12d and rac-

((1R,2R,5R)-2-(4-methoxy)benzyloxymethyl-1-methyl-1-

hydroxy-6-oxo-7-oxaspiro[4.4]nonane) 13d

To a stirred solution of SmI₂(0.1 M in THF, 10.9 mL, 1.09 mmol,

3.0 equiv)andMeOH(2.82 mL)at0 °C was addeda solution of lactone

10d (120 mg, 0.36 mmol, 1.0 equiv) in THF (0.61 mL) and the reaction

stirred for 90 min. Air was introduced into the reaction vessel and the

reaction quenchedwith saturated, aqueous NH₄Cl solution. The aque-

ous layerwas extractedwithEtOAc (4 Â 25 ml). The combined organ-

ic layers were dried over MgSO₄, ﬁltered and concentrated in vacuo.

The crude residue was puriﬁed by chromatography (silica gel, 40%

EtOAc in petroleum ether (40–60 °C)) to give the two spirocycles

12d (41 mg, 0.122 mmol, 34%) and 13d (26 mg, 0.078 mmol, 21%)

in a 1.6:1 ratio as colourless oils. For the all-syn isomer 12d: m_max(thin

ﬁlm)/cm^À13474w (OH), 2965 m, 1740s, 1707s, 1606s, 1512 m,

1465w, 1420w, 1371 m, 1317 m, 1277s, 1256s, 1204w, 1168s,

1148w, 1115 m, 1104 m, 1025s, 848 m, 771 m; ¹H NMR (500 MHz,

CDCl₃) d 1.39 (3H, s, HOCCH₃), 1.77–1.86 (2H, m, 1H from CH₂CH₂CH,

1H from CH₂CH₂CH), 1.98 (1H, ddd, J = 13, 7, 2.5 Hz, 1H from

CH₂CH₂OC@O), 2.02–2.08 (1H, m, 1H from CH₂CH₂CH), 2.20–2.34

(3H, m, 1H from CH₂CH₂OC@O, 1H from CH₂CH₂CH, CH₂CH₂CH),

3.85 (3H, s, OCH₃), 4.21–4.26 (1H, m, 1H from CH₂CH₂OC@O), 4.35

2 Â ArH); ¹³C NMR (125 MHz, CDCl₃)

d 22.0 (CH₃), 25.5

(CH₂CH₂CH), 32.2 (CH₂CH₂CH), 32.6 (CH₂CH₂OC@O), 47.1

(CHCH₂OC@O), 55.5 (CH₂CH₂OC(O)C), 64.2 (CHCH₂OC@O), 65.4

(CH₂CH₂OC@O), 81.7 (CH₃COH), 128.4 (ArC), 129.6 (ArC), 130.3

(ArC), 133.0 (ArC), 166.6 (CH₂CH₂OC@O), 181.7 (ArC@O), MS: m/z

1254

T. M. Baker et al. / Tetrahedron: Asymmetry 21 (2010) 1246–1261

(ES+ mode) 405 (23%), 327 (68%) [M+Na]⁺, 179 (100%), 101 (84%);

HRMS Calcd for C₁₇H₂₀O₅Na: 327.1203. Found: 327.1196. For the

syn–anti isomer 13e: m_max(thin ﬁlm)/cm^À13578 m, 2913 m,

2849w, 2362w, 2333w, 1753s (C@O), 1713 (C@O), 1449w,

1372w, 1273s, 1174w, 1113 m, 1024 m, 712 m; ¹H NMR

(500 MHz, CDCl₃) d 1.24 (3H, s, CH₃), 1.52–1.57 (1H, m, 1H from

CH₂CH₂CH), 1.76 (1H, ddd, J = 14.5, 11.1, 4.1 Hz, 1H from

CH₂CH₂CH), 2.02 (1H, ddd, J = 12.9, 6.6, 3.8 Hz, 1H from

CH₂CH₂CH), 2.15–2.31 (2H, m, 1H from CH₂CH₂CH, 1H from

CH₂CH₂OC@O), 2.54 (1H, dt, J = 12.6, 6.4 Hz, 1H from

CH₂CH₂OC@O), 2.81 (1H, s, OH), 3.15 (1H, tt, J = 9.5, 7.3 Hz,

CH₂CH₂CH), 4.22 (1H, apparent dt, J = 9.2, 6.7 Hz, 1H from

CH₂CH₂OC@O), 4.35–4.39 (2H, m, 1H from CH₂CH₂OC@O, 1H from

CHCH₂OC@O), 4.44 (1H, dd, J = 11.0, 6.9 Hz, 1H from CHCH₂OC@O),

7.45 (2H, t, J = 8.2 Hz, 2 Â ArH), 7.58 (1H, tt, J = 7.6, 1.3 Hz, ArH),

8.03 (2H, dd, J = 8.2, 1.0 Hz, 2 Â ArH); ¹³C NMR (125 MHz, CDCl₃)

from CH₂CH₂OC@O), 4.64 (2H, s, OCH₂O); ¹³C NMR d 18.79

(C^q(OH)CH₃), 23.49 (C^qCH₂CH₂CH), 31.17 (CH₂CH₂OC@O), 46.19

(CHCH₂O), 56.30 (C^q), 59.06 (OCH₃), 65.57 (CHCH₂O), 67.09 (OCH_2-

CH₂O), 68.56 (CH₂OC@O), 71.73 (OCH₂CH₂O), 81.43 (C^q), 95.72

(OCH₂O), 180.82 (C@O); MS: m/z (ESI)⁺311.2 (100%) [M+Na]⁺;

HRMS Calcd for C₁₄H₂₄O₆Na: 311.1465. Found: 311.1454;

4.5. Asymmetric synthesis of 5

4.5.1. (2S,3S)-2-Allyl-5-benzyloxy-pentane-1,3-diol

To a stirred solution of aldol adduct 17 (889 mg, 2.10 mmol,

1 equiv) in THF (21.3 mL) at 0 °C was added dropwise a solution

of NaBH₄(317 mg, 8.40 mmol, 4 equiv) in distilled H₂O (5.4 mL).

The solution was warmed to room temperature and stirred for

2 h. The reaction was cooled to 0 °C and quenched with 1 M HCl

(ꢀ40 mL). The aqueous phase was separated and extracted with

CH₂Cl₂(4 Â 20 mL). The combined organic phases were dried

(MgSO₄), ﬁltered and concentrated in vacuo. The residue was puri-

ﬁed by column chromatography (eluting with 40% EtOAc in petro-

leum ether (40–60 °C)) giving the product (2S,3S)-2-allyl-5-

benzyloxy-pentane-1,3-diol (468 mg, 1.87 mmol, 89%) as a colour-

less oil. m_max(ATR)/cm^À13376bs, 2922 m, 2866 m, 1641 m,

d

18.7 (CH₃), 24.1 (CH₂CH₂CH), 31.2 (CH₂CH₂CH), 31.4

(CH₂CH₂OC@O), 46.5 (CHCH₂OC@O), 56.1 (CH₂CH₂OC(O)C), 65.1

(CHCH₂OC@O), 65.7 (CH₂CH₂OC@O), 81.0 (CH₃COH), 128.5 (ArC),

129.6 (ArC), 130.0 (ArC), 133.1 (ArC), 166.6 (CH₂CH₂OC@O), 181.7

(ArC@O), MS: m/z (ES+ mode) 405 (18%), 327 (100%) [M+Na]⁺,

322 (19%) [M+NH₄]⁺, 179 (48%), 101 (48%); HRMS Calcd for

C₁₇H₂₀O₅Na: 327.1203. Found: 327.1196.

1448 m, 1094 m, 1029 m; [a]

_D= +14.0 (c 1.00, CHCl₃); ¹H NMR

(500 MHz, CDCl₃) d 1.58 (1H, dtd, J = 14.5, 2.8, 2.2 Hz, 1H from

CH₂CH(OH)), 1.71–1.75 (1H, m, CHCH(OH)), 1.81–1.89 (1H, m, 1H

from CH₂CH(OH)), 1.99–2.02 (2H, m, CH₂CH@CH₂), 3.56–3.69

(4H, m, CH₂OBn, CH₂OH), 4.00 (1H, dt, J = 10.0, 2.2 Hz, CH(OH)),

4.44 (2H, s, OCH₂Ph), 4.92–4.99 (2H, m, CH₂@CH), 5.72 (1H, ddt,

J = 17.0, 10.1, 7.0 Hz, CH@CH₂), 7.21–7.28 (5H, m, 5 Â ArCH); ¹³C

NMR (100 MHz, CDCl₃) d 30.8 (CH₂CH@CH₂), 32.5 (CH₂CH(OH)),

44.3 (CHCH₂CH@CH₂), 64.1 (CH₂OH), 69.7 (CH₂OBn), 73.4

(OCH₂Ph), 74.4 (CH(OH)), 116.3 (CH₂@CH), 127.7 (2 Â ArCH),

127.8 (ArCH), 128.5 (2 Â ArCH), 137.0 (CH@CH₂), 137.7 (ArC);

MS: m/z (CI mode) 268 (20%) [M+NH₄]⁺, 251 (100%) [M+H]⁺, HRMS

Calcd for C₁₅H₂₂O₃: 250.1563. Found: 250.1568.

4.4.6. rac-(5S,6S,7R)-6-Hydroxy-7-(2-methoxy-ethoxymethoxy

methyl)-6-methyl-2-oxa-spiro[4.4]nonan-1-one 12f and rac-

(5S,6S,7S)-6-hydroxy-7-(2-methoxy-ethoxymethoxymethyl)-6-

methyl-2-oxa-spiro[4.4]nonan-1-one 13f

To a solution of SmI₂(10.4 mL, 0.1 M in THF, 1.04 mmol,

4.0 equiv) at 0 °C was added dry MeOH (2.44 mL), and the solution

stirred for 10 min. Next, the MEM protected cyclisation substrate

10f (80 mg, 0.26 mmol, 1.0 equiv) was added and the reaction stir-

red at 0 °C for 40 min. The reaction was quenched by exposure to

air followed by the addition of saturated aqueous NaCl solution

(10 mL). The aqueous phase was extracted with EtOAc

(4 Â 15 mL) and the combined organic extracts dried (MgSO₄)

and concentrated to give the crude product. Puriﬁcation by column

chromatography (eluting with 60% EtOAc in petroleum ether (40–

60 °C)) gave the all syn (28 mg, 0.097 mmol, 37%) and syn, anti

(35 mg, 0.122 mmol, 47%) spirocycles 12f and 13f, respectively,

as clear oils. For the all syn spirocycle 12f: m_max(thin ﬁlm)/cm^À1

3482 m, 2921 m, 1739s (lactone C@O), 1372s, 1201s; ¹H NMR d

1.27 (3H, s, C(OH)CH₃), 1.65–1.72 (2H, m, 1H from C^qCH₂CH₂CH,

1H from CH₂CHCH₂O), 1.88–1.20 (3H, m, 1H from CH₂CH₂OC@O,

CH₂CHCH₂O, 1H from C^qCH₂CH₂CH), 2.18–2.26 (2H, m, 1H from

CH₂CH₂OC@O, 1H from CH₂CHCH₂O), 3.34 (3H, s, OCH₃), 3.50–

3.16 (2H, m, OCH₂CH₂O), 3.54–3.55 (1H, m, 1H from CH₂CHCH₂O),

3.63–3.65 (2H, m, OCH₂CH₂O), 3.81 (1H dd, J = 10, 6.5 Hz, 1H from

CH₂CHCH₂O), 4.17 (1H, dt, J = 9, 7 Hz, 1H from CH₂OC@O), 4.28

(1H, dt, J = 9, 3 Hz, 1H from CH₂OC@O), 4.66 (2H, dd, J = 7, 4.5 Hz,

OCH₂O); ¹³C NMR d 22.11 (C^q(OH)CH₃), 26.00 (CH₂CHCH₂O),

32.39 (C^qCH₂CH₂CH), 32.58 (CH₂CH₂OC@O), 47.86 (CHCH₂O),

55.53 (C^q), 59.06 (OCH₃), 65.36 (CHCH₂O), 66.83, OCH₂CH₂O),

67.54 (CH₂OC@O), 71.80 (OCH₂CH₂O), 81.91 (C^q), 95.68 (OCH₂O),

181.62 (C@O); MS: m/z (ESI)⁺311.1 (100%) [M+Na]⁺; HRMS Calcd

for C₁₄H₂₄O₆Na: 311.1465. Found: 311.1455. For the syn, anti spiro-

cycle 13f: m_max(thin ﬁlm)/cm^À13483 m, 2920 m, 1759s (lactone

C@O), 1372 m, ¹H NMR d 1.13 (3H, s, C(OH)CH₃), 1.22–1.27 (1H,

m, 1H from CH₂CHCH₂O), 1.54–1.60 (1H, m, 1H from C^qCH₂CH₂CH),

1.93–2.00 (2H, m, 1H from CH₂CHCH₂O, 1H from C^qCH₂CH₂CH),

2.07–2.13 (1H, m, 1H from CH₂CH₂OC@O), 2.40–2.45 (1H, ddd,

J = 14, 8, 7.5 Hz, 1H from CH₂CH₂OC@O), 2.91–2.98 (1H, m,

CH₂CHCH₂O), 3.33 (3H, s, OCH₃), 3.49–3.51 (2H, m, OCH₂CH₂O),

3.57–3.59 (2H, m, CH₂CHCH₂O), 3.62–3.64 (2H, m, OCH₂CH₂O),

4.09–4.14 (1H, m, 1H from CH₂CH₂OC@O), 4.23–4.28 (1H, m, 1H

4.5.2. (S)-2-(3-Benzyloxy-1-(S)-hydroxy-propyl)-pent-4-en-1-yl

acetate

To a stirred solution of (2S,3S)-2-allyl-5-benzyloxy-pentane-

1,3-diol (93 mg, 0.370 mmol, 1 equiv) in CH₂Cl₂(8.0 mL), at 0 °C

was added triethylamine (0.23 mL, 2.22 mmol, 6 equiv) and acetic

anhydride (0.097 mL, 1.11 mmol, 3 equiv). The reaction was

warmed to room temperature and stirred for 36 h. The reaction

was quenched by the addition of saturated aqueous NaHCO₃solu-

tion (10 mL). The aqueous phase was separated and extracted with

CH₂Cl₂(4 Â 10 mL). The combined organic phases were dried

(MgSO₄), ﬁltered and concentrated in vacuo. The residue was puri-

ﬁed by column chromatography (eluting with 30% EtOAc in petro-

leum ether (40–60 °C)) giving the product (S)-2-(3-benzyloxy-1-

(S)-hydroxy-propyl)-pent-4-en-1-yl acetate (82 mg, 0.28 mmol,

76%) as a colourless oil. m_max(thin ﬁlm)/cm^À12429 m (OH),

2913w, 2849w, 1736s (C@O), 1451w, 1362 m, 1239s, 1090s,

1073s, 1036s, 915w, 769w, 737w; [a]

_D= +9.7 (c 0.67, CHCl₃); ¹H

NMR (400 MHz, CDCl₃) d 1.68–1.71 (1H, m, 1H from CH₂CH₂OBn),

1.82–1.91 (2H, m, 1H from CH₂CH₂OBn, CHCH₂OAc), 2.06 (3H, s,

CH₃C(O)), 2.08–2.16 (1H, m, 1H from CH₂@CHCH₂), 2.26–2.33

(1H, m, 1H from CH₂@CHCH₂), 3.06 (1H, d, J = 2.8 Hz, OH), 3.63–

3.69 (1H, m, 1H from CH₂CH₂OBn), 3.73–3.78 (1H, m, 1H from

CH₂CH₂OBn), 3.91–3.94 (1H, m, CHOH), 4.09 (1H, dd, J = 11.4,

5.3 Hz, 1H from CHCH₂OAc), 4.16 (1H, dd, J = 11.4, 7.1 Hz, 1H from

CHCH₂OAc), 4.52 (1H, d, J = 11.8 Hz, 1H from PhCH₂OCH₂), 4.55

(1H, d, J = 11.8 Hz, 1H from PhCH₂OCH₂), 5.02–5.09 (2H, m,

CH₂@CH), 5.76–5.90 (1H, m, CH₂@CH), 7.30–7.38 (5H, m,

5 Â ArCH); ¹³C NMR (100 MHz, CDCl₃) d 21.0 (CH₃C@O), 31.0

(CH₂CH@CH₂), 33.5 (CH₂CH₂OBn), 42.9 (AcOCH₂CH), 64.3

(CH₂OAc), 69.5 (CH₂CH₂OBn), 70.9 (CHOH), 73.4 (PhCH₂OCH₂),

T. M. Baker et al. / Tetrahedron: Asymmetry 21 (2010) 1246–1261

1255

116.6 (CH₂CH@CH₂), 127.7 (2 Â ArCH), 127.8 (ArCH), 128.5

(2 Â ArCH), 136.6 (CH₂CH@CH₂), 137.8 (ArC), 171.3 (CH₃C@O);

MS: m/z (ES+ mode) 315 (100%) [M+Na]⁺, 293 (44%) [M+H]⁺, HRMS

Calcd for C₁₇H₂₅O₄: 293.1747. Found: 293.1745.

tion from CHCl₃, giving phosphorane 19 (18.0 g, 50.1 mmol, 74%) as

a cream coloured solid (decomposed at 194.6 °C).⁸

m_max(thin ﬁlm)/

cm^À13061w, 2946w, 2913w, 2878w, 1724w, 1588s, 1565 m,

1480 m, 1461w, 1436 m, 1394 m, 1344 m, 1298 m, 1214w,

1142 m, 1093s, 1070s, 998w, 920w, 755 m, 716w; ¹H NMR

4.5.3. (4S)-1-Benzyloxy-4-(acetoxymethyl)-hept-6-en-3-one 18

To a stirred solution of (S)-2-(3-benzyloxy-1-(S)-hydroxy-pro-

pyl)-pent-4-en-1-yl acetate (57 mg, 0.195 mmol, 1 equiv) in

CH₂Cl₂(4 mL), was added crushed, oven dried 4 Å molecular sieves

and the suspension stirred for 10 min. NMO (91.9 mg, 0.780 mmol,

4.0 equiv) was added followed by TPAP (2.5 mg, cat.) and the reac-

tion stirred for 3 h. The crude reaction mixture was passed through

a plug of silica gel (eluting with 30% EtOAc in petroleum ether (40–

60 °C)), giving the product ketone 18 (57 mg, 0.195 mmol, 100%) as

a colourless oil that was used without further puriﬁcation. m_max

(thin ﬁlm)/cm^À12923w, 2854w, 2357w, 1743s (C@O), 1713s

(C@O), 1642w, 1451w, 1365 m, 1233s, 1097 m, 1039 m, 918w,

(300 MHz, CDCl₃)

d

1.82–1.94 (4H, m, CH₂CH₂CH₂OC@O,

CH₂CH₂CH₂OC@O), 4.25–4.28 (2H, m, CH₂CH₂CH₂OC@O), 7.43–

7.49 (6H, m, 6 Â ArCH), 7.52–7.58 (3H, m, 3 Â ArCH), 7.62–7.71

(6H, m, 6 Â ArCH); ¹³C NMR (75 MHz, CDCl₃) d 24.2 (d, J = 11.3 Hz,

CH₂CH₂CH₂OC@O), 24.6 (d, J = 9.8 Hz, CH₂CH₂CH₂OC@O), 35.6 (d,

J = 123.0 Hz, C@PPh₃), 67.4 (CH₂CH₂CH₂OC@O), 126.8 (d, J = 90 Hz,

3 Â ArC-P), 128.7 (d, J = 15 Hz, 6 Â ArCH), 131.9 (d, J = 3 Hz,

3 Â ArCH), 133.7 (d, J = 9.8 Hz, 6 Â ArCH), 170.2 (d, J = 13.5 Hz,

C=O); MS: m/z (ES+ mode) 383 (82%) [M+Na]⁺, 361 (100%) [M+H]⁺,

HRMS Calcd for C₂₃H₂₂O₂P: 361.1352. Found: 361.1362.

799w, 737w; [a]

_D= +3.5 (c 0.34, CHCl₃) ¹H NMR (400 MHz, CDCl₃)

4.5.5. (E)-3-((3S)-6-Benzyloxy-4-oxo-3-(acetoxymethyl)-

hexylidene)-tetrahydro-pyran-2-one 5

d 2.00 (3H, s, CH₃C@O), 2.19–2.27 (1H, m, 1H from CH₂CH@CH₂),

2.37–2.45 (1H, m, 1H from CH₂CH@CH₂), 2.79 (2H, dt, J = 6.3,

2.0 Hz, CH₂CH₂OBn), 2.91–2.98 (1H, m, CHCH₂OAc), 3.76 (2H, t,

J = 6.6 Hz, CH₂CH₂OBn), 4.22 (2H, d, J = 6.8 Hz, CHCH₂OAc), 4.51

(2H, s, PhCH₂OCH₂), 5.05–5.11 (2H, m, CH₂@CH), 5.71 (1H, ddt,

J = 17.2, 10.1, 7.1 Hz, CH@CH₂), 7.28–7.37 (5H, m, 5 Â ArCH); ¹³C

NMR (100 MHz, CDCl₃) d 20.8 (OC(O)CH₃), 32.4 (CH₂@CHCH₂),

43.0 (CH₂CH₂OBn), 50.7 (CHCH₂OAc), 63.8 (CH₂OAc), 65.0

(CH₂OBn), 73.3 (PhCH₂O), 117.9 (CH₂@CH), 127.7 (3 Â ArCH),

128.4 (2 Â ArCH), 134.2 (CH₂@CH), 138.1 (ArC), 170.7 (CH₃C@O),

209.1 (CH₂C@O); MS: m/z (ES+ mode) 213 (100%) [M+Na]⁺, HRMS

Calcd for C₁₇H₂₂O₄Na: 313.1410. Found: 313.1418.

Pyridine (12 lL) was added to a stirred solution of K₂CO₃

(252 mg, 1.83 mmol, 3.0 equiv) and K₃[Fe(CN)₆] (606 mg,

1.83 mmol, 3.0 equiv) in H₂O (7.7 mL) at room temperature. Next,

t-BuOH (5.3 mL) and OsO₄(2.5% in t-BuOH, 0.61 mL, 0.061 mmol,

0.1 equiv) were added sequentially and the reaction cooled to

0 °C before the addition of alkene 18 in Et₂O (5.3 mL). The reaction

was warmed to room temperature and stirred for 4 h. Sodium sul-

ﬁte (906 mg, 3.65 mmol, 6 equiv) was added and the aqueous

phase separated and extracted with EtOAc (3 Â 15 mL). The com-

bined organic phases were dried (MgSO₄), ﬁltered and concen-

trated in vacuo. The residue was re-dissolved in (1:1) THF/H₂O

(15 mL) to which KHCO₃(169 mg, 1.22 mmol, 2.0 equiv) and NaIO₄

(314 mg, 1.46 mmol, 2.4 equiv) were added. The reaction was stir-

red for 13 h. The reaction was quenched with saturated aqueous

NaCl solution (ꢀ15 mL) and the aqueous phase was extracted with

EtOAc (4 Â 15 mL). The combined organic phases were dried

(MgSO₄), ﬁltered and concentrated in vacuo giving the correspond-

ing aldehyde (171 mg, 0.585 mmol, 96%) as a colourless oil which

was used without further puriﬁcation.

4.5.4. 3-(Triphenylphosphoranylidene)tetrahydro-2H-pyran-2-

one 19

To a stirred solution of diisopropylamine (15.7 mL, 110 mmol,

1.1 equiv) in THF (115 mL) at À78 °C was added n-BuLi (51.2 mL,

2.15 M in hexanes, 110 mmol, 1.1 equiv) dropwise and the resulting

solution was stirred for 40 min. The reaction was warmed to room

temperature and stirred for 10 min before being re-cooled to

À78 °C and stirred for an additional 10 min. A solution of d-valero-

lactone (9.30 mL, 100 mmol, 1.0 equiv) in THF (10 mL) was added

dropwise and the reaction stirred for 10 min. Chlorotrimethylsilane

(21.7 mL, 170 mmol, 1.7 equiv) was added in 1 portion and the reac-

tion stirred for 1 h. The reaction was concentrated under vacuum at

35 °C and the remaining salts slurried in dry pentane, ﬁltered under

vacuum and concentrated. Puriﬁcation was carried out by distilla-

tion under high vacuum at 60 °C giving the pure TMS ketene acetal

(13.5 g, 78.5 mmol, 79%) as a colourless liquid. This was dissolved

in CH₂Cl₂(106 mL) and cooled to À15 °C. Triethylamine (13.2 mL,

94.2 mmol, 1.2 equiv) was added and after 5 min, a solution of bro-

mine (4.10 mL, 78.5 mmol, 1.0 equiv) in CH₂Cl₂(22 mL) was added

dropwise over 10 min and the reaction stirred for a further 30 min.

The reaction mixture was washed with saturated aqueous NH₄Cl

solution (2 Â 30 mL). The organic phase was dried (MgSO₄), ﬁltered

and concentrated in vacuo. The dark brown residue was eluted

through a short plug of silica gel (eluting with 40% EtOAc in petro-

The aldehyde (303 mg, 0.930 mmol, 1 equiv) was dissolved in

CH₂Cl₂(15.2 mL) at room temperature. Phosphorane 19 (666 mg,

1.86 mmol, 2 equiv) was added and the reaction stirred for seven

days. The reaction mixture was concentrated in vacuo and eluted

through a plug of silica gel (eluting with 50% EtOAc in petroleum

ether (40–60 °C)). After concentration, the resulting oil was puri-

ﬁed by column chromatography (eluting in 20% i-PrOH in petro-

leum ether (40–60 °C)) giving the lactone 5 (309 mg, 0.826 mmol,

89%) as a pale yellow oil. m_max(thin ﬁlm)/cm^À12948w, 2913w,

2859w, 1736s (C@O), 1708s (C@O), 1634 m, 1630 m, 1449w,

1362w, 1313w, 1231s, 1175 m, 1090 m, 1073 m, 1041 m, 967w,

735w; [a]

_D= +25.1 (c 0.35, CHCl₃) ¹H NMR (400 MHz, CDCl₃) d

1.86–1.92 (2H, m, CH₂CH₂CH₂OC@O), 2.02 (3H, s, CH₃C@O), 2.25–

2.32 (1H, m, 1H from CH₂CH@C), 2.50–2.59 (3H, m, 1H from

CH₂CH@C, CH₂CH₂CH₂OC@O), 2.73 (2H, t, J = 6.0 Hz, CH₂CH₂OBn),

3.05 (1H, quint, J = 6.6 Hz, CHCH₂Oac), 3.75 (2H, dt, J = 6.3, 1.5 Hz,

CH₂CH₂Obn), 4.23 (2H, d, J = 5.8 Hz, CHCH₂Oac), 4.26–4.29 (2H,

m, CH₂CH₂CH₂OC@O), 4.50 (2H, s, PhCH₂O), 6.92 (1H, tt, J = 7.6,

2.5 Hz, CH@C), 7.28–7.37 (5H, m, 5 Â ArCH); ¹³C NMR (100 MHz,

leum ether (40–60 °C)) giving a-bromo-d-valerolactone as a brown

oil (12.1 g, 67.9 mmol, 85%).²¹This compound was dissolved in THF

(29.6 mL). Triphenylphosphine (17.8 g, 67.9 mmol, 1.0 equiv) was

added and the solution heated to reﬂux overnight. The reaction

was concentrated in vacuo and the residue slurried in H₂O

(100 mL) and NaOH (170 mL, 20% concd in H₂O) was added drop-

wise. The aqueous phase was extracted with CHCl₃(4 Â 100 mL)

and the combined organic phases dried (MgSO₄), ﬁltered and con-

centrated in vacuo. The crude product was puriﬁed by recrystallisa-

CDCl₃)

d

20.7 (OC(O)CH₃), 22.5 (CH₂CH₂CH₂OC@O), 23.6

(CH₂CH₂CH₂OC@O), 26.8 (CH₂CH@C), 43.0 (BnOCH₂CH₂C@O),

50.1 (CHCH₂Oac), 63.8 (CHCH₂Oac), 65.0 (BnOCH₂CH₂), 68.6

(CH₂CH₂CH₂OC@O), 73.3 (ArCH₂O), 127.7 (2 Â ArCH), 127.8

(2 Â ArCH), 128.4 (ArCH, CH₂CH@C), 138.0 (ArC), 141.4 (CH₂CH@C),

166.0

(CH₂CH₂CH₂OC@O),

170.6

(CHCH₂OC@O),

208.4

(CH₂CH₂C@O); MS: m/z (ES+ mode) 397 (100%) [M+Na]⁺, HRMS

Calcd for C₂₁H₃₀O₆N [M+NH₄]⁺: 392.2068. Found: 392.2061.

1256

T. M. Baker et al. / Tetrahedron: Asymmetry 21 (2010) 1246–1261

4.6. SmI₂-mediated cyclisations of 5

COH), 127.7 (ArCH), 128.3 (2 Â ArCH), 128.6 (2 Â ArCH), 137.8

(ArC), 171.1 (CHCH₂OC@O), 178.2 (CH₂CH₂CH₂OC@O); MS: m/z

(ES+ mode) 399 (100%) [M+Na]⁺, HRMS Calcd for C₂₁H₂₈O₆Na:

399.1778. Found: 399.1781.

4.6.1. (1R,2S,5R)-2-Acetoxymethyl-1-(2-(benzyloxy)ethyl)-1-

hydroxy-6-oxo-7-oxaspiro[4.5]decane 14 and ((1S,2S,5S)-2-

acetoxymethyl-1-(2-(benzyloxy)ethyl)-1-hydroxy-6-oxo-7-

oxaspiro[4.5]decane

4.6.2. (1R,2S,5R)-2-Acetoxymethyl-1-hydroxy-1-(2-

To

a

stirred solution of SmI₂in THF (0.1 M, 2.94 mL,

hydroxyethyl)-6-oxo-7-oxaspiro[4.5]decanane 20

0.294 mmol, 2.2 equiv) was added degassed, distilled H₂O

(0.82 mL) resulting in the formation of a dark red solution. The

solution was cooled to 0 °C and a solution of lactone 5 (50 mg,

0.134 mmol, 1.0 equiv) in THF (0.30 mL) added. The reaction was

stirred for 3 min before being quenched by the addition of satu-

rated aqueous NH₄Cl solution (10 mL). Saturated aqueous Na₂S₂O₃

(1.0 mL) and saturated aqueous K/Na tartrate (1.0 mL) solutions

were added and the mixture vigorously stirred for 10 min. The

aqueous phase was extracted with EtOAc (4 Â 10 mL) and the com-

bined organic phases were dried (MgSO₄), ﬁltered and concen-

trated in vacuo. The residue was puriﬁed by column

chromatography (eluting with 40% EtOAc in petroleum ether

(40–60 °C)) giving spirocyclic lactone 14 (28.3 mg, 0.075 mmol,

56%) as a colourless oil. Upon further elution, the syn, anti–spirocy-

clic lactone (3.3 mg, 0.0088 mmol, 7%) was also isolated as a col-

ourless oil. For all-syn isomer 14: m_max(thin ﬁlm)/cm^À13360w,

2923w, 2854w, 1736s (C@O), 1676s, 1449w, 1399 m, 1365 m,

1236s, 1174s, 1115 m, 1093w, 1031w, 977w, 749w, 737w;

To a stirred solution of spirocyclic lactone 14 (26 mg,

0.069 mmol, 1 equiv) in Et₂O (0.05 mL) at room temperature was

added Pd(OH)₂/C (5 mg, 0.0138 mmol, 20 mol %) and the suspen-

sion was vigorously stirred overnight under an atmosphere of H₂.

The reaction mixture was ﬁltered through a plug of Celite, washing

with MeOH. The ﬁltrate was concentrated in vacuo giving crude

diol that was recrystalized from hexane and EtOAc to give 20 as

a white crystaline solid (9.0 mg, 0.031 mmol, 45%). Mp 94.9–

95.8 °C; m_max(thin ﬁlm)/cm^À13370 m (OH), 1953 m, 1736s

(C@O), 1676s, 1451w, 1399 m, 1365 m, 1261s, 1239s, 1177 m,

1034 m, 979w, 898w, 843w, 725w; [

a

]

_D= À5.1 (c 0.86, CHCl₃), ¹H

NMR (400 MHz, CDCl₃)

d

1.50–1.57 (1H, m, 1H from

CH₂CH₂CH₂OC@O), 1.64–1.73 (2H, m, 1H from CH₂CH₂CH₂OC@O,

1H from CH₂CH₂CH), 1.80–1.86 (1H, m, 1H from CH₂CH₂CH),

1.88–2.08 (4H, m, 1H from CH₂CH₂CH, 1H from CH₂CH₂CH₂OC@O,

CH₂CH₂OH), 2.05 (3H, s, CH₃C@O), 2.12 (1H, ddd, J = 12.6, 3.6,

2.0 Hz, 1H from CH₂CH₂CH₂OC@O), 2.17–2.30 (2H, m, 1H from

CH₂CH₂CH, CH₂CH₂CH), 3.77 (1H, dt, J = 10.1, 4.0 Hz, 1H from

CH₂CH₂CH₂OC@O), 3.94 (1H, dt, J = 10.1, 2.8 Hz, 1H from

CH₂CH₂CH₂OC@O), 4.17 (1H, dd, J = 10.8, 7.0 Hz, 1H from CH₂OAc),

4.33–4.40 (3H, m, 1H from CH₂OAc, CH₂CH₂OH), 6.41 (1H, d,

[a

]

_D= À28.3 (c 0.58, CHCl₃), ¹H NMR (400 MHz, CDCl₃) d 1.44–

1.49 (1H, m, 1H from CH₂CH₂CH₂OC@O), 1.16–1.72 (2H, m, 1H

from CH₂CH₂CH₂OC@O, 1H from CH₂CH₂CH), 1.87–1.97 (4H, m,

1H from CH₂CH₂CH₂OC@O, 1H from CH₂CH₂CH, 1H from

CH₂CH₂CH, 1H from CH₂CH₂OBn), 2.00–2.11 (2H, m, 1H from

CH₂CH₂CH₂OC@O, 1H from CH₂CH₂OBn), 2.02 (3H, s, CH₃C@O),

2.13–2.26 (2H, m, 1H from CH₂CH₂CH, CH₂CH₂CH), 3.52–3.63

(2H, m, CH₂CH₂OBn), 3.75 (1H, ddd, J = 12.6, 10.8, 3.3 Hz, 1H from

CH₂CH₂CH₂OC@O), 4.04–4.09 (1H, m, 1H from CH₂CH₂CH₂OC@O),

4.16 (1H, dd, J = 11.1, 7.0 Hz, 1H from CH₂OAc), 4.22 (1H, d,

J = 11.8 Hz, 1H from PhCH₂OCH₂), 4.34 (1H, dd, J = 11.1, 6.8 Hz,

1H from CH₂OAc), 4.49 (1H, d, J = 11.8 Hz, 1H from PhCH₂OCH₂),

6.55 (1H, d, J = 1.2 Hz, OH), 7.27–7.36 (5H, m, 5 Â ArCH); ¹³C

NMR (100 MHz, CDCl₃) d 20.5 (CH₂CH₂CH₂OC@O), 21.1 (CH₃C@O),

24.8 (CH₂CH₂CH), 26.6 (CH₂CH₂CH₂OC@O), 34.7 (CH₂CH₂OBn), 35.6

(CH₂CH₂CH), 46.2 (CH₂CH₂CH), 54.0 (CH₂CH₂OC(O)C), 64.8

(CHCH₂OAc), 65.6 (BnOCH₂), 69.3 (CH₂CH₂CH₂OC@O), 72.3

(ArCH₂O), 83.7 (OCH₂CH₂COH), 127.7 (ArCH), 128.3 (2 Â ArCH),

128.5 (2 Â ArCH), 137.9 (ArC), 171.1 (CHCH₂OC@O), 178.4

(CH₂CH₂CH₂OC@O); MS: m/z (ES+ mode) 394 (58%) [M+Na]⁺, 377

(100%) [M+H]⁺, HRMS Calcd for C₂₁H₃₂O₆N: 394.2224. Found:

394.2223. For syn-anti isomer: m_max(thin ﬁlm)/cm^À13340w (OH),

2953 m, 2918 m, 2849 m, 1731s (C@O), 1674s, 1397w, 1362w,

J = 1.0 Hz, OH); ¹³C NMR (100 MHz, CDCl₃)

d

20.7

(CH₂CH₂CH₂OC@O), 21.1 (CH₃C@O), 24.9 (CH₂CH₂CH), 26.9

(CH₂CH₂CH₂OC@O), 35.7 (CH₂CH₂OH), 36.0 (CH₂CH₂CH), 46.4

(CH₂CH₂CH), 54.3 (CH₂CH₂OC(O)C), 58.0 (CH₂CH₂CH₂OC@O), 64.8

(CH₂OAc), 69.9 (CH₂CH₂OH), 83.9 (HOCH₂CH₂COH), 171.1

(CHCH₂OC@O), 179.2 (CH₂CH₂CH₂OC@O); MS: m/z (ES+ mode)

309 (100%) [M+Na]⁺, 304 (39%) [M+NH₄]⁺, 287 (62%) [M+H]⁺, HRMS

Calcd for C₁₄H₂₃O₆: 287.1489. Found: 287.1492.

4.6.3. (1S,2R,3S)-1-Acetoxymethyl-2-(2-(benzyloxy)ethyl)-2-hy-

droxy-3-(hydroxymethyl)-3-(3-hydroxypropyl)cyclopentane 4

To

a stirred solution of SmI₂in THF (0.1 M, 6.40 mL,

0.637 mmol, 12 equiv) at 0 °C was added degassed, distilled H₂O

(1.6 mL) resulting in the formation of a dark red solution. A solu-

tion of lactone 5 (20 mg, 0.0531 mmol, 1 equiv) in THF (0.5 mL)

was added and the reaction stirred at 0 °C for 5 min. The reaction

was warmed to room temperature and stirred for 16 h before

quenching with saturated aqueous NH₄Cl solution (1.5 mL). Satu-

rated aqueous Na₂S₂O₃(1.0 mL) and K/Na tartrate (1.5 mL) solu-

tions were added and the mixture stirred for 20 min. The

aqueous phase was extracted with EtOAc (5 Â 10 mL) and the com-

bined organic phases were dried (MgSO₄), ﬁltered and concen-

trated in vacuo. The crude product was ﬁltered through a short

plug of silica gel (eluting with 50% EtOAc in petroleum ether

(40–60 °C)) giving triol 4 (17.3 mg, 0.0455 mmol, 86%) as a 6:1

mixture of diastereoisomers. For the major diastereoisomer 4: m_max

(thin ﬁlm)/cm^À13340s (OH), 2948 m, 2868 m, 1736s (C@O),

1654w, 1459w, 1362 m, 1241s, 1145w, 1098 m, 1071 m, 1031s,

1234s, 1167s, 1088 m, 1026 m, 957w, 745w; [

a

]

_D= À27.7 (c 0.40,

CHCl₃) ¹H NMR (400 MHz, CDCl₃)

d

1.44–1.55 (2H, m,

CH₂CH₂CH₂OC@O), 1.65–1.71 (1H, m, 1H from CH₂CH₂CH₂OC@O),

1.79 (1H, ddd, J = 14.9, 3.8, 2.5 Hz, 1H from CH₂CH₂OBn), 1.84–

2.11 (4H, m, 1H from CH₂CH₂CH₂OC@O, 1H from CH₂CH₂CH, 1H

from CH₂CH₂OBn, 1H from CH₂CH₂CH), 2.04 (3H, s, CH₃C@O),

2.17–2.35 (2H, m, 1H from CH₂CH₂CH, 1H from CH₂CH₂CH),

2.42–2.50 (1H, m, CH₂CH₂CH), 3.56–3.60 (1H, m, 1H from CH₂OAc),

3.63–3.69 (1H, m, 1H from CH₂OAc), 3.76 (1H, dt, J = 11.8, 3.5 Hz,

1H from CH₂CH₂CH₂OC@O), 3.93 (1H, dd, J = 11.1, 8.0 Hz, 1H from

CH₂OBn), 4.06–4.12 (2H, m, 1H from CH₂CH₂OBn, 1H from

CH₂CH₂CH₂OC@O), 4.25 (1H, d, J = 11.9 Hz, 1H from PhCH₂O),

4.49 (1H, d, J = 11.9 Hz, 1H from PhCH₂O), 6.78 (1H, d, J = 1.0 Hz,

OH), 7.28–7.36 (5H, m, 5 Â ArCH); ¹³C NMR (100 MHz, CDCl₃) d

20.5 (CH₂CH₂CH₂OC@O), 21.0 (CH₃C@O), 25.1 (CH₂CH₂CH), 25.2

(CH₂CH₂CH₂OC@O), 33.4 (CH₂CH₂OBn), 35.5 (CH₂CH₂CH), 50.1

(CH₂CH₂CH), 53.8 (CH₂CH₂OC(O)C), 65.3 (CHCH₂OAc), 66.5

(BnOCH₂), 68.1 (CH₂CH₂CH₂OC@O), 72.4 (ArCH₂O), 84.9 (OCH₂CH_2-

739w; [

a

]

_D= À12.5 (c 2.50, CHCl₃), ¹H NMR (400 MHz, CDCl₃) d

1.09–1.17 (1H, m, 1H from CH₂CH₂CH₂OH), 1.34–1.40 (1H, m, 1H

from CH₂CH₂CH), 1.47–1.59 (4H, m, 1H from CH₂CH₂CH₂OH, 1H

from CH₂CH₂CH, CH₂CH₂CH₂OH), 1.64 (1H, ddd, J = 14.9, 4.3,

2.8 Hz, 1H from CH₂CH₂OBn), 1.75–1.90 (2H, m, 1H from

CH₂CH₂CH, 1H from CH₂CH₂CH), 2.05 (3H, s, CH₃C@O), 2.16 (1H,

ddd, J = 14.9, 10.6, 4.3 Hz, 1H from CH₂CH₂OBn), 2.23–2.28 (1H,

m, CH₂CH₂CH), 3.57 (1H, d, J = 11.8 Hz, 1H from CCH₂OH), 3.63

(2H, t, J = 5.8 Hz, CH₂CH₂CH₂OH), 3.71 (1H, d, J = 11.8 Hz, 1H from

CCH₂OH), 3.86 (1H, dt, J = 9.6, 4.3 Hz, 1H from CH₂CH₂OBn),

T. M. Baker et al. / Tetrahedron: Asymmetry 21 (2010) 1246–1261

1257

3.95–4.02 (2H, m, 1H from CH₂OAc, 1H from CH₂CH₂OBn), 4.40

(1H, dd, J = 11.1, 5.0 Hz, 1H from CH₂OAc), 4.47 (1H, s, OH), 4.50

(1H, d, J = 11.6 Hz, 1H from PhCH₂O), 4.60 (1H, d, J = 11.6 Hz, 1H

from PhCH₂O), 7.30–7369 (5H, m, 5 Â ArCH); ¹³C NMR (100 MHz,

CDCl₃) d 21.1 (CH₃C@O), 26.6 (CH₂CH₂CH), 27.7 (CH₂CH₂CH₂OH),

28.0 (CH₂CH₂CH₂OH), 29.1 (CH₂CH₂CH), 34.9 (CH₂CH₂OBn), 45.7

(CHCH₂OC@O), 52.7 (CCH₂OH), 63.5 (CH₂CH₂CH₂OH), 64.6

(CCH₂OH), 66.8 (CH₂OAc), 68.2 (BnOCH₂), 73.7 (PhCH₂O), 87.2

(BnCH₂CH₂COH), 128.0 (2 Â ArCH), 128.1 (ArCH), 128.6 (2 Â ArCH),

137.0 (ArC), 171.3 (CH₃C@O); MS: m/z (ES+ mode) 403 (100%)

[M+Na]⁺, 381 (30%) [M+H]⁺, HRMS Calcd for C₂₁H₃₃O₆: 381.2272.

Found: 381.2268.

giving the corresponding thiocarbonate (57 mg, 0.091 mmol, 90%)

as a yellow oil.

The thiocarbonate (105 mg, 0.166 mmol, 1.0 equiv) was imme-

diately dissolved in toluene (8.8 mL). Next, AIBN (5.5 mg,

0.033 mmol, 0.2 equiv) and n-Bu₃SnH (144.8 lL, 0.499 mmol,

3.0 equiv) were added and the reaction stirred at 95 °C for 2 h.

The mixture was cooled to room temperature and concentrated

in vacuo. The residue was puriﬁed by column chromatography

(eluting with 10% EtOAc in petroleum ether (40–60 °C)), giving

the deoxygenated product 22 (57.3 mg, 0.120 mmol, 72%) as a col-

ourless oil. m_max(thin ﬁlm)/cm^À12948 m, 2923 m, 2854w, 2357s,

2328 m, 1733 m (C@O), 1649w, 1362w, 1254 m, 1098 m, 1029w,

833w, 774w; [

a]

_D= À8.0 (c 0.55, CHCl₃), ¹H NMR (400 MHz, CDCl₃)

4.6.4. (1S,2R,3S)-1-Acetoxymethyl-2-(2-(benzyloxy)ethyl)-3-(3-

((tert-butyldimethylsilyl)oxy)propyl)-2-hydroxy-3-

(hydroxymethyl)cyclopentane 21

d 0.06 (6H, s, Si(CH₃)₂), 0.90 (9H, s, SiC(CH₃)₃), 0.98 (3H, s, CCH₃),

1.17–1.23 (2H, m, CH₂CH₂CH₂OTBS), 1.40–1.62 (5H, m, 1H from

CH₂CH₂CH, CH₂CH₂CH, CH₂CH₂CH₂OTBS), 1.70–1.80 (1H, m, 1H

from CH₂CH₂CH), 1.85–1.99 (2H, m, CH₂CH₂OBn), 2.04 (3H, s,

CH₃C@O), 2.21–2.28 (1H, m, CH₂CH₂CH), 3.59 (2H, t, J = 6.6 Hz,

CH₂CH₂CH₂OTBS), 3.70 (1H, s, OH), 3.82–3.85 (2H, m, CH₂CH₂OBn),

4.02 (1H, dd, J = 11.1, 8.3 Hz, 1H from CH₂OAc), 4.40 (1H, dd,

J = 11.1, 5.8 Hz, 1H from CH₂OAc), 4.49 (1H, d, J = 11.3 Hz, 1H from

PhCH₂O), 4.53 (1H, d, J = 11.3 Hz, 1H from PhCH₂O), 7.28–7.37 (5H,

m, 5 Â ArCH), ¹³C NMR (100 MHz, CDCl₃) d À5.2 (Si(CH₃)₂), 18.4

(SiC(CH₃)₃), 19.0 (CCH₃), 21.2 (CH₃C@O), 25.7 (CH₂CH₂CH), 26.0

(SiC(CH₃)₃), 28.2 (CH₂CH₂CH₂OTBS), 31.6 (CH₂CH₂CH₂OTBS), 33.4

(CH₂CH₂CH), 34.0 (CH₂CH₂OBn), 45.9 (CHCH₂OAc), 49.7 (CCH₃),

63.9 (CH₂OTBS), 66.9 (CH₂OAc), 68.2 (BnOCH₂), 73.6 (PhCH₂O),

84.2 (BnOCH₂CH₂COH), 127.9 (3 Â ArCH), 128.5 (2 Â ArCH), 137.4

(ArC), 171.3 (CH₃C@O); MS: m/z (ES+ mode) 501 (100%) [M+Na]⁺,

HRMS Calcd for C₂₇H₅₀O₅NSi: 496.3453. Found: 496.3446.

To a stirred solution of triol 4 (440 mg, 1.156 mmol, 1.0 equiv)

in CH₂Cl₂(33.8 mL) at room temperature was added imidazole

(236 mg, 3.47 mmol, 3.0 equiv) then TBSCl (174 mg, 1.16 mmol,

1.0 equiv) and the reaction stirred for 6.5 h. The reaction was

quenched by the addition of saturated aqueous NaHCO₃solution

(20 mL), the aqueous phase was extracted with Et₂O (4 Â 20 mL)

and the combined organic phases dried (MgSO₄), ﬁltered and con-

centrated in vacuo. The crude product was puriﬁed by column

chromatography (eluting with 50% EtOAc in petroleum ether

(40–60 °C)) giving the diol 21 (421 mg, 0.851 mmol, 74% (82%

based on recovered starting amterial)) as a colourless oil.

ﬁlm)/cm^À13429 m (OH), 1953 m, 2923 m, 2854 m, 1738 m (C@O),

1461w, 1362w, 1246s, 1098s, 1034 m, 836s, 774w; [

_D= À10.1 (c

m_max(thin

a]

1.45, CHCl₃), ¹H NMR (400 MHz, CDCl₃) d 0.045 (6H, s, Si(CH₃)₂),

0.89 (9H, s, SiC(CH₃)₃), 1.05–1.13 (1H, m, 1H from

CH₂CH₂CH₂OTBS), 1.28–1.35 (1H, m, 1H from CH₂CH₂CH₂OTBS),

1.39 (1H, ddd, J = 13.4, 7.8, 5.8 Hz, 1H from CH₂CH₂CH), 1.45–

1.58 (3H, m, 1H from CH₂CH₂CH, CH₂CH₂CH₂OTBS), 1.67 (1H,

ddd, J = 14.9, 4.6, 3.0 Hz, 1H from CH₂CH₂OBn), 1.74–1.83 (1H, m,

1H from CH₂CH₂CH), 1.94 (1H, dt, J = 13.1, 8.3 Hz, 1H from

CH₂CH₂CH), 2.05 (3H, s, CH₃C@O), 2.14 (1H, ddd, J = 14.9, 10.4,

4.3 Hz, 1H from CH₂CH₂OBn), 2.19–2.26 (1H, m, CH₂CH₂CH),

3.53–3.65 (4H, m, CH₂CH₂CH₂OTBS, CCH₂OH), 3.85–3.89 (1H, m,

1H from CH₂CH₂OBn), 3.94–4.01 (2H, m, 1H from CH₂CH₂OBn,

1H from CH₂OAc), 4.41 (1H, dd, J = 11.1, 5.0 Hz, 1H from CH₂OAc),

4.47 (1H, s, OH), 4.51 (1H, d, J = 11.4 Hz, 1H from PhCH₂O), 4.60

(1H, d, J = 11.4 Hz, 1H from PhCH₂O), 7.30–7.39 (5H, m, 5 Â ArCH);

¹³C NMR (100 MHz, CDCl₃) d À5.3 (SiCH₃), À5.2 (SiCH₃), 18.3

(SiC(CH₃)₃), 21.1 (CH₃C@O), 26.0 (SiC(CH₃)₃), 26.5 (CH₂CH₂CH),

27.8 (CH₂CH₂CH₂OTBS), 28.1 (CH₂CH₂CH₂OTBS), 28.5 (CH₂CH₂CH),

34.5 (CH₂CH₂OBn), 45.8 (CH₂CH₂CH), 52.8 (CCH₂OH), 63.6

(CH₂CH₂CH₂OTBS), 64.6 (CCH₂OH), 66.8 (CH₂OAc), 68.3 (BnOCH₂),

73.7 (PhCH₂O), 87.4 (BnOCH₂CH₂COH), 128.0 (2 Â ArCH), 128.1

(ArCH), 128.6 (2 Â ArCH), 137.0 (ArC), 171.3 (CH₃C@O); MS: m/z

(ES+ mode) 517 (92%) [M+Na]⁺, 495 (100%) [M+H]⁺, HRMS Calcd

for C₂₇H₄₇O₆Si: 495.3136. Found: 495.3124.

4.6.6. (1R,2S,5S)-1-(2-(Benzyloxy)ethyl)-2-(3-((tert-

butyldimethylsilyl)oxy)propyl)-5-(hydroxymethyl)-2-

methylcyclopentanol

To

a stirred solution of acetate 22 (79 mg, 0.165 mmol,

1.0 equiv) in MeOH (7.9 mL) at room temperature was added

K₂CO₃(68.5 mg, 0.495 mmol, 3.0 equiv) and the reaction heated

to 40 °C for 1 h. The reaction was cooled to room temperature, con-

centrated in vacuo and slurried in brine (10 mL). The aqueous

phase was extracted with CH₂Cl₂(4 Â 10 mL) and the combined

organics dried (MgSO₄), ﬁltered and concentrate in vacuo giving

(1R,2S,5S)-1-(2-(benzyloxy)ethyl)-2-(3-((tert-butyldimethylsi-

lyl)oxy)propyl)-5-(hydroxymethyl)-2-methylcyclopentanol (70

mg, 0.160 mmol, 97%) as a colourless oil that was used without

puriﬁcation. m_max(thin ﬁlm)/cm^À13434 m (OH), 2948s, 2928s,

2854 m, 1619w, 1461w, 1385w, 1360w, 1254 m, 1095s, 1026w,

969w, 937w, 833s, 774 m, 732w; [

a

]

_D= À4.9 (c 0.6, CHCl₃); ¹H

NMR (300 MHz, CDCl₃) d 0.05 (6H, s, Si(CH₃)₂), 0.90 (9H, s,

SiC(CH₃)₃), 0.99 (3H, s, CCH₃), 1.18–1.26 (2H, m, CH₂CH₂CH₂OTBS),

1.47–1.67 (5H, m, CH₂CH₂CH₂OTBS, CH₂CH₂CH, 1H from

CH₂CH₂CH), 1.75–1.87 (2H, m, 1H from CH₂CH₂CH, 1H from

CH₂CH₂OBn), 1.95–2.10 (2H, m, 1H from CH₂CH₂OBn, CH₂CH₂CH),

3.43 (1H, dd, J = 9.1, 2.6 Hz, CH₂OH), 3.60 (2H, t, J = 6.6 Hz,

CH₂CH₂CH₂OTBS), 3.61–3.68 (1H, m, 1H from CH₂OH), 3.76–3.81

(1H, m, 1H from CH₂CH₂OBn),3.87 (1H, dd, J = 9.2, 3.6 Hz, 1H from

CH₂CH₂OBn), 3.95 (1H, dt, J = 11.3, 2.8 Hz, 1H from CH₂OH), 4.21

(1H, d, J = 0.8 Hz, OH), 4.51 (2H, s, PhCH₂O), 7.28–7.40 (5H, m,

5 Â ArCH); ¹³C NMR (75 MHz, CDCl₃) d À5.2 (Si(CH₃)₂), 18.3

(SiC(CH₃)₃), 19.0 (CCH₃), 23.2 (CH₂CH₂CH), 26.0 (SiC(CH₃)₃), 28.1

(CH₂CH₂CH₂OTBS), 31.6 (CH₂CH₂CH₂OTBS), 34.3 (CH₂CH₂OBn),

48.0 (CH₂CH₂CH), 49.6 (CCH₃), 63.3 (CH₂OH), 63.8 (CH₂OTBS),

68.2 (BnOCH₂), 73.7 (PhCH₂O), 86.9 (BnOCH₂CH₂COH), 128.0

(3 Â ArCH), 128.6 (2 Â ArCH), 137.2 (ArC); MS: m/z (ES+ mode)

459 (100%) [M+Na]⁺, HRMS Calcd for C₂₅H₄₄O₄Na: 459.2901.

Found: 459.2906.

4.6.5. (1S,2R,3S)-1-Acetoxymethyl-2-(2-(benzyloxy)ethyl)-3-(3-

((tert-butyldimethylsilyl)oxy)propyl)-2-hydroxy-3-

methylcyclopentane 22

To a stirred solution of diol 21 (50 mg, 0.101 mmol, 1.0 equiv) in

CH₂Cl₂(2.7 mL) at room temperature was added pyridine (22.3

and DMAP (5 mg) and the mixture stirred for 2 min. O-Phenyl chlo-

rothionoformate (40.3 L, 0.303 mmol, 3.0 equiv) was added drop-

lL)

l

wise and the reaction stirred for 4 h. The reaction was diluted with

EtOAc (ꢀ5 mL) forming a white suspension and the organic phase

was washed with brine (3 mL), dried (MgSO₄), ﬁltered and concen-

trated. The residue was puriﬁed immediately by column chroma-

tography (eluting with 30% EtOAc in petroleum ether (40–60 °C))

1258

T. M. Baker et al. / Tetrahedron: Asymmetry 21 (2010) 1246–1261

4.6.7. (1R,2R,3S)-Methyl-2-(2-(benzyloxy)ethyl)-3-(3-((tert-

butyldimethylsilyl)oxy)propyl)-2-hydroxy-3-

methylcyclopentanecarboxylate 23

the tertiary alcohol 24 (3.5 mg, 7.75 Â 10^À3mmol, 100%) as a clear

oil. m_max(thin ﬁlm)/cm^À13459 m (OH), 1953s, 2923s, 2854 m,

1471 m, 1360 m, 1254 m, 1095s, 937w, 836s, 774 m, 732w;

To a stirred solution of (1R,2S,5S)-1-(2-(benzyloxy)ethyl)-2-(3-

((tert-butyldimethylsilyl)oxy)propyl)-5-(hydroxymethyl)-2-meth-

ylcyclopentanol (28.8 mg, 0.066 mmol, 1.0 equiv) in CH₂Cl₂

(16.7 mL) at room temperature was added NaHCO₃(11.5 mg,

0.132 mmol, 2.0 equiv). Dess–Martin periodinane (42 mg,

0.0989 mmol, 1.5 equiv) was added and the turbid reaction was

stirred for 3 h. The reaction was diluted with EtOAc (35 mL) and

a solution of saturated aqueous NaHCO₃solution (35 mL) contain-

ing Na₂S₂O₃(2.77 g) was added. After stirring vigorously for

30 min, EtOAc (35 mL) was added, the organic layer separated

and washed with saturated aqueous NaHCO₃solution (25 mL).

The organic phase was dried (MgSO₄), ﬁltered and concentrated.

The crude aldehyde product was dissolved in t-BuOH (1.56 mL)

and 2-methyl-2-butene (0.64 mL) was added. In a separate ﬂask,

a mixture of NaClO₂(150 mg) and NaH₂PO₄(150 mg) was dis-

solved in H₂O (1 mL). Upon complete dissolution, a portion of this

solution (0.35 mL) was added to the aldehyde solution and the

reaction stirred for 30 min. DMS (12 drops) was added and the

reaction stirred for a further 30 min. The reaction mixture was di-

luted with brine (5 mL) and the aqueous phase extracted with

CH₂Cl₂(4 Â 5 mL). The combined organic phases were dried

(MgSO₄), ﬁltered and concentrated to give the crude carboxylic

acid that was then dissolved in a 4:1 mixture of toluene/MeOH

(1.8 mL). A solution of TMS-diazomethane (2.0 M in hexanes,

[a]

_D= À4.40 (c 1.0, CHCl₃); ¹H NMR (400 MHz, CDCl₃) d 0.06 (6H,

s, Si(CH₃)₂), 0.90 (9H, s, SiC(CH₃)₃), 1.01 (CCH₃), 1.15 (3H, s,

C(CH₃)₂OH), 1.22–1.26 (2H, m, CH₂CH₂CH₂OTBS), 1.45 (3H, s,

C(CH₃)₂OH), 1.39–1.63 (5H, m, CH₂CH₂CH₂OTBS, CH₂CH₂CH, 1H

from CH₂CH₂CH), 1.81–1.89 (3H, m, CH₂CH₂CH, 1H from

CH₂CH₂CH, 1H from CH₂CH₂OBn), 2.43 (1H, ddd, J = 15.4, 10.6,

4.6 Hz, 1H from CH₂CH₂OBn), 3.60 (2H, dt, J = 6.6, 1.2 Hz,

CH₂CH₂CH₂OTBS), 3.72 (1H, dt, J = 9.5, 4.6 Hz, 1H from

CH₂CH₂OBn), 3.91 (1H, ddd, J = 10.6, 9.5, 3.0 Hz, 1H from

CH₂CH₂OBn), 4.18 (1H, s, OH), 4.35 (1H, s, OH), 4.49 (2H, s,

PhCH₂O), 7.30–7.39 (5H, m, 5 Â ArCH); ¹³C NMR (100 MHz, CDCl₃)

d À5.2 (Si(CH₃)₂), 18.3 (CCH₃), 19.4 (SiC(CH₃)₃), 24.3 (CH₂CH₂CH),

26.0 (SiC(CH₃)₃), 28.1 (CH₂CH₂CH₂OTBS), 29.7 (HOC(CH₃)₂), 31.2

(HOC(CH₃)₂), 31.4 (CH₂CH₂CH₂OTBS), 34.7 (CH₂CH₂CH), 35.7

(CH₂CH₂OBn), 49.8 (CCH₃), 54.8 (CH₂CH₂CH), 63.9 (CH₂OTBS),

68.7 (BnOCH₂), 73.1 ((CH₃)₂COH), 73.6 (PhCH₂O), 87.7

(BnOCH₂CH₂COH), 127.9 (2 Â ArCH), 128.0 (ArCH), 128.6

(2 Â ArCH), 137.2 (ArC); MS: m/z (ES+ mode) 487 (67%) [M+Na]⁺,

465 (100%) [M+H]⁺, HRMS Calcd for C₂₇H₄₈O₄NaSi: 487.3220.

Found: 487.3215.

4.6.9. (1R,2S,5S)-2-(3-((tert-Butyldimethylsilyl)oxy)propyl)-1-(2-

hydroxyethyl)-5-(2-hydroxypropan-2-yl)-2-

methylcyclopentanol

46.8

l

L, 0.145 mmol, 2.2 equiv) was added dropwise and the reac-

A solution of benzyl ether 24 (16.7 mg, 0.036 mmol, 1.0 equiv)

and Pd/C (10% activated charcoal) (37.9 mg, 0.036 mmol, 1.0 equiv)

in MeOH (0.84 mL) at rt was degassed with H₂. The reaction mix-

ture was subsequently stirred under an H₂atmosphere for 3 h.

The suspension was ﬁltered through a plug of Celite and washed

through with MeOH (2 Â 5 mL). The organics were concentrated

in vacuo giving the primary alcohol (1R,2S,5S)-2-(3-((tert-butyldi-

methylsilyl)oxy)propyl)-1-(2-hydroxyethyl)-5-(2-hydroxypropan-

2-yl)-2-methylcyclopentanol (12.0 mg, 0.032 mmol, 89%) that was

used without further puriﬁcation. m_max(thin ﬁlm)/cm^À13335 m

(OH), 2953s, 2928s, 2854s, 1471 m, 1377 m, 1254 m, 1097s,

tion stirred for 2 h. The reaction mixture was concentrated in va-

cuo and puriﬁed directly by column chromatography (eluting

with 30% EtOAc in petroleum ether (40–60 °C)) to give the methyl

ester 23 (23.1 mg, 0.050 mmol, 75% over three steps) as a clear oil.

m_max(thin ﬁlm)/cm^À13459w (OH), 1945s, 1912s, 2854 m, 1705 m,

1454w, 1360w, 1254 m, 1199 m, 1177w, 1098s, 937w, 833s,

774 m, 734w; [

a]

_D= À15.1 (c 1.15, CHCl₃); ¹H NMR (400 MHz,

CDCl₃) d 0.06 (6H, s, Si(CH₃)₂), 0.91 (9H, s, SiC(CH₃)₃), 0.99 (3H, s,

CCH₃), 1.11–1.26 (2H, m, CH₂CH₂CH₂OTBS), 1.44–1.63 (3H, m,

CH₂CH₂CH₂OTBS, 1H from CH₂CH₂CH), 1.71–1.78 (1H, m, 1H from

CH₂CH₂CH), 1.83–1.99 (4H, m, CH₂CH₂CH, CH₂CH₂OBn), 2.94 (1H,

dd, J = 10.3, 7.8 Hz, CH₂CH₂CH), 3.53 (3H, s, OCH₃), 3.60 (2H, dt,

J = 6.6, 3.3 Hz, CH₂CH₂CH₂OTBS), 3.67–3.72 (2H, m, CH₂CH₂OBn),

4.45 (2H, s, PhCH₂O), 4.84 (1H, s, OH), 7.26–7.36 (5H, m, 5 Â ArCH);

¹³C NMR (100 MHz, CDCl₃) d À5.2 (Si(CH₃)₂), 18.0 (SiC(CH₃)₃), 18.4

(CCH₃), 25.7 (CH₂CH₂CH), 26.0 (SiC(CH₃)₃), 28.2 (CH₂CH₂CH₂OTBS),

31.4 (CH₂CH₂CH₂OTBS), 33.4 (CH₂CH₂CH), 34.7 (CH₂CH₂OBn), 49.0

(CH₂CH₂CH), 49.3 (CCH₃), 50.0 (OCH₃), 63.8 (CH₂OTBS), 66.9

(BnOCH₂), 73.0 (PhCH₂O), 83.8 (BnOCH₂CH₂COH), 127.4

(2 Â ArCH), 12.5 (ArCH), 127.6 (2 Â ArCH), 138.1 (ArC), 177.1

(C@O); MS: m/z (ES+ mode) 525 (100%), 487 (30%) [M+Na]⁺, 482

(23%) [M+NH₄]⁺, 465 (17%) [M+H]⁺, HRMS Calcd for C₂₆H₄₄O₅SiNa:

487.2856. Found: 487.2862.

937w, 836s, 774 m;

[

a]

_D= À9.0 (c 0.62, CHCl₃); ¹H NMR

(300 MHz, CDCl₃) d 0.00 (6H, s, Si(CH₃)₂), 0.84 (9H, s, SiC(CH₃)₃),

1.00 (3H, s, CCH₃), 1.17 (3H, s, (CH₃)₂COH), 1.17–1.22 (2H, m,

CH₂CH₂CH₂OTBS), 1.33–1.63 (5H, m, CH₂CH₂CH₂OTBS, CH₂CH₂CH,

1H from CH₂CH₂CH), 1.43 (3H, s, (CH₃)₂COH), 1.69–1.81 (2H, m,

1H from CH₂CH₂CH, 1H from CH₂CH₂OH), 1.85–1.91 (1H, m,

CH₂CH₂CH), 2.09–2.19 (1H, m, 1H from CH₂CH₂OH), 2.89 (1H, t,

J = 4.4 Hz, OH), 3.31 (1H, s, OH), 3.55 (2H, t, J = 6.4 Hz,

CH₂CH₂CH₂OTBS), 3.80–3.88 (1H, m, 1H from CH₂CH₂OH), 3.96–

4.01 (1H, m, 1H from CH₂CH₂OH), 4.37 (1H, s, OH); ¹³C NMR

(75 MHz, CDCl₃) d À5.2 (Si(CH₃)₂), 18.3 (CCH₃), 19.3 (SiC(CH₃)₃),

24.5 (CH₂CH₂CH), 26.0 (SiC(CH₃)₃), 28.2 (CH₂CH₂CH₂OTBS), 30.0

(HOC(CH₃)₂), 31.2 (HOC(CH₃)₂), 31.9 (CH₂CH₂CH₂OTBS), 34.7

(CH₂CH₂CH), 37.9 (CH₂CH₂OH), 49.8 (CCH₃), 54.5 (CH₂CH₂CH),

60.7 (CH₂CH₂OH), 63.9 (CH₂OTBS), 74.1 ((CH₃)₂COH), 87.6

(HOCH₂CH₂COH); MS: m/z (ES+ mode) 397 (100%) [M+Na]⁺, 375

(64%) [M+H]⁺, HRMS Calcd for C₂₀H₄₃O₄Si: 375.2925. Found:

375.2937.

4.6.8. (1R,2S,5S)-1-(2-(Benzyloxy)ethyl)-2-(3-((tert-

butyldimethylsilyl)oxy)propyl)-5-(2-hydroxypropan-2-yl)-2-

methylcyclopentanol 24

To

a

stirred solution of methyl ester 23 (3.6 mg,

7.75 Â 10^À3mmol, 1.0 equiv), in Et₂O (0.01 mL) at À78 °C was

added a solution of MeMgBr (3.0 M in Et₂O, 10.3

lL, 0.031 mmol,

4.6.10. (1R,2S,5S)-2-(3-((tert-Butyldimethylsilyl)oxy)propyl)-5-

(2-hydroxypropan-2-yl)-2-methyl-1-vinylcyclopentanol 25

To a stirred solution of (1R,2S,5S)-2-(3-((tert-butyldimethylsi-

lyl)oxy)propyl)-1-(2-hydroxyethyl)-5-(2-hydroxypropan-2-yl)-2-

methylcyclopentanol (30 mg, 0.080 mmol, 1.0 equiv) in THF

(0.3 mL) at room temperature was added 2-nitrophenyl selenocya-

nate(27.3 mg, 0.120 mmol, 1.5 equiv). n-Bu₃P (29.7 lL, 0.120 mmol,

1.5 equiv) was added dropwise, forming a dark red solution, and the

reaction stirred for 36 h. The reaction mixture was cooled to 0 °C and

4.0 equiv). The reaction was warmed to room temperature and

stirred for 4 h. The reaction mixture was cooled to 0 °C and

quenched by the dropwise addition of saturated aqueous NH₄Cl

solution (1.0 mL). The aqueous phase was extracted in 80% EtOAc

in petroleum ether (40–60 °C), (4 Â 2 mL) and the combined or-

ganic phases were dried (MgSO₄), ﬁltered and concentrated in va-

cuo. The crude residue was puriﬁed by column chromatography

(eluting with 30% EtOAc in petroleum ether (40–60 °C)) giving

T. M. Baker et al. / Tetrahedron: Asymmetry 21 (2010) 1246–1261

1259

H₂O₂(30% w/w aq) was added. The reaction was warmed to room

temperature and stirred for 4 h before being quenched by the addi-

tion of saturated aqueous NaHCO₃solution (3.0 mL). The aqueous

phase was extracted with EtOAc (4 Â 5 mL) and the combined

organics were dried (MgSO₄), ﬁltered and concentrated in vacuo.

The crude, yellow oil was puriﬁed by column chromatography (elut-

ing with 20% EtOAc in petroleum ether (40–60 °C)) giving the allylic

methylcyclopentane) (55 mg, 0.142 mmol, 1.0 equiv) in THF

(0.67 mL) at room temperature was added 2-nitrophenyl selenocy-

anate (48.3 mg, 0.212 mmol, 1.5 equiv). n-Bu₃P (52.3

lL,

0.212 mmol, 1.5 equiv) was added dropwise forming a dark red

solution that was stirred for 36 h. The reaction mixture was cooled

to 0 °C and H₂O₂(30% w/w aq 0.08 mL, 0.807 mmol, 5.7 equiv)

added. The reaction was warmed to room temperature and stirred

for 4 h before being quenched by the addition of saturated aqueous

NaHCO₃solution (3.0 mL). The aqueous phase was extracted with

CH₂Cl₂(4 Â 5 mL) and the combined organic phases dried (MgSO₄),

ﬁltered and concentrated in vacuo. The dark yellow oil was puriﬁed

by column chromatography (eluting with 30% EtOAc in petroleum

ether (40–60 °C)) giving the allylic alcohol 26 (45.3 mg,

0.122 mmol, 86%) as a pale yellow oil. m_max(thin ﬁlm)/cm^À1

3479w (OH), 2953s, 2928s, 2854 m, 2357w, 1740 m, 1726 m,

1464 m, 1385 m, 1367 m, 1251s, 1091s, 1034 m, 1004w, 935w,

alcohol 25 (20.7 mg, 0.058 mmol, 72%) as a pale yellow oil. m_max(thin

ﬁlm)/cm^À13390 m (OH), 2953s, 2923s, 2854 m, 2362w, 1528w,

1471 m, 1380w, 1256 m, 1162w, 1098s, 1004w, 937w, 917w,

833s, 774 m; [

a]

_D= À21.8 (c 0.9, CHCl₃); ¹H NMR (300 MHz, CDCl₃)

d 0.06 (6H, s, (Si(CH₃)₂), 0.80 (CCH₃), 0.90 (9H, s, SiC(CH₃)₃), 1.06–

1.13 (1H, m, 1H from CH₂CH₂CH₂OTBS), 1.16 (3H, s, (CH₃)₂COH),

1.23–1.30 (1H, m, 1H from CH₂CH₂CH₂OTBS), 1.33 (3H, s,

(CH₃)₂COH), 1.42–1.52 (2H, m, CH₂CH₂CH₂OTBS), 1.59–1.66 (2H,

m, CH₂CH₂CH), 1.69–1.84 (1H, m, 1H from CH₂CH₂CH), 1.93–2.05

(1H, m, 1H from, CH₂CH₂CH), 2.19 (1H, dd, J = 10.4, 7.4 Hz,

CH₂CH₂CH), 2.91 (1H, s, OH), 3.14 (1H, s, OH), 3.58 (2H, dt, J = 6.4,

2.5 Hz, CH₂CH₂CH₂OTBS), 5.18 (1H, dd, J = 10.9, 1.5 Hz, 1H from

CH@CH₂), 5.27 (1H, dd, J = 17.3, 1.5 Hz, 1H from CH@CH₂), 5.99

(1H, dd, J = 17.3, 10.9 Hz, CH@CH₂); ¹³C NMR (75 MHz, CDCl₃) d

À5.2 (Si(CH₃)₂), 16.6 (CCH₃), 18.3 (SiC(CH₃)₃), 23.1 (CH₂CH₂CH),

26.0 (SiC(CH₃)₃), 28.2 (CH₂CH₂CH₂OTBS), 30.4 (HOC(CH₃)₂), 30.8

(HOC(CH₃)₂), 31.8 (CH₂CH₂CH₂OTBS), 32.8 (CH₂CH₂CH), 51.9

(CCH₃), 53.5 (CH₂CH₂CH), 63.8 (CH₂OTBS), 73.9 ((CH₃)₂COH), 87.2

(CH₂@CHCOH), 112.9 (CH@CH₂), 142.9 (CH@CH₂); MS: m/z (ES+

mode) 357 (100%) [M+H]⁺, HRMS Calcd for C₂₀H₄₁O₃Si: 357.2819.

Found: 357.2829.

920w, 836s, 774 m;

[

a]

_D= À58.7 (c 1.5, CHCl₃); ¹H NMR

(400 MHz, CDCl₃) d 0.05 (6H, s, Si(CH₃)₂), 0.87 (3H, s, CCH₃), 0.90

(9H, s, SiC(CH₃)₃), 1.08–1.17 (1H, m, 1H from CH₂CH₂CH₂OTBS),

1.21–1.30 (1H, m, 1H from CH₂CH₂CH₂OTBS), 1.34–1.41 (1H, m,

1H from CH₂CH₂CH), 1.42–1.51 (2H, m, CH₂CH₂CH₂OTBS), 1.64–

1.69 (2H, m, CH₂CH₂CH), 1.77–1.85 (1H, m, 1H from CH₂CH₂CH),

1.97 (3H, s, CH₃C@O), 2.31 (1H, s, OH), 2.54–2.62 (1H, m,

CH₂CH₂CH), 3.52–3.62 (2H, m, CH₂OTBS), 3.93 (1H, dd, J = 11.4,

6.1 Hz, 1H from CH₂OAc), 4.43 (1H, dd, J = 11.4, 8.8 Hz, 1H from

CH₂OAc), 5.14 (1H, dd, J = 10.8, 1.5 Hz, 1H from CH@CH₂), 5.21

(1H, dd, J = 17.4, 1.5 Hz, 1H from CH@CH₂), 5.87 (1H, dd, J = 17.4,

10.8 Hz, CH@CH₂); ¹³C NMR (100 MHz, CDCl₃) d À5.2 (Si(CH₃)₂),

17.1 (CCH₃), 18.3 (SiC(CH₃)₃), 21.0 (CH₃C@O), 24.3 (CH₂CH₂CH),

26.0 (SiC(CH₃)₃), 28.1 (CH₂CH₂CH₂OTBS), 32.1 (CH₂CH₂CH₂OTBS),

32.7 (CH₂CH₂CH), 45.7 (CH₂CH₂CH), 51.0 (CCH₃), 63.8 (CH₂OTBS),

64.4 (CH₂OAc), 84.4 (CH₂@CHCOH), 113.8 (CH₂@CH), 140.7

(CH₂@CH), 172.1 (CH₃C@O); MS: m/z (ES+ mode) 393 (100%)

[M+Na]⁺, HRMS Calcd for C₂₀H₃₉O₄Si: 371.2612. Found: 371.2615.

4.6.11. ((1S,2R,3S)-1-Acetoxymethyl-3-(3-((tert-

butyldimethylsilyl)oxy)propyl)-2-hydroxy-2-(2-hydroxyethyl)-

3-methylcyclopentane)

To a stirred solution of benzyl ether 22 (21 mg, 0.0439 mmol,

1.0 equiv) in EtOH (0.9 mL) at room temperature was added Pd/C

(10% activated charcoal) (46.2 mg, 0.044 mmol, 1.0 equiv) and the

resulting suspension degassed with H₂. The reaction mixture was

stirred vigorously under H₂for 4 h before being ﬁltered through

Celite, washing through with EtOH (2 Â 5 mL). Concentration of

the organic ﬁltrate gave ((1S,2R,3S)-1-acetoxymethyl-3-(3-((tert-

butyldimethylsilyl)oxy)propyl)-2-hydroxy-2-(2-hydroxyethyl)-3-

methylcyclopentane) (16.6 mg, 0.043 mmol, 97%) that was used

without further puriﬁcation. m_max(thin ﬁlm)/cm^À13424 m (OH),

2953s, 2883w 2854 m, 1738s (C@O), 1716w, 1471 m, 1461 m,

1385 m, 1365 m, 1251s, 1098s, 1031 m, 940w, 833s, 774 m;

4.6.13. (1R,2S,5S)-2-(3-((tert-Butyldimethylsilyl)oxy)propyl)-5-

(hydroxymethyl)-2-methyl-1-vinylcyclopentanol 27

To

a stirred solution of acetate 26 (45 mg, 0.121 mmol,

1.0 equiv) in MeOH (5.8 mL) at room temperature was added

K₂CO₃(50 mg, 0.364 mmol, 3.0 equiv) and the mixture heated to

40 °C for 1 h. The reaction mixture was cooled to room tempera-

ture and concentrated in vacuo and the residue was slurried in

brine (4.0 mL) and extracted with CH₂Cl₂(5 Â 5 mL). The combined

organics were dried (MgSO₄), ﬁltered and concentrated in vacuo

giving the diol 27 (39.6 mg, 0.121 mmol, 100%) as a pale yellow

oil which was used without further puriﬁcation. m_max(thin ﬁlm)/

cm^À13385 m (OH), 2953s, 2928s, 2854 m, 1471 m, 1461 m,

1406w, 1385w, 1254 m, 1098s, 1029w, 1002w, 972w, 937w,

[

a]

_D= À23.4 (c 1.83, CHCl₃); ¹H NMR (400 MHz, CDCl₃) d 0.05

(6H, s, Si(CH₃)₂), 0.89 (9H, s, SiC(CH₃)₃), 1.01 (3H, s, CCH₃), 1.16–

1.27 (3H, m, CH₂CH₂CH₂OTBS, OH), 1.40–1.57 (5H, m,

CH₂CH₂CH₂OTBS, CH₂CH₂CH, 1H from CH₂CH₂CH), 1.71–1.90 (3H,

m, CH₂CH₂OH, 1H from CH₂CH₂CH), 2.06 (3H, s, CH₃C@O), 2.25–

2.32 (1H, m, CH₂CH₂CH), 3.59 (2H, t, J = 6.5 Hz, CH₂CH₂CH₂OTBS),

3.99 (2H, t, J = 5.8 Hz, CH₂CH₂OH), 4.06 (1H, dd, J = 11.1, 7.3 Hz,

1H from CH₂OAc), 4.43 (1H, dd, J = 11.1, 5.8 Hz, 1H from CH₂OAc);

¹³C NMR (100 MHz, CDCl₃) d À5.2 (Si(CH₃)₂), 18.3 (SiC(CH₃)₃), 18.8

(CCH₃), 21.2 (CH₃C@O), 25.4 (CH₂CH₂CH), 26.0 (SiC(CH₃)₃), 28.1

(CH₂CH₂CH₂OTBS), 31.6 (CH₂CH₂CH₂OTBS), 33.3 (CH₂CH₂CH),

36.1 (CH₂CH₂OH), 45.8 (CH₂CH₂CH), 49.7 (CCH₃), 60.4 (CH₂CH₂OH),

63.8 (CH₂OTBS), 66.5 (CH₂OAc), 85.2 (HOCH₂CH₂COH), 171.4

(CH₃C@O); MS: m/z (ES+ mode) 411 (100%) [M+Na]⁺, HRMS Calcd

for C₂₀H₄₀O₅NaSi: 411.2537. Found: 411.2543.

922w, 833s, 774 m;

[

a]

_D= À61.7 (c 0.92, CHCl₃); ¹H NMR

(400 MHz, CDCl₃) d 0.05 (6H, s, Si(CH₃)₂), 0.86 (3H, s, CCH₃), 0.90

(9H, s, SiC(CH₃)₃), 1.12–1.20 (1H, m, 1H from CH₂CH₂CH₂OTBS),

1.26–1.34 (1H, m, 1H from CH₂CH₂CH₂OTBS), 1.46–1.53 (2H, m,

CH₂CH₂CH₂OTBS), 1.61–1.70 (2H, m, CH₂CH₂CH), 1.72–1.80 (2H,

m, CH₂CH₂CH), 2.25 (1H, s, OH), 2.27–2.34 (1H, m, CH₂CH₂CH),

3.54–3.64 (2H, m, CH₂OTBS), 3.70 (1H, dd, J = 11.3, 5.8 Hz, 1H from

CHCH₂OH), 3.82 (1H, dd, J = 11.1, 3.5 Hz, 1H from CHCH₂OH), 5.24

(1H, dd, J = 10.8, 1.5 Hz, 1H from CH@CH₂), 5.35 (1H, dd, J = 17.2,

1.5 Hz, 1H from CH@CH₂), 5.97 (1H, dd, J = 17.2, 10.8 Hz, CH@CH₂);

¹³C NMR (100 MHz, CDCl₃) d À5.2 (Si(CH₃)₂), 17.3 (CCH₃), 18.3

(SiC(CH₃)₃),

22.9

(CH₂CH₂CH),

26.0

(SiC(CH₃)₃),

28.2

4.6.12. (1S,2R,3S)-1-Acetoxymethyl-3-(3-((tert-

butyldimethylsilyl)oxy)propyl)-2-hydroxy-3-methyl-2-

vinylcyclopentane 26

To a stirred solution of ((1S,2R,3S)-1-acetoxymethyl-3-(3-((tert-

butyldimethylsilyl)oxy)propyl)-2-hydroxy-2-(2-hydroxyethyl)-3-

(CH₂CH₂CH₂OTBS), 32.1 (CH₂CH₂CH₂OTBS), 33.5 (CH₂CH₂CH),

46.8 (CH₂CH₂CH), 50.8 (CCH₃), 62.5 (CHCH₂OH), 63.8 (CH₂OTBS),

87.3 (CH₂@CHCOH), 114.3 (CH@CH₂), 140.7 (CH@CH₂); MS: m/z

(ES+ mode) 351 (100%) [M+Na]⁺, 329 (13%) [M+H]⁺.

1260

T. M. Baker et al. / Tetrahedron: Asymmetry 21 (2010) 1246–1261

4.6.14. (4aS,7S,7aR)-7-(3-((tert-Butyldimethylsilyl)oxy)propyl)-

7-methyl-7a-vinylhexahydrocyclopenta[d][1,3]dioxin-2-one 3

To a stirred solution of diol 27 (72 mg, 0.203 mmol, 1.0 equiv) in

CH₂Cl₂(12.8 mL) at room temperature was added pyridine

(7H, m, 7 Â 1H from CH₂), 1.97–2.10 (1H, m, 1H from CH₂), 2.32

(1H, dd, J = 13.8, 11.1 Hz, 1H from CH₂@CCH₂CHOH), 2.40–2.50

(1H, m, CH₂CH₂CH), 2.67 (1H, d, J = 13.8 Hz, 1H from

CH₂@CCH₂CHOH), 2.83 (1H, s, OH), 3.55–3.68 (4H, m, CH₂OTBS,

CHOH, 1H from CH₂@CCH₂OBn), 3.79 (1H, dd, J = 10.8, 2.3 Hz, 1H

from CH₂@CCH₂OBn), 3.96–4.02 (2H, m, CHCH₂O), 4.56 (2H, s,

PhCH₂OCH₂), 5.12 (1H, s, 1H from CH₂@C), 5.22 (1H, s, 1H from

CH₂@C), 7.30–7.40 (5H, m, 5 Â ArCH).

(257

l

L, 3.05 mmol, 15 equiv). The mixture was cooled to À78 °C

and a solution of triphosgene (54.4 mg, 0.203 mmol, 1.0 equiv) in

CH₂Cl₂(6.4 mL) was added dropwise. The reaction was warmed

to room temperature and stirred overnight before being quenched

by the addition of saturated aqueous NH₄Cl solution (6.0 mL). The

aqueous phase was extracted in CH₂Cl₂(5 Â 10 mL) and the com-

bined organic phases were dried (MgSO₄), ﬁltered and concen-

trated in vacuo. The crude product was puriﬁed by column

chromatography (eluting with 20% EtOAc in petroleum ether

(40–60 °C)) giving the allylic carbonate 3 (71.6 mg, 0.202 mmol,

100%) as a pale yellow oil. m_max(thin ﬁlm)/cm^À12955 m, 2929 m,

2858 m, 1755s (C@O), 1472w, 1394w, 1256 m, 1208w, 1132 m,

4.6.16. (1R,2S,5S)-1-(3-((Benzyloxy)methyl)-1-hydroxybut-3-en-

1-yl)-5-(((tert-butyldimethylsilyl)oxy)methyl)-2-(3-((tert-

butyldimethylsilyl)oxy)propyl)-2-methylcyclopentanol

To a stirred solution of the major diastereoisomer of homoallylic

alcohol 24 (6.1 mg, 0.0124 mmol, 1 equiv) in CH₂Cl₂(0.5 mL) at room

temperature was added imidazole (4.0 mg, 0.0588 mmol, 4.7 equiv),

then TBSCl (5.3 mg, 0.0353 mmol, 2.8 equiv) and the reaction stirred

for 3 h. The reaction was quenched by the addition of saturated aque-

ous NaHCO₃solution (2.0 mL) and the aqueous phase extracted with

Et₂O (4 Â 3.0 mL). The combined organics were dried (MgSO₄), ﬁl-

tered and concentrated in vacuo and the crude residue was puriﬁed

by column chromatography (eluting with 10% EtOAc in petroleum

ether (40–60 °C)) to give (1R,2S,5S)-1-(3-((Benzyloxy)methyl)-1-

hydroxybut-3-en-1-yl)-5-(((tert-butyldimethylsilyl)oxy)methyl)-

2-(3-((tert-butyldimethylsilyl)oxy)propyl)-2-methylcyclopentanol

(4.8 mg, 7.9 Â 10^À3mmol, 67%). ¹H NMR (500 MHz, CDCl₃) d 0.04

(6H, s, Si(CH₃)₂), 0.09 (6H, s, Si(CH₃)₂), 0.90 (18H, s, 2 Â SiC(CH₃)₃),

1.03 (3H, s, CCH₃), 1.27–1.34 (2H, m, 2 Â 1H from CH₂), 1.36–1.42

(1H, m, 1H from CH₂), 1.47–1.53 (3H, m, 3 Â 1H from CH₂), 1.59–

1.64 (1H, m, 1H from CH₂), 1.86–1.71 (1H, m, 1H from CH₂), 2.23

(1H, dd, J = 14.2, 11.3 Hz, 1H from CH₂@CCH₂CHOH), 2.30–2.35

(1H, m, CH₂CH₂CH), 2.58 (1H, d, J = 14.2 Hz, 1H from

CH₂@CCH₂CHOH), 3.48–3.53 (1H, m, 1H from CH₂OTBS), 3.56–3.62

(1H, m, 1H from CH₂OTBS), 3.59 (1H, s, OH), 3.75–3.76 (2H, m,

CHCH₂OTBS), 3.83 (1H, ddd, J = 11.3, 3.5, 2.6 Hz, CHOH), 3.99 (1H,

d, J = 12.3 Hz, 1H from CH₂@CCH₂OBn), 4.10–4.12 (2H, m, 1H from

CH₂@CCH₂OBn, OH), 4.49 (1H, d, J = 11.7 Hz, 1H from PhCH₂OCH₂),

4.54 (1H, d, J = 11.7 Hz, 1H from PhCH₂OCH₂), 5.06 (1H, s, 1H from

CH₂@C), 5.15 (1H, s, 1H from CH₂@C), 7.28–7.35 (5H, m, 5 Â ArCH);

MS: m/z (ES+ mode) 629 (100%) [M+Na]⁺, 607 (48%) [M+H]⁺, HRMS

Calcd for C₃₄H₆₃O₅Si₂: 607.4209. Found: 607.4211.

1100 m, 1045w, 1007w, 938w, 836 m, 813w, 776 m; [

a]

_D= À32.8

(c 0.72, CHCl₃); ¹H NMR (400 MHz, CDCl₃) d 0.05 (6H, s, Si(CH₃)₂),

0.09 (9H, s, SiC(CH₃)₃), 1.02 (3H, s, CCH₃), 1.17–1.34 (2H, m,

CH₂CH₂CH₂OTBS), 1.44–1.62 (3H, m, 1H from CH₂CH₂CH,

CH₂CH₂CH₂OTBS), 1.77–1.86 (2H, m, 1H from CH₂CH₂CH, 1H from

CH₂CH₂CH), 1.97–2.08 (1H, m, 1H from CH₂CH₂CH), 2.55 (1H, ddt,

J = 11.2, 6.6, 2.8 Hz, CH₂CH₂CH), 3.54–3.66 (2H, m, CH₂OTBS), 4.18

(1H, dd, J = 11.2, 2.3 Hz, 1H from CH₂OC(O) O), 4.33 (1H, dd,

J = 11.2, 2.8 Hz, 1H from CH₂OC(O)O), 5.41 (1H, dd, J = 11.1,

1.0 Hz, 1H from CH@CH₂), 5.44 (1H, m, 17.2, 1.0 Hz, 1H from

CH@CH₂), 5.83 (1H, dd, J = 17.2, 11.1 Hz, CH@CH₂); ¹³C NMR

(100 MHz, CDCl₃) d À6.3 (Si(CH₃)₂), 16.1 (CCH₃), 17.3 (SiC(CH₃)₃),

22.6 (CH₂CH₂CH), 24.9 (SiC(CH₃)₃), 26.6 (CH₂CH₂CH₂OTBS), 30.5

(CH₂CH₂CH₂OTBS), 32.4 (CH₂CH₂CH), 36.9 (CH₂CH₂CH), 50.6

(CCH₃), 62.3 (CH₂OTBS), 66.3 (CH₂OC(O)O), 96.5 (CH₂@CHCO-

C(O)O), 117.6 (CH@CH₂), 133.0 (CH@CH₂), 148.1 (CH₂OC(O)O);

MS: m/z (ES+ mode) 372 (100%) [M+NH₄]⁺, HRMS Calcd for

C₁₉H₃₄O₄NaSi: 377.2119. Found: 377.2120.

4.6.15. (1R,2S,5S)-1-(3-((Benzyloxy)methyl)-1-hydroxybut-3-en-

1-yl)-2-(3-((tert-butyldimethylsilyl)oxy)propyl)-5-

(hydroxymethyl)-2-methylcyclopentanol 29

A stirred solution of alkene 3 (20 mg, 0.056 mmol, 1.0 equiv) in

CH₂Cl₂(1.0 mL) at À78 °C was degassed with N₂then O₂for 5 min.

Next, O₃was bubbled through the reaction until a persistant blue

colour was observed. The reaction was subsequently degassed with

O₂then N₂until the colour discipated. DMS (0.1 mL) was added

dropwise and the reaction warmed to room temperature and stir-

red for 4 h. The reaction was quenched by the addition of saturated

aqueous NaHCO₃solution (2.0 mL) and the aqueous phase was ex-

tracted in Et₂O (3 Â 4.0 mL). The combined organic phases were

dried (MgSO₄), ﬁltered and concentrated in vacuo giving the alde-

hyde 28 (19 mg, 0.053 mmol, 95%) that was used immediately

without puriﬁcation.

The aldehyde was re-dissolved in a 1:1 mixture of THF/H₂O

(2.0 mL) at room temperature and 2-benzyloxymethyl-3-bromo-

propene (21.8 mg, 0.091 mmol, 1.7 equiv) was added. Indium pow-

der (6.7 mg, 0.059 mmol, 1.1 equiv) was then added and the

reaction stirred vigorously overnight. The reaction was quenched

by the addition of saturated aqueous NH₄Cl solution (2.0 mL) and

the aqueous phase was extracted in EtOAc (4 Â 5 mL) and the com-

bined organic layers dried (MgSO₄), ﬁltered and concentrated in

vacuo. The crude mixture was puriﬁed by chromatography (eluting

in 30% EtOAc in petroleum ether (40–60 °C)) giving the major dia-

stereoisomer of homoallylic alcohol 29 (6.1 mg, 0.0124 mmol, 23%)

as a colourless oil together with a mixture of 29 and another ste-

reoisomer (6.5 mg, 0.0132 mmol, 25%), and a mixture of both ster-

eoisomers from which the TBS group had been lost (4.0 mg,

0.0106 mmol, 20%). ¹H NMR (400 MHz, CDCl₃) d 0.05 (6H, s,

Si(CH₃)₂), 0.90 (9H, s, SiC(CH₃)₃), 1.05 (3H, s, CCH₃), 1.09–1.79

4.6.17. (5R,6S,9S)-4-(2-((Benzyloxy)methyl)allyl)-9-(((tert-butyl

dimethylsilyl)oxy)methyl)-6-(3-((tert-butyldimethylsilyl)

oxy)propyl)-6-methyl-1,3-dioxaspiro[4.4]nonan-2-one 30

To a stirred solution of (1R,2S,5S)-1-(3-((benzyloxy)methyl)-1-

hydroxybut-3-en-1-yl)-5-(((tert-butyldimethylsilyl)oxy)methyl)-

2-(3-((tert-butyldimethylsilyl)oxy)propyl)-2-methylcyclopentanol

(4.8 mg, 7.9 Â 10^À3mmol, 1.0 equiv) in CH₂Cl₂(1.0 mL) at room

temperature was added pyridine (10 lL, 0.119 mmol, 15 equiv).

The reaction was cooled to À78 °C and a solution of triphosgene

(2 mg, 7.9 Â 10^À3mmol, 1.0 equiv) in CH₂Cl₂(0.5 mL) was added

dropwise. The reaction was warmed to room temperature and stir-

red overnight. The reaction was then quenched by the addition of

saturated aqueous NH₄Cl solution (2.0 mL). The aqueous phase was

extracted in CH₂Cl₂(5 Â 3 mL) and the combined organic phases

dried (MgSO₄), ﬁltered and concentrated in vacuo. The crude prod-

uct was puriﬁed by column chromatography (eluting with 5%

EtOAc in petroleum ether (40–60 °C)) giving the spirocyclic car-

bonate 30 (3.4 mg, 5.4 Â 10^À3mmol, 68%) as a colourless oil. m_max

(thin ﬁlm)/cm^À12953 m, 2928 m, 2854 m, 1800 m (C@O), 1468w,

1461w, 1357w, 1256s, 1197 m, 1172 m, 1095s, 836s, 811 m,

720 m; [

a

]

_D= À29.4 (c 0.34, CHCl₃); ¹H NMR (400 MHz, CDCl₃) d

0.05 (6H, s, Si(CH₃)₂), 0.05 (3H, s, Si(CH₃)₂), 0.87 (9H, s, SiC(CH₃)₃),

0.89 (9H, s, SiC(CH₃)₃), 1.14 (3H, s, CCH₃), 1.17–1.27 (1H, m, 1H

from CH₂), 1.37–1.42 (1H, m, 1H from CH₂), 1.48–1.70 (5H, m,

5 Â 1H from CH₂), 1.74–1.85 (1H, m, 1H from CH₂), 2.48–2.57

T. M. Baker et al. / Tetrahedron: Asymmetry 21 (2010) 1246–1261

1261

Springer: Berlin, 1999; p 155; (c) Steel, P. G. J. Chem. Soc., Perkin Trans. 1

2001, 2727; (d) Kagan, H. B. Tetrahedron 2003, 59, 10351; (e) Dahlén, A.;

Hilmersson, G. Eur. J. Inorg. Chem. 2004, 3393; (f) Edmonds, D. J.; Johnston, D.;

Procter, D. J. Chem. Rev. 2004, 104, 3371; (g) Gopalaiah, K.; Kagan, H. B. New J.

Chem. 2008, 32, 607; (h) Nicolaou, K. C.; Ellery, S. P.; Chen, J. S. Angew. Chem.,

Int. Ed. 2009, 48, 7140; (i) Procter, D. J.; Flowers, R. A., II; Skrydstrup, T. Organic

(2H, m, 1H from CH₂@CCH₂OC(O)O, CH₂CH₂CH), 2.70 (1H, d,

J = 14.9 Hz, 1H from CH₂@CCH₂OC(O)O), 3.53–3.62 (2H, m,

CH₂OTBS), 3.62 (1H, dd, J = 10.1 5.5 Hz, 1H from CHCH₂OTBS),

3.82 (1H, dd, J = 10.1, 8.8 Hz, 1H from CHCH₂OTBS), 3.97 (1H, d,

J = 12.1 Hz, 1H from CH₂@CCH₂OBn), 4.07 (1H, d, J = 12.1 Hz, 1H

from CH₂@CCH₂OBn), 4.48 (H, d, J = 12.0 Hz, 1H from PhCH₂O),

4.52 (1H, d, J = 12.0 Hz, 1H from PhCH₂O) 5.09 (1H, s, 1H from

CH₂@C), 5.20 (1H, s, 1H from CH₂@C), 5.24 (1H, dd, J = 11.8,

2.0 Hz, CH₂CHOC(O)O), 7.28–7.38 (5H, m, 5 Â ArCH); ¹³C NMR

(100 MHz, CDCl₃) d À5.7 (Si(CH₃)₂), 5.3 (Si(CH₃)₂), 18.2 (SiC(CH₃)₃),

18.3 (SiC(CH₃)₃), 18.5 (CCH₃), 22.9 (CH₂CH₂CH), 25.9 (SiC(CH₃)₃),

25.9 (SiC(CH₃)₃), 27.7 (CH₂CH₂CH₂OTBS), 30.4 (CH₂CH₂CH₂OTBS),

33.8 (CH₂CH₂CH), 34.3 (CH₂@CCH₂CHO), 47.8 (CHCH₂OTBS), 49.5

(CCH₃), 62.6 (CH₂OTBS), 63.1 (CH₂OTBS), 72.0 (BnOCH₂), 72.8

(PhCH₂O), 81.5 (CHOC(O)O), 96.6 (COC(O)O), 115.6 (C@CH₂),

127.7 (2 Â ArCH), 127.7 (ArCH), 128.4 (2 Â ArCH), 138.1 (ArC),

141.2 (C@CH₂), 154.4 (OC(O)O); MS: m/z (ES+ mode) 655 (100%)

[M+Na]⁺, 652 (72%), 650 (36%) [M+NH₄]⁺, HRMS Calcd for

C₃₅H₆₀O₆NaSi₂: 655.3821. Found: 655.3833.

Synthesis using Samarium Diiodide:

A Practical Guide; RSC Publishing:

Cambridge, 2010.

3. Mori, K.; Iguchi, K.; Yamada, N.; Yamada, Y.; Inouye, Y. Tetrahedron Lett. 1987,

28, 5673.

4. Yabe, T.; Yamada, H.; Shimomura, M.; Miyaoka, H.; Yamada, Y. J. Nat. Prod.

2000, 63, 433.

5. Miyaoka, H.; Baba, T.; Mitome, H.; Yamada, Y. Tetrahedron Lett. 2001, 42, 9233.

6. (a) Hutton, T. K.; Muir, K.; Procter, D. J. Org. Lett. 2002, 4, 2345; (b) Hutton, T. K.;

Muir, K.; Procter, D. J. Org. Lett. 2003, 5, 4811; (c) Guazzelli, G.; Duffy, L. A.;

Procter, D. J. Org. Lett. 2008, 10, 4291.

7. Sloan, L. A.; Baker, T. M.; Macdonald, S. J. F.; Procter, D. J. Synlett 2007, 3155.

8.

a-(Triphenylphosphoraneylidene)-c-butyrolactone was prepared by adapting

the procedure of Baldwin: Baldwin, J. E.; Moloney, M. G.; Parsons, A. F.

Tetrahedron 1992, 48, 9373.

9. (a) Duffy, L. A.; Matsubara, H.; Procter, D. J. J. Am. Chem. Soc. 2008, 130, 1136;

(b) Parmar, D.; Duffy, L. A.; Sadasivam, D. V.; Matsubara, H.; Bradley, P. A.;

Flowers, R. A., II; Procter, D. J. J. Am. Chem. Soc. 2009, 131, 15467.

10. Evans, D. A.; Bartroli, J.; Shih, T. L. J. Am. Chem. Soc. 1981, 103, 2127.

11. Kamenecka, T. M.; Danishefsky, S. J. Angew. Chem., Int. Ed. 1998, 37, 2995.

12. Oxidation of commercially available 3-benzyloxypropan-1-ol gave 16 (py.SO₃,

DMSO, NEt₃, CH₂Cl₂, 78%).

13. Ley, S. V.; Norman, J.; Grifﬁth, W. P.; Marsden, S. P. Synthesis 1994, 639.

14. For a review of the chemistry of samarium enolates, see: Rudkin, I. M.; Miller, L.

C.; Procter, D. J. Organomet. Chem. 2008, 34, 19.

15. CCDC number 747958. The minor diastereoisomer formed in the cascade

reaction is derived from the alternative syn-spirocycle.

16. Evans, D. A.; Rajapakse, H. A.; Stenkamp, D. Angew. Chem., Int. Ed. 2002, 41,

4569.

17. (a) Grieco, P. A.; Gilman, S. J. Org. Chem. 1976, 41, 1485; (b) Crimmins, M. T.;

Tabet, E. A. J. Org. Chem. 2001, 66, 4012.

Acknowledgments

We thank the EPSRC (DTA project studentship, T.M.B.), EPSRC

and GSK (Industrial CASE award, L.A.S), Royal Society (India Fellow-

ship, L.H.C.) and Japan Society for the Promotion of Science (Fel-

lowship, M.M.) and the University of Manchester.

References

18. Ozonolysis of allylic alcohol 27 resulted in decomposition of the starting

material. For examples, see: Jung, M. E.; Davidov, P. Org. Lett. 2001, 3, 627.

19. Green, A. P.; Hardy, S.; Thomas, E. J. Synlett 2008, 2103.

20. Panizza, P.; Onetto, S.; Rodríguez, S. Biocatal. Biotransform. 2007, 25, 414.

21. (a) Wolf, J.; Frenking, G.; Harms, K. Chem. Ber. 1991, 124, 551; (b) Gilleron, P.;

Millet, R.; Domarkas, J.; Farce, A.; Houssin, R.; Hénichart, J. J. Peptide Sci. 2006,

12, 140.

1. (a) Namy, J. L.; Girard, P.; Kagan, H. B. Nouv. J. Chim. 1977, 1, 5; (b) Girard, P.;

Namy, J.-L.; Kagan, H. B. J. Am. Chem. Soc. 1980, 102, 2693.

2. For recent reviews on the use of samarium(II) iodide: (a) Molander, G. A.;

Harris, C. R. Tetrahedron 1998, 54, 3321; (b) Kagan, H.; Namy, J. L. In

Lanthanides: Chemistry and Use in Organic Synthesis; Kobayashi, S., Ed.;

Article Doi

A stereoselective cyclisation cascade mediated by SmI2-H 2O: Synthetic studies towards stolonidiol

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