Synthesis of the bis-spiroacetal moiety of the polyether antibiotic CP44,161

Article abstract of DOI:10.1039/b008159k

The syntheses of bis-spiroacetals 25a, 25c and 40 which constitute the central framework of the polyether antibiotic CP44,161 4, are described. The tricyclic bis-spiroacetal ring is formed by oxidative cyclisation of hydroxyspiroacetal 9 which in turn is assembled from lactone 10 and acetylene 11. The key stereogenic centres in acetylene 11 were assembled using a Sharpless asymmetric dihydroxylation and an Evans asymmetric alkylation of a chiral oxazolidinone. Asymmetric dihydroxylation of alkene 14 using (DHQ)₂PHAL (hydroquinine phthalazine-1,4-diyl diether) led to acetylene 22 which in turn was converted to bis-spiroacetals 25a and 25c. Construction of the isomeric acetylene 11 was effected via Sharpless asymmetric dihydroxylation of alkene 14 using the pseudoenantiomeric chiral ligand (DHQD)₂PHAL which in turn led to the formation of bis-spiroacetal 40 with the same configuration at C-2 as that present in antibiotic CP44,161 4. Barbier addition of bromide 8 to bisspiroacetal aldehyde 27 afforded alcohol 28 which was then converted to polyethers 32 and 33 via an epoxidation cyclization strategy. This latter reaction sequence demonstrated the feasibility of appending the E ring to the tricyclic bis-spiroacetal BCD ring system of antibiotic CP44,161 4.

Full text of DOI:10.1039/b008159k

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Synthesis of the bis-spiroacetal moiety of the polyether antibiotic
CP44,161
Paul R. Allen, Margaret A. Brimble*† and Hishani Prabaharan
1
School of Chemistry, F11, University of Sydney, Camperdown, NSW 2006, Australia
Received (in Cambridge, UK) 10th October 2000, Accepted 7th December 2000
First published as an Advance Article on the web 1st February 2001
The syntheses of bis-spiroacetals 25a, 25c and 40 which constitute the central framework of the polyether
antibiotic CP44,161 4, are described. The tricyclic bis-spiroacetal ring is formed by oxidative cyclisation of
hydroxyspiroacetal 9 which in turn is assembled from lactone 10 and acetylene 11. The key stereogenic centres in
acetylene 11 were assembled using a Sharpless asymmetric dihydroxylation and an Evans asymmetric alkylation
of a chiral oxazolidinone. Asymmetric dihydroxylation of alkene 14 using (DHQ)2PHAL (hydroquinine phthalazine-
1,4-diyl diether) led to acetylene 22 which in turn was converted to bis-spiroacetals 25a and 25c. Construction of
the isomeric acetylene 11 was effected via Sharpless asymmetric dihydroxylation of alkene 14 using the pseudo-
enantiomeric chiral ligand (DHQD)2PHAL which in turn led to the formation of bis-spiroacetal 40 with the
same configuration at C-2 as that present in antibiotic CP44,161 4. Barbier addition of bromide 8 to bis-
spiroacetal aldehyde 27 afforded alcohol 28 which was then converted to polyethers 32 and 33 via an epoxidation
cyclization strategy. This latter reaction sequence demonstrated the feasibility of appending the E ring to the
tricyclic bis-spiroacetal BCD ring system of antibiotic CP44,161 4.
The polyether antibiotics salinomycin 1,1 narasin A 2,2 epi-17-
deoxy-(O-8)-salinomycin 3,3 noboritomycin,4 CP44,161 45 and
X-14766A6 contain a characteristic tricyclic 1,6,8-trioxa-
dispiro[4.1.5.3]pentadec-13-ene bis-spiroacetal ring system in
which two acetal carbons are linked in a spiro fashion. These
polyether antibiotics that contain a bis-spiroacetal moiety play
an important role in the poultry industry as coccidiostats and
are used as feed additives to improve feed utilisation in cattle,
sheep and goats. Whilst the synthesis of polyether ionophores
which contain a simpler bicyclic spiroacetal ring system has
received significant attention7 from the synthetic community,
the synthesis of these polyether antibiotics that contain a more
complex tricyclic bis-spiroacetal has been less explored.8
To date there have been three total syntheses of salinomycin 1
which made use of a stereoselective aldol reaction to construct
the C9–C10 bond. In the first synthesis by Kishi et al.9 the
bis-spiroacetal moiety was formed by assembly of a highly
functionalised dithiane which provided a latent carbonyl group
for the C21 spiro centre. Yonemitsu and co-workers10–13 used
a “chiral pool” approach to prepare salinomycin 1 from
-glucose, -mannitol and (S)-lactic acid using a strategy
wherein the B and E rings were assembled prior to construction
of the bis-spiroacetal system by an acid catalysed cyclisation.
In the most recent approach to salinomycin 1 by Kocienski
and co-workers14–16 the bis-spiroacetal core was constructed
by an elegant oxidative rearrangement of an acylfuran or by
hydrolysis of an allenol ether that was used as an acyl anion
equivalent.
an iodoetherification–ring expansion strategy. Unfortunately
the critical silver-assisted ring expansion of the terminal
tetrahydrofuran ring to a tetrahydropyran ring proved to be
incompatible with the sensitive bis-spiroacetal ring system.
Our recent synthetic endeavours20 have therefore focused on
the synthesis of polyether antibiotic CP44,161 4 which has
a tetrahydrofuran as the terminal E ring thereby avoiding
the necessity to effect the problematic ring expansion in the
presence of a bis-spiroacetal ring system.
Results and discussion
Antibiotic CP44,161 4 has not been synthesised to date and
the bis-spiroacetal ring system has the same stereochemistry
as that present in salinomycin 1. Aside from the aromatic
A ring and the five membered E ring in CP44,161 4, the main
differences between the bis-spiroacetal moieties of these two
molecules is the absence of a hydroxy group in the C ring, the
presence of an additional methyl group in the D ring, and an
ethyl rather than a methyl group in the D ring of antibiotic
CP44,161 4.
The four possible stereoisomers of the bis-spiroacetal ring
system are illustrated (Fig. 1). Diastereomer A depicts the
stereochemistry adopted by salinomycin 1 and CP44,161 4 and
has three stabilising anomeric effects but exhibits unfavourable
1,3-dipole–dipole interactions. 21-epi-Salinomycin and 21-epi-
CP44,161‡ B have only one anomeric effect and is the thermo-
dynamically least stable diastereomer. The 17-epi-diastereomer
C exhibits three anomeric effects and although it exhibits
unfavourable 1,3-diaxial interactions between the C17 oxygen
atom and the C21 methylene it lacks the unfavourable 1,3-
dipole–dipole interactions exhibited by diastereomer A and
17-epi-21-epi-diastereomer D.
Whilst the synthetic approaches to salinomycin 1 by Kishi,
Yonemitsu and Kocienski, have focused on late assembly of the
C ring after appending the D,E rings to the B ring, our synthetic
efforts have focused on the construction of a tricyclic bis-
spiroacetal core containing the B,C,D rings with the idea of
appending the A and E rings at a later stage in the synthesis.17–19
Towards this end we reported19 our model work wherein we
studied the appendage of the E ring to a B,C,D fragment using
This qualitative analysis leads to the assumption that 17-epi-
diastereomer C exhibits the most thermodynamically stable
configuration. It transpires that in the cyclic structure that
† Present address: Department of Chemistry, University of Auckland,
Private Bag 92019, Auckland, New Zealand. Fax: ϩ64 9 3737422;
E-mail: m.brimble@auckland.ac.nz
‡ Note that the numbering system for the bis-spiroacetal ring system
present in salinomycin is also used for antibiotic CP44,161 in order to
facilitate comparisons between the two compounds.
DOI: 10.1039/b008159k
J. Chem. Soc., Perkin Trans. 1, 2001, 379–389
This journal is © The Royal Society of Chemistry 2001
379

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mixture of diastereomeric lactones which rendered further
synthetic manipulation difficult owing to the production of
isomeric product mixtures. It therefore eventuated that we
herein report the conversion of lactone 17 to acetylene 21 which
demonstrates methodology for the synthesis of close analogues
of the bis-spiroacetal moiety of antibiotic CP44,161 4. Intro-
duction of the ethyl group with the correct stereochemistry,
however, needs further attention.
The synthesis of acetylene 21 from lactone 17 proceeded by
reduction with lithium borohydride to afford triol 18 which
afforded acetonide 19 after protection of the 1,2-diol. Oxid-
ation of the remaining primary alcohol then afforded aldehyde
20. Subsequent Grignard addition of prop-2-ynylmagnesium
bromide to aldehyde 20 resulted in the formation of alcohol 21
as a 1:1 mixture of diastereomers which were protected as silyl
ethers 22 in preparation for their union with lactone 10.
With acetylene 22 and lactone 10 in hand, assembly of the
bis-spiroacetal core was effected using methodology previously
applied to the synthesis of the bis-spiroacetal moiety of epi-17-
deoxy-(O-8)-salinomycin 3 (Scheme 3). Addition of the lithium
acetylide derived from acetylene 22 to lactone 10 followed by
treatment of the intermediate lactol with methanol and Amber-
lite IR 118 resin effected hydrolysis of the acetonide group
and formation of more stable methyl acetals as a mixture
of diastereomers that were not separated. After protection of
the primary hydroxy group as an acetate the resultant acetates
23 were readily purified by flash chromatography. Partial
hydrogenation of the alkyne 23 to a cis-olefin followed by acid
catalysed cyclisation resulted in a 1:1 mixture of spiroacetals
24a and 24b (87% yield) that were inseparable by flash chrom-
atography. This initial spirocyclisation is carried out under
thermodynamically controlled conditions such that the most
stable configuration is afforded at the newly fomed spiro centre
owing to maximum stabilisation by the anomeric effect. The
two isomers of spiroacetal 24 therefore only differ in the
position that the side chain adopts.
Spiroacetals 24a and 24b were treated with (diacetoxyiodo)-
benzene and iodine to afford a 3.3:1 mixture of tricyclic bis-
spiroacetals 25a and 25c. The preference for cis bis-spiroacetal
25a in this cyclisation reaction can be attributed to the presence
of the additional methyl group in the D ring, which causes
unfavourable steric interactions upon formation of the minor
trans bis-spiroacetal 25b. trans Bis-spiroacetal 25b therefore
undergoes rapid epimerisation at the allylic spirocentre to cis
bis-spiroacetal 25c. The presence of the additional methyl
group exhibited a marked effect on the stereochemical outcome
of the oxidative cyclisation in that the oxidative cyclisation of
related spiroacetals which lack this methyl group provided the
trans isomer as the major product.17,18
The major bis-spiroacetal 25a isolated from this oxidative
cyclisation has the 17-epi-21-epi-salinomycin stereochemistry
(Fig. 1) whereas the minor cis isomer 25c has the correct bis-
spiroacetal stereochemistry for salinomycin 1 and CP44,161 4.
The proton NMR data support this assignment in that the
vinylic protons in bis-spiroacetal 25a resonate at δ 5.55 (H-13Ј)
and 5.91 (H-14Ј) respectively, whereas H-14Ј in bis-spiroacetal
25c resonates at δ 5.96 whilst H-13Ј resonates further downfield
at δ 6.20 with a similar chemical shift to that observed§ for the
analogous vinylic proton in antibiotic CP44,161 4 (H-14Ј at
δ 5.96 and H-13Ј at 6.06).
In previous total syntheses of salinomycin 1 the correct
stereochemistry for the bis-spiroacetal ring system was only
obtained via a thermodynamically controlled cyclisation after
the whole carbon skeleton of the natural product had been
assembled. Given that it is now well established that long
range hydrogen bonding in the final molecule can dramatic-
ally alter the position of the bis-spiroacetal equilibrium, it
was decided to pursue appendage of the E ring to the major
Fig. 1
salinomycin 1 adopts, the repulsive 1,3-dipolar interactions in
diastereomer A are compensated for by a hydrogen bond
between the C9 and C20 hydroxy groups. Bis-spiroacetals
whose structures preclude this remote hydrogen bond do not
adopt the salinomycin configuration A.
Our synthetic plan (Scheme 1) for the synthesis of CP44,161
4 is based on the same aldol disconnection initially used by
Kishi et al.9 The synthesis of the A ring, namely aldehyde 5, has
already been reported by Kishi et al.21 and Ireland et al.22 in
synthetic studies towards lasalocid A. The right hand fragment
6 is formed by addition of the Grignard reagent of bromide 8 to
bis-spiroacetal aldehyde 7. In turn bis-spiroacetal 7 is antici-
pated to be prepared via oxidative cyclisation of bicyclic spiro-
acetal 9 using methodology previously used in our synthesis of
the bis-spiroacetal moiety of epi-17-deoxy-(O-8)-salinomycin
3.17 Further disconnection of bicyclic hydroxyspiroacetal 9
leads to lactone 10 and acetylene 11.
The synthesis of lactone 10 has already been reported16,17
hence our initial attention focused on the synthesis of acetylene
11. The proposed synthesis of acetylene 11 hinged on introduc-
tion of the methyl group using an Evans asymmetric alkylation
of a chiral oxazolidinone with the oxygen functionality being
introduced using Sharpless asymmetric dihydroxylation
(Scheme 2). The synthesis of the desired acetylene 11 therefore
commenced with the alkylation of propionyloxazolidinone 12
with allyl iodide 13 to form alkene 14 in moderate yield. Based
on the Sharpless mnemonic, asymmetric dihydroxylation23 of
the terminal olefin using potassium osmate and (DHQ)2PHAL,
was expected to afford diol 16, however, it actually transpired
that lactone 17 produced by cyclisation of the unexpected diol
15, was in fact formed. Lactone 17 contains the incorrect
stereochemistry at C5 to that required for the formation of the
desired acetylene 11. It is unclear why the facial selectivity of
dihydroquinine ligands did not follow the Sharpless mnemonic,
however, the presence of the chiral oxazolidinone moiety may
have been a contributing factor.
The stereochemistry of the lactone 17 isolated from the
Sharpless dihydroxylation of alkene 14 using (DHQ)2PHAL
was in fact confirmed by X-ray crystallography in the final
stages of our work after lactone 17 had already been converted
to acetylene 21 and thence to a bis-spiroacetal. Subsequent
re-examination of the Sharpless dihydroxylation of alkene 14
using the complementary (DHQD)2PHAL (hydroquinidine
phthalazine-1,4-diyl diether) ligand (vide infra) afforded a
§ We thank Pfizer for a sample of natural CP44,161 4.
380
J. Chem. Soc., Perkin Trans. 1, 2001, 379–389

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Scheme 1
isomer of the BCD fragment 25a that we had prepared in the
present work.
chloropentanone 36 with sodium hydroxide resulted in cyclis-
ation to cyclopropyl ketone 37 which upon reduction with
lithium aluminium hydride afforded alcohol 38 in 99% yield.
Finally, reaction of alcohol 38 with lithium bromide and
phosphorus tribromide for 2.5 h followed by treatment with
zinc bromide for 2.5 h resulted in the formation of the desired
(E)-bromide 8 in 50% yield.
Applying methodology established in synthetic approaches
to the D and E rings of epi-17-deoxy-(O-8)-salinomycin 3,19 the
union of bromide 8 and aldehyde 27 using a Barbier reac-
tion was attempted next. Barbier reaction using an excess of
bromide 8 with bis-spiroacetal aldehyde 27 resulted in the suc-
cessful synthesis of a 4.7:1 mixture of erythro alcohol 28 and
threo alcohol 29 in 85% yield (Scheme 4). After separation by
flash chromatography the stereochemistry of alcohols 28 and
29 was assigned by comparison with analogous compounds19
whereby the CHOH proton resonated further downfield in the
With the bis-spiroacetal ring assembled, hydrolysis of the
major cis bis-spiroacetal acetate 25a using potassium carbonate
in methanol afforded alcohol 26 in moderate yield. Subse-
quent oxidation using tetrapropylammonium perruthenate and
N-methylmorpholine N-oxide then afforded aldehyde 27 in
preparation for attachment of the terminal tetrahydrofuran E
ring via acid catalysed cyclisation of a γ-hydroxyepoxide
(Scheme 4). Bromide 8 provides the additional carbon atoms
for appendage of this E ring.
The key step in the synthesis of bromide 8 involved a Julia
reaction of alcohol 38 (Scheme 5) as previously used for the
synthesis of a related bromide. Methylation of the anion gen-
erated from 2-acetyl-γ-butyrolactone 34 with methyl iodide
followed by chloride assisted decarboxylation of lactone 35
afforded chloropentanone 36 in 83% yield. Treatment of
J. Chem. Soc., Perkin Trans. 1, 2001, 379–389
381

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i
Scheme 2 Reagents, conditions and yields: (i) nBuLi, Pr2NH, THF,
t
0 ЊC (55%); (ii) K2CO3, K3Fe(CN)6, (DHQ)2PHAL, K2OsO4, BuOH–
H2O, 0 ЊC (77%); (iii) LiBH4, Et2O (63%); (iv) acetone, pTsOH, room
temp. (75%); (v) TPAP, NMO, CH2Cl2 (76%); (vi) prop-2-ynyl bromide,
Mg, HgCl2, Et2O (83%); (vii) TMS–imid, CH2Cl2 (87%).
Scheme 3 Reagents, conditions and yields: (i) nBuLi, Ϫ78 ЊC, THF;
(ii) MeOH, amberlite resin IR 118; (iii) Ac2O, NEt3, CH2Cl2 (37% over
3 steps); (iv) H2, Lindlar, 9:1 pentane–EtOAc; (v) pyridinium toluene-
p-sulfonate, CH2Cl2, room temp. (87% over 2 steps); (vi) PhI(OAc)2, I2,
cyclohexane, hν (46%).
erythro alcohols than the corresponding threo alcohols. In
the present work, H-1Ј in erythro alcohol 28 resonated as a
double doublet at δ 3.59 (J1Ј,2ЈA 8.0 and J1Ј,2ЈB 2.5 Hz) whilst this
same proton in threo alcohol 29 resonated as a double doublet
at δ 3.36 (J1Ј,2ЈA 10.4 and J1Ј,2ЈB 2.0 Hz).
strategy adopted include the oxidative cyclisation of a bicyclic
hydroxyspiroacetal to a bis-spiroacetal which provides cis
bis-spiroacetal aldehyde 25a preferentially; the addition of a
Grignard reagent derived from bis-homoallylic bromide 8
to a neopentyl-like aldehyde 27; and acid catalysed cyclisation
of a γ-hydroxyepoxide to a disubstituted tetrahydrofuran in the
presence of a sensitive bis-spiroacetal.
Treatment of erythro-alcohol 28 with dimethyldioxirane
resulted in an inseparable 1:1 mixture of epoxides 30 and 31
and was confirmed by the characteristic upfield shift of the
resonance assigned to H-5Ј from δ 5.18 in alcohol 28 to δ 3.84–
1
3.89 in the H NMR spectrum of epoxides 30 and 31. Finally,
cyclisation of epoxides 30 and 31 using a catalytic quantity of
pyridinium toluene-p-sulfonate in dichloromethane at 0 ЊC
afforded a 1:1 mixture of polyethers 32 and 33 in 60% yield.
After initial purification by flash chromatography, the indi-
vidual diastereomers were separated by high performance
liquid chromatography.
The stereochemistry of tetrahydrofurans 32 and 33 was con-
firmed by comparison of their 1H NMR spectra with that
observed for related bistetrahydrofurans.19,24,25 The resonances
for H-2Ј and H-1Љ in cis 2,5-disubstituted tetrahydrofurans
occur further downfield than the corresponding resonances for
trans 2,5-disubstituted tetrahydrofurans. In the present case,
H-2Ј in cis 2,5-disubstituted tetrahydrofuran 32 resonated as
a double doublet at δ 4.11 (J2Ј,3ЈA 7.0, J2Ј,3ЈB 7.0 Hz) whilst this
same proton in trans 2,5-disubstituted tetrahydrofuran 33
resonated as a multiplet at δ 4.05–4.09. Furthermore, H-1Љ in
cis 2,5-disubstituted tetrahydrofuran 32 resonated as a quartet
at δ 3.77 (J1Љ,2Љ 6.4 Hz) whilst this same proton was shifted
further upfield and resonated as a multiplet at δH 3.65–3.72 in
trans 2,5-disubstituted tetrahydrofuran 33.
The synthetic work outlined thus far provides a framework
on which to synthesise the bis-spiroacetal moiety of antibiotic
CP44,161 4. Synthesis of the bis-spiroacetal ring system with
the desired (S) stereochemistry at C-2 as required for the syn-
thesis of the natural product CP44,161 4 was next addressed
by examining the key Sharpless asymmetric dihydroxylation
of alkene 14 using the pseudoenantiomeric (DHQD)2PHAL
ligand (Scheme 6).
Treatment of alkene 14 with potassium osmate and
(DHQD)2PHAL afforded lactone 39 in 76% yield as an 83:17
inseparable mixture with lactone 17 presumably via diol 16.
Despite the fact that in this latter case the chirality of the oxazo-
lidinone auxiliary and the Sharpless ligands were clearly “mis-
matched” lactone 39 (albeit as a mixture containing lactone 17)
was converted to acetylene 11 in a similar manner to that
described above for the conversion of lactone 17 to acetylene
22. Although the production of isomeric mixtures was a dif-
ficulty when starting from an isomeric mixture of lactones
in the present case, nevertheless, the synthesis of bis-spiroacetal
41 was demonstrated by subjecting lactone 39 to the same syn-
thetic manipulations that were demonstrated above in the
conversion of lactone 17 to bis-spiroacetal 25.
Polyethers 32 and 33 were thus synthesised from aldehyde
27 and bromide 8. Noteworthy features of the synthetic
382
J. Chem. Soc., Perkin Trans. 1, 2001, 379–389

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Scheme 4 Reagents, conditions and yields: (i) K2CO3, MeOH (53%); (ii) TPAP, NMO (80%); (iii) Mg, Et2O (85%); (iv) dimethyldioxirane, K2CO3,
acetone, 0 ЊC (86%); (v) pyridinium toluene-p-sulfonate, CH2Cl2, 0 ЊC (60%).
CP44,161¶ (D, Fig. 1) and would not be converted to the
configuration present in CP44,161 4 (A, Fig. 1) until after
appendage of the A and E rings to this central fragment.
In summary our synthetic efforts towards the synthesis of the
bis-spiroacetal moiety of the polyether antibiotic CP44,161 4
has unmasked the subtle differences observed in the key spiro-
cyclisation reaction when a simple methyl group is introduced
onto the terminal tetrahydrofuran ring of the bis-spiroacetal
ring system present in salinomycin 1. The syntheses of bis-
spiroacetals 25 and 40 reported herein provide a framework on
which to construct antibiotic CP44,161 4 and analogues thereof
whereby further modification is possible as exemplified by the
conversion of bis-spiroacetal 25 to tetracycle 33.
Experimental
Mps were determined on a Kofler hot-stage apparatus and are
uncorrected. IR spectra were recorded using a Perkin-Elmer
1600 Fourier Transform IR spectrophotometer as thin films
between sodium chloride plates. Absorption spectra are
expressed in wavenumbers (cmϪ1) with the following abbrevi-
1
ations: s = strong, m = medium, w = weak and br = broad. H
NMR spectra were recorded on a Bruker AC 200 (200 MHz) or
a Bruker DRX 400 (400 MHz) spectrometer at ambient tem-
perature. All J-values are given in Hz. Chemical shifts are
expressed in parts per million downfield shift from tetramethyl-
silane as an internal standard, and reported as position
(δH), relative integral, multiplicity (s = singlet, br s = broad
singlet, d = doublet, dd = double doublet, ddd = double double
Scheme 5 Reagents, conditions and yields: (i) Na, MeOH, benzene,
MeI, ∆ (83%); (ii) 14.5% HCl, ∆ (89%); (iii) NaOH, ∆ (58%);
(iv) LiAlH4, 0 ЊC (99%); (v) LiBr, PBr3, 2,4,6-trimethylpyridine,
Et2O, Ϫ50 ЊC to room temp. then ZnBr2, Et2O, Ϫ40 ЊC to room temp.
(50%).
Following a similar procedure to that used for the conversion
of acetylene 22 to spiroacetal 24 (Scheme 3) union of acetylene
11 with lactone 10 afforded bicyclic spiroacetal 9 which then
underwent oxidative cyclisation to afford bis-spiroacetal 40
with the correct (S) stereochemistry at C-2 as present in
¶ Note that the numbering system for the bis-spiroacetal ring system
present in salinomycin is also used for antibiotic CP44,161 in order to
facilitate comparisons between the two compounds.
J. Chem. Soc., Perkin Trans. 1, 2001, 379–389
383

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wise to a solution of sodium iodide (14 g, 94 mmol) in acetone
(100 ml). The reaction was stirred for 16 h at room temperature
then filtered and the filtrate concentrated under reduced pres-
sure. The residue was partitioned between hexane and water
and the organic phase dried over MgSO4. The solvent was
removed under reduced pressure and the residue distilled in a
short path distillation apparatus (20 Torr, 75 ЊC) to give the title
compound 13 (4.28 g, 28%) as an unstable pale brown liquid
that was used immediately upon preparation; δH (200 MHz;
CDCl3) 1.07 (3H, t, J 7.4, CH3), 2.28 (2H, qt, J 7.4 and J 1.0,
CH CH ), 3.94 (2H, s, CH I), 4.91–4.93 (1H, m, ᎐CH H ),
᎐
2
3
2
A
B
5.22–5.23 (1H, m, ᎐CH H ).
᎐
A
B
(2ЈR,4S,5R)-(؊)-3-(2Ј-Methyl-4Ј-ethyl-1Ј-oxopent-4Ј-enyl)-4-
methyl-5-phenyloxazolidin-2-one 14
To a solution of diisopropylamine (1.06 g, 10.5 mmol) in dry
tetrahydrofuran (25 ml), cooled to 0 ЊC under nitrogen, was
added n-butyllithium (6.4 ml of a 1.5 M solution in hexane, 9.62
mmol). After stirring at 0 ЊC for 15 min, the reaction mixture
was cooled to Ϫ78 ЊC, whereupon a solution of (4S,5R)-(Ϫ)-4-
methyl-3-(1Ј-oxopropyl)-5-phenyloxazolidin-2-one28,29 (2.04 g,
8.75 mmol) in dry tetrahydrofuran (10 ml) was added. After
stirring at Ϫ78 ЊC for 20 min, a solution of freshly distilled
iodide 13 (3.43 g, 17.5 mmol) in dry tetrahydrofuran (10 ml)
was added dropwise. The reaction mixture was stirred at
Ϫ78 ЊC for 2.5 h then allowed to warm to room temperature.
After quenching with saturated ammonium chloride solution
(10 ml), the reaction mixture was extracted with ethyl acetate
(3 × 50 ml) and dried over magnesium sulfate. Removal of the
solvent at reduced pressure afforded a yellow oil which was
purified by flash chromatography using hexane–ethyl acetate
(9:1) as eluent to give the title compound 14 (1.46 g, 55%) as a
colourless oil (Found: C, 71.5; H, 7.6; N, 4.5; Mϩ, 301.1712.
C18H23O3N requires C, 71.7; H, 7.7; N, 4.7%; Mϩ, 301.1678);
Scheme 6 Reagents, conditions and yields: (i) K2CO3, K3Fe(CN)6,
t
(DHQD)2PHAL, K2OsO4, BuOH–H2O, 0 ЊC (76%); (ii) LiBH4, Et2O;
(iii) acetone, pTsOH, room temp.; (iv) TPAP, NMO, CH2Cl2; (v) prop-2-
ynyl bromide, Mg, HgCl2, Et2O; (vi) TMS–imid, CH2Cl2; (vii) nBuLi,
Ϫ78 ЊC, THF; (viii) MeOH, amberlite resin IR 118; (ix) Ac2O, NEt3,
CH2Cl2; (x) H2, Lindlar catalyst, 9:1 pentane–EtOAc; (xi) pyridinium
toluene-p-sulfonate, CH2Cl2, room temp.; (xii) PhI(OAc)2, I2, cyclo-
hexane.
[α]D Ϫ34.4 (c 1.0, CH2Cl2); νmax (film)/cmϪ1 3070w (᎐CH), 2968,
᎐
doublet, t = triplet, q = quartet, m = multiplet, qt = quartet of
triplets) and assignment. 13C NMR spectra were recorded on a
Bruker AC 200 (50.3 MHz) or a Bruker DRX 400 (100.5 MHz)
spectrometer at ambient temperature with complete proton
decoupling. Chemical shifts are expressed in parts per million
downfield shift from tetramethylsilane as an internal standard
and reported as position (δC), multiplicity (aided by DEPT135,
DEPT 90, COSY and HETCOR experiments) and assignment.
Low resolution mass spectra were recorded on a VG70-250S,
a VG70-SD or an AEI model MS902 double focusing
magnetic sector mass spectrometer operating with an ionisation
potential of 70 eV (EI, DEI, CI and DCI). High resolution
mass spectra were recorded at nominal resolution of 5000 or
10 000 as appropriate. Major fragments are given as percent-
ages relative to the base peak and assigned where possible.
Ionisation methods employed were either electron impact or
chemical ionisation with ammonia or methane as reagent gas
(CI). Low resolution chemical ionisation mass spectra were also
recorded on a Hewlett Packard 5989A mass spectrometer using
ammonia as reagent gas with the sample dissolved in methanol.
Flash chromatography was performed using Merck Kieselgel
60 (230–400 mesh) with the indicated solvents. Thin layer
chromatography (TLC) was performed using 0.2 mm thick pre-
coated silica gel plates (Merck Kieselgel 60 F254 or Riedel-de
Haen Kieselgel S F254). Compounds were visualised by ultra-
violet fluorescence or by staining with iodine or vanillin in
methanolic sulfuric acid. When NMR data are reported for
isomeric mixtures, resonances for the minor isomer are denoted
by an asterisk (*). 2-(Chloromethyl)but-1-ene was prepared
from 2-ethylprop-2-en-1-ol26 using the chlorination procedure
described by Johnson et al.27
2935, 2877s (CH), 1790s (-OCON), 1694s (-NCOC) and 1646w
(C᎐C); δ (400 MHz; CDCl3) 0.85 (3H, d, J 6.5, 4-Me), 1.03
᎐
H
(3H, t, J 7.4, CH2CH3), 1.17 (3H, d, J 6.8, 2Ј-Me), 2.04–2.10
(3H, m, CH2CH3 and 3Ј-HA), 2.54 (1H, dd, JB,A 14.0, JB,2Ј 7.2,
3Ј-HB), 4.02–4.07 (1H, m, 2Ј-H), 4.73–4.80 (3H, m, 4-H and
5Ј-CH2), 5.65 (1H, d, J 7.3, 5-H) and 7.29–7.43 (5H, m, Ar-H);
δC (100.6 MHz; CDCl3) 12.2, 14.5, 16.9 (CH3, 4-Me, 2Ј-Me and
CH2CH3), 28.5 (CH2, CH2CH3), 35.8 (CH, C-2Ј), 40.2 (CH2,
C-3Ј), 54.8 (CH, C-4), 78.7 (CH, C-5), 109.9 (CH2, C-5Ј), 123.9
(CH, Ar-C), 128.7 (CH, Ar-C), 133.4 (quat., Ar-C), 148.5
(quat., C-4Ј), 152.7 (quat., C-2) and 176.8 (quat., C-1Ј); m/z
(EI) 301 (Mϩ, 17%), 233 (23), 184 (18), 178 (19) and 160 (25).
(3R,5R)-(؊)-3-Methyl-5-ethyl-5-hydroxymethyltetrahydro-
furan-2-one 17
To a suspension of K2CO3 (0.42 g, 3.0 mmol), K3Fe(CN)6
(1.0 g, 3.0 mmol), (DHQ)2PHAL (40 mg, 0.05 mmol) and
K2OsO4ؒ2H2O (3 mg, 0.001 mmol) in 1:1 tert-butanol (2-
methylprop-2-ol)–water (10 ml), cooled to 0 ЊC, was added
alkene 14. After stirring at 0 ЊC for 30 min, the reaction mixture
was quenched with sodium sulfite (2.24 g), allowed to warm to
room temperature, then extracted with ethyl acetate (3 × 20 ml)
and dried over magnesium sulfate. Removal of the solvent at
reduced pressure afforded a pale brown oil which was purified
by flash chromatography with hexane–ethyl acetate (2:1) as
eluent to give the title compound 17 (122 mg, 77%) as a colour-
less oil (Found: C, 60.6; H, 8.6. C8H14O3 requires C, 60.7; H,
8.9%); [α]D Ϫ17.6 (c 1.7, CH2Cl2); νmax (film)/cmϪ1 3640–3077
(br s, OH), 2973, 2937, 2882s (CH) and 1763s (C᎐O); δH (200
᎐
MHz; CDCl3) 0.94 (3H, t, J 7.5, CH2CH3), 1.29 (3H, d, J 7.0,
3-Me), 1.69 (2H, q, J 7.5, CH2CH3), 1.95 (1H, dd, J4A,4B 12.9,
J4A,3 9.9, 4-HA), 2.19 (1H, dd, J4A,4B 12.9, J4B,3 9.9, 4-HB), 2.69–
2.91 (1H, m, 3-H), 3.45 (1H, dd, J1ЈA,1ЈB 12.2, J1ЈA,OH 7.4, 1Ј-HA)
and 3.75 (1H, dd, J1ЈA,1ЈB 12.2, J1ЈB,OH 4.8, 1Ј-HB); δC (100.6
2-(Iodomethyl)but-1-ene 13
2-(Chloromethyl)but-1-ene (8.16 g, 78 mmol) was added drop-
384
J. Chem. Soc., Perkin Trans. 1, 2001, 379–389

View Article Online
MHz; CDCl3) 7.7 (CH3, 3-Me), 16.0 (CH3, CH2CH3), 28.7
(CH2, CH2CH3), 34.4 (CH2, C-4), 35.3 (CH, C-3), 66.4 (CH2, C-
1Ј), 86.7 (quat., C-5) and 179.7 (quat., C-2); m/z (CI, CH4) 159
(MHϩ).
morpholine N-oxide (0.53 g, 4.5 mmol) and powdered 4 Å
molecular sieves (1.6 g). The mixture was stirred at room tem-
perature for 10 min then cooled to 0 ЊC and tetra-n-propyl-
ammonium perruthenate (53 mg, 0.15 mmol) was added. After
stirring at room temperature for 2 h the reaction mixture was
filtered through Celite and the solvent evaporated to give a
colourless oil which was purified by flash chromatography using
hexane–ethyl acetate (9:1) as eluent to give the title compound
20 (458 mg, 76%) as a colourless oil (Found: MHϩ, 201.1483.
(3R,5S)-3-Methyl-5-ethyl-5-hydroxymethyltetrahydrofuran-2-
one 39
The above reaction was repeated using (DHQD)2PHAL instead
of (DHQ)2PHAL to give the title compound 39 which contained
17% of lactone 17 in 76% yield; δH (200 MHz; CDCl3) 0.94 (3H,
t, J 7.5, CH2CH3), 1.26 (3H, d, J 7.3, 3-Me), 1.66–1.76 (3H, m,
CH2CH3, 4-HA), 2.43 (1H, dd, J4A,4B 13.0, J4B,3 10.0, 4-HB),
2.87–3.04 (1H, m, 3-H), 3.58 (1H, d, J1ЈA,1ЈB 12.0, 1Ј-HA) and
3.72 (1H, d, J1ЈA,1ЈB 12.0, 1Ј-HB).
C11H20O3 requires MH, 201.1491); νmax (film)/cmϪ1 1724 (C᎐O);
᎐
δH [200 MHz; (CD3)2CO] 0.86 (3H, t, J 7.4, CH2CH3), 1.06 (3H,
d, J 6.9, 2-Me), 1.28 (3H, s, 2Ј-Me), 1.30 (3H, s, 2Ј-Me), 1.48–
1.78 (4H, m, CH2CH3 and 3-CH2), 2.46–2.55 (1H, m, 2-H), 3.70
(1H, d, J 8.6, 5Ј-HA), 3.82 (1H, d, J 8.6, 5Ј-HB) and 9.58 (1H, d,
J 3.0, CHO); δC [50 MHz; (CD3)2CO] 8.89 (CH3, CH2CH3),
15.8 (CH3, 2-Me), 27.2 (CH3, 2Ј-Me), 27.3 (CH3, 2Ј-Me), 30.7
(CH2, CH2CH3), 39.4 (CH, C-2), 43.0 (CH2, C-3), 73.5 (CH2,
C-5Ј), 83.9 (quat., C-4Ј), 109.7 (quat., C-2Ј) and 204.6 (CH,
CHO); m/z (CI, CH4) 201 (MHϩ, 6%).
(2R,4R)-(؉)-2-Ethyl-4-methylpentane-1,2,5-triol 18
To a solution of lactone 17 (0.83 g, 5.25 mmol) in dry diethyl
ether (200 ml) under nitrogen, was added lithium borohydride
(0.23 g, 10.5 mmol). After stirring for 1 h the reaction mixture
was quenched with water (20 ml). The solvent was removed at
reduced pressure and the residue filtered through a plug of
silica gel using methanol as eluent. Removal of solvent at
reduced pressure afforded a colourless oil that was purified by
flash chromatography using ethyl acetate as eluent to give the
title compound 18 (0.53 g, 63%) as a colourless oil (Found: MHϩ
163.1325. C8H18O3 requires MH, 163.1334); [α]D ϩ14.6 (c 1.3,
CH2Cl2); νmax (film)/cmϪ1 3012–3676 (br s OH) and 2964 (br s,
CH); δH [400 MHz; (CD3)2CO] 0.84 (3H, t, J 7.6, CH2CH3),
0.90 (3H, d, J 6.9, 4-Me), 1.41 (1H, dd, J3A,3B 14.6, J3A,4 4.2,
3-HA), 1.49 (1H, dd, J3B,3A 14.6, J3B,4 7.3, 3-HB), 1.57 (2H,
m, CH2CH3), 1.82–1.94 (1H, m, 4-H), 3.26–3.46 (4H, m,
2 × CH2OH) and 3.59 (1H, t, J 5.8, OH), 3.90 (1H, s, OH), 4.27
(1H, t, J 5.2, OH); δC [100.6 MHz; (CD3)2CO] 8.5 (CH3,
CH2CH3), 19.8 (CH3, 4-Me), 29.7 (CH2, CH2CH3), 31.8 (CH,
C-4), 42.2 (CH2, C-3), 68.1 (CH2, C-5), 69.3 (CH2, C-1) and
74.6 (quat., C-2); m/z (CI, NH3) 163 (MHϩ, 3%).
(2R,3S,4ЈR)- and (2R,3R,4ЈR)-1-(4-Ethyl-2,2-dimethyl-1,3-
dioxolan-4-yl)-2-methylhex-5-yn-3-ol 21
To a suspension of magnesium (11 mg, 0.45 mmol), iodine
(1 mg) and mercuric chloride (1 mg) in dry diethyl ether (1 ml)
under nitrogen was added a solution of prop-2-ynyl bromide
(0.065 ml, 0.45 mmol) in dry diethyl ether (1 ml) dropwise. The
reaction mixture was then cooled to 0 ЊC and a solution of
aldehyde 20 (60 mg, 0.30 mmol) in dry diethyl ether (2 ml)
added. After stirring at room temperature for 30 min the reac-
tion mixture was quenched with saturated ammonium chloride
solution (1 ml), extracted with ethyl acetate (3 × 10 ml), washed
with brine (10 ml) and dried over potassium carbonate.
Removal of solvent at reduced pressure afforded a yellow oil
which was purified by flash chromatography using hexane–ethyl
acetate (8:2) as eluent to give the title compound 21 (63 mg,
83%) as a colourless oil and as a 1:1 mixture of diastereomers
(Found: MHϩ, 241.1776. C14H24O3 requires MH, 241.1804);
δH (400 MHz; CDCl3) 0.84–0.97 (6H, m, CH2CH3, 2-Me), 1.40
(2R,4ЈR)-(؉)-3-(4-Ethyl-2,2-dimethyl-1,3-dioxolan-4-yl)-2-
methylpropan-1-ol 19
(3H, s, 2Ј-Me), 1.41 (3H, s, 2Ј-Me), 1.45–1.81 (4H, m, 2 × CH2),
᎐
1.87–2.04 (2H, m, 2-H and C᎐CH), 2.34–2.42 (2H, m,
᎐
᎐
A solution of triol 18 (0.65 g, 4.0 mmol) in acetone (70 ml) was
treated with toluene-p-sulfonic acid (10 mg, 0.06 mmol). After
stirring the reaction mixture for 1 h, potassium carbonate (1.0
g) was added and stirring continued for 10 min. The solvent was
removed under reduced pressure, the resultant residue dissolved
in ethyl acetate (100 ml) and washed with water (50 ml), satur-
ated potassium carbonate solution (50 ml) and dried over
potassium carbonate. Removal of solvent under reduced
pressure afforded a colourless oil which was purified by flash
chromatography using hexane–ethyl acetate (1:1) as eluent to
give the title compound 19 (0.60 g, 75%) as a colourless oil
(Found: MHϩ 203.1625. C11H22O3 requires MH, 203.1647); [α]D
ϩ5.6 (c 0.18, CH2Cl2); νmax (film)/cmϪ1 3418s (OH), 2934, 2875s
(CH), 1456s, 1369s, 1250s, 1214s and 1052s; δH (400 MHz;
CDCl3) 0.85 (3H, t, J 7.6, CH2CH3), 0.89 (3H, d, J 6.8, 2-Me),
1.40 (3H, s, 2Ј-Me), 1.41 (3H, s, 2Ј-Me), 1.52–1.82 (4H, m,
CH2CH3 and 3-CH2), 1.86–1.96 (1H, m, 2-H), 2.74 (1H, br s,
OH), 3.37 (1H, dd, J1A,1B 11.2, J1A,2 7.6, 1-HA), 3.54 (1H, dd,
J1B,1A 11.2, J1B,2 3.7, 1-HB), 3.64 (1H, d, J 8.6, 5Ј-HA) and 3.90
(1H, d, J 8.6, 5Ј-HB); δC (100.6 MHz; CDCl3) 9.0 (CH3,
CH2CH3), 19.3 (CH3, 2-Me), 26.9 (CH3, 2Ј-Me), 27.1 (CH3,
2Ј-Me), 29.3 (CH2, CH2CH3), 32.0 (CH, C-2), 43.5 (CH2, C-3),
68.9 (CH2, C-1), 73.6 (CH2, C-5Ј), 84.1 (quat., C-4Ј) and 109.5
(quat., C-2Ј); m/z (CI, NH3) 203 (MHϩ, 5%).
CH C᎐C) and 3.49–3.97 (3H, m, 3-H, 5Ј-CH ); δ (100.6 MHz;
᎐
2 2 C
CDCl3) 8.9, 9.1 (CH3, CH2CH3), 15.4, 18.9 (CH3, 2-Me), 23.5,
24.7 (CH2, CH2CH3), 26.7–27.3 (CH3, 2 × 2Ј-Me), 29.4, 29.7
(CH2, C-1), 33.1, 34.1 (CH, C-2), 39.9, 42.4 (CH2, C-4), 69.7,
70.1 (quat., C-5), 71.8, 74.2 (CH2, C-5Ј), 73.5 (CH, C-6), 81.3,
81.8 (CH, C-3), 83.9, 84.1 (quat., C-4Ј) and 109.4, 109.5 (quat.,
C-2Ј); m/z (CI, CH4) 241 (MHϩ, 40%), 183 (20), 143 (40) and
105 (100).
(2R,3S,4ЈR)- and (2R,3R,4ЈR)-1-(4-Ethyl-2,2-dimethyl-1,3-
dioxolan-4-yl)-2-methyl-3-trimethylsilyloxyhex-5-yne 22
To a solution of alcohol 21 (53 mg, 0.22 mmol) in dry dichloro-
methane (10 ml) under nitrogen was added 1-(trimethylsilyl)-
imidazole (0.25 ml, 1.8 mmol). After stirring for 1 h, the
reaction mixture was quenched with water (0.5 ml), washed
with brine (5 ml) and dried over potassium carbonate. Removal
of the solvent at reduced pressure afforded a pale yellow oil
which was purified by flash chromatography using hexane–ethyl
acetate (9:1) as eluent to give the title compound 22 (60 mg,
87%) as a colourless oil (Found: MHϩ, 313.22110. C17H32O3Si
requires MH, 313.21990); δH (400 MHz; CDCl3) 0.13 (9H, s,
Me3Si), 0.87–0.93 (6H, m, CH2CH3 and 2-Me), 1.36 (3H, s,
2Ј-Me), 1.40 (3H, s, 2Ј-Me), 1.52–1.75 (4H, m, 2 × CH2), 1.79–
᎐
1.90 (1H, m, 2-H), 1.94–1.96 (1H, m, C᎐CH), 2.29–2.33 (2H, m,
᎐
᎐
CH C᎐C) and 3.72–3.78 (3H, m, 3-H, 5Ј-CH ); δ (100.6 MHz;
᎐
2
2
C
(2R,4ЈR)-3-(4-Ethyl-2,2-dimethyl-1,3-dioxolan-4-yl)-2-methyl-
propanal 20
CDCl3) 0.4 (CH3, SiMe3), 8.7 (CH3, CH2CH3), 15.9, 17.8 (CH3,
2-Me), 24.0, 24.4 (CH2, CH2CH3), 26.9–27.4 (CH3, 2 × 2Ј-Me),
29.7, 30.0 (CH2, C-1), 34.0, 34.2 (CH, C-2), 38.3, 39.3 (CH2,
C-4), 69.7, 69.8 (quat., C-5), 73.2, 73.3 (CH2, C-5Ј), 75.8, 76.1
To a solution of alcohol 19 (0.60 g, 3.0 mmol) in dichloro-
methane (40 ml) under nitrogen was added N-methyl-
J. Chem. Soc., Perkin Trans. 1, 2001, 379–389
385

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(CH, C-6 and C-3), 84.1, 84.2 (quat., C-4Ј) and 109.1 (quat.,
C-2Ј); m/z (CI, CH4) 313 (MHϩ, 20%), 297 (M Ϫ CH3, 35), 255
(50), 239 (M Ϫ SiCH3, 30), 226 (20) and 215 (100).
(2ЈR,4ЈR,5ЈR,7ЈS,9ЈS,10ЈS,12ЈR,1ЉS)- and (2ЈR,4ЈR,5ЈS,7ЈS,
9ЈS,10ЈS,12ЈR,1ЉS)-{9-[1-(tert-Butyldiphenylsilyloxymethyl)-
propyl]-2-ethyl-4,10,12-trimethyl-1,6,8-trioxadispiro[4.1.5.3]-
pentadec-13-en-2-yl}methyl acetate 25a, 25c
(2R,4R,5S*,2ЈS*,3ЈR,5ЈS,6ЈS,1ЉS)- and (2R,4R,5R*,2ЈS*,
3ЈR,5ЈS,6ЈS,1ЉS)-8-{6-[1-(tert-Butyldiphenylsilyloxymethyl)-
propyl]-2-methoxy-3,5-dimethyltetrahydro-2H-pyran-2-yl}-2-
ethyl-2,5-dihydroxy-4-methyloct-7-yn-1-yl acetate 23
A mixture of spiroacetals 24 (30 mg, 0.045 mmol), iodine (23
mg, 0.09 mmol) and (diacetoxyiodo)benzene (29 mg, 0.09
mmol) in cyclohexane (10 ml) was purged with nitrogen and
irradiated with a 500 W tungsten filament lamp keeping the
temperature maintained at approximately 20 ЊC. After 7 h
the solution was diluted with ether (20 ml), washed with 10%
aqueous sodium thiosulfate (10 ml), water (10 ml), brine (10 ml)
and dried over potassium carbonate. The solvent was evapor-
ated under reduced pressure and the resultant oil purified
by flash chromatography using hexane–ethyl acetate (9:1) as
eluent to afford the following.
To a solution of acetylene 22 (58 mg, 0.185 mmol) in dry tetra-
hydrofuran (5 ml) cooled to Ϫ78 ЊC under nitrogen was added
n-butyllithium (0.14 ml of a 1.3 M solution in hexane, 0.185
mmol) dropwise. After stirring at Ϫ78 ЊC for 1 h, a solution of
lactone 1029 (81 mg, 0.185 mmol) in dry tetrahydrofuran (1 ml)
was added in one portion. After gradually warming to room
temperature over 1.5 h sodium dihydrogen phosphate (10%
aqueous solution, 0.5 ml) was added. The reaction mixture was
extracted with ethyl acetate (3 × 10 ml), washed with brine (10
ml) and dried over potassium carbonate. Removal of solvent at
reduced pressure gave a pale yellow oil which was redissolved
in dry methanol (15 ml) and stirred overnight with amberlite
IR 118 resin. Removal of the resin by filtration followed by
removal of solvent at reduced pressure yielded an orange oil
which was purified by flash chromatography using ethyl acetate
as eluent to afford a triol (89 mg) as a colourless oil. This was
immediately redissolved in dry dichloromethane (10 ml) and
treated with dry triethylamine (0.04 ml, 0.272 mmol) and acetic
anhydride (0.014 ml, 0.15 mmol) and 4-dimethylaminopyridine
(1 mg). The reaction mixture was stirred at room temperature
for 1 h, quenched with water (1 ml), extracted with dichloro-
methane (3 × 10 ml), washed with brine (10 ml) and dried over
anhydrous potassium carbonate. Removal of solvent under
reduced pressure gave a colourless oil which was purified
by flash chromatography using hexane–ethyl acetate (1:1) as
eluent to afford the title compound 23 (90 mg, 37% over 3 steps)
as a colourless oil and as a mixture of diastereomers (Found:
MHϩ, 695.4311. C41H62O7Si requires MH, 695.4343); νmax (film)/
(i) Bis-spiroacetal 25a (10 mg, 36%) as a colourless oil
(Found: MHϩ, 663.4092. C40H58O6Si requires MH, 663.4081);
νmax (film)/cmϪ1 2925s, 2854s (C-H) and 1741s (C᎐O); δ (400
᎐
H
MHz; CDCl3) 0.68 (3H, t, J 7.6, 2Ј-CH2CH3), 0.80 (3H, d, J 6.7,
4Ј-Me), 0.82–0.86 (6H, m, 12Ј-Me, 1Љ-CH2CH3), 0.94 (3H,
d, J 6.7, 10Ј-Me), 1.06 (9H, s, t-Bu), 1.06–1.10 (2H, m, 1Љ-
CH2CH3), 1.26–1.81 (10H, m, 2Ј-CH2CH3, 3Ј-CH2, 11Ј-CH2,
3 × CHMe, CHEt), 1.93–1.99 (1H, m, 15Ј-HA), 2.06 (3H, s,
COCH3), 2.26–2.28 (1H, m, 15Ј-HB), 3.59 (1H, dd, JA,B 10.2,
JA,1Љ 5.8, CHACHBOSi), 3.68 (1H, dd, JB,A 10.2, JB,1Љ 7.4,
CHACHBOSi), 3.78 (1H, d, J9Ј,10Ј 11.8, 9Ј-H), 4.11 (1H, d, JA,B
11.1, CHACHBOAc), 4.14 (1H, d, JB,A 11.1, CHACHBOAc),
5.55 (1H, ddd, J13Ј,14Ј 10.1, J13Ј,15ЈA 1.8, J13Ј,15ЈB 1.8, 13Ј-H), 5.91
(1H, ddd, J14Ј,13Ј 10.1, J14Ј,15ЈA 4.6, J14Ј,15ЈB 4.5, 14Ј-H), 7.35–7.39
(6H, m, Ar-H) and 7.64–7.67 (4H, m, Ar-H); δC (100.6 MHz;
CDCl3) 8.4 (CH3, 2Ј-CH2CH3), 13.0 (CH3, 1Љ-CH2CH3), 14.3
(CH3, 4Ј-Me), 15.8 (CH3, 10Ј-Me), 18.2 (CH3, 12Ј-Me), 18.3
(CH2, 1Љ-CH2CH3), 19.1 (quat., CMe3), 21.0 (CH3, COCH3),
27.0 (CH3, CMe3), 29.1, 29.7, 36.1, 39.2 (CH2, 2Ј-CH2CH3,
C-3Ј, C-11Ј, C-15Ј), 31.8, 39.9, 44.2, 44.7 (CH, C-1Љ, C-4Ј,
C-10Ј, C-12Ј), 65.2 (CH2, CH2OSi), 70.5 (CH2, C-1), 75.2 (CH,
C-9Ј), 82.5 (quat., C-2Ј), 97.4 (quat., C-7Ј), 107.4 (quat., C-5Ј),
124.9 (CH, C-13Ј), 127.2 (CH, Ar-C), 129.5 (CH, Ar-C), 130.5
(CH, C-14Ј), 134.4 (quat., Ar-C), 135.6 (CH, Ar-C), 135.8 (CH,
Ar-C) and 171.1 (quat., C᎐O); m/z (CI, CH ) 663 (MHϩ, 80%)
cmϪ1 3410s (OH), 2241w (C᎐C) and 1740 (C᎐O); δ (200 MHz;
᎐
᎐
᎐
H
CDCl3) 0.62 (3H, t, J 7.6, 2-CH2CH3), 0.75–1.04 (12H, m, 4-Me,
t
3Ј-Me, 5Ј-Me, 1Љ-CH2CH3), 1.05 (9H, s, Bu), 1.22–1.90 (12H,
m, 4 × CH2, 4 × CH), 2.10 (3H, s, CH3CO), 2.21–2.46 (2H, m,
᎐
4
᎐
CH C᎐C), 3.36, 3.37, 3.43, 3.44 (3H, s, CH O), 3.30–4.02 (6H,
and 647 (M Ϫ CH3, 100).
᎐
2
3
m, CH2OAc, CH2OSi, 5-H, 6Ј-H), 7.36–7.41 (6H, m, ArH) and
7.65–7.74 (4H, m, ArH); m/z (CI, CH4) 695 (MHϩ, 4%).
(ii) Bis-spiroacetal 25c (3 mg, 10%) as a colourless oil (Found:
MHϩ, 663.4087. C40H58O6Si requires MH, 663.4081); δH (400
MHz; CDCl3) 0.72–0.89 (15H, m, 5 × CH3), 1.02 (9H, s, t-Bu),
0.96–2.05 (12H, m, 4 × CH2, 3 × CHMe, CHEt), 2.05 (3H, s,
COCH3), 2.16 (1H, dd, J15ЈA,15ЈB 17.2, J15ЈA,14Ј 5.6, 15Ј-HA), 2.34
(1H, ddd, J15ЈA,15ЈB 17.2, J15ЈB,14Ј 2.8, J15ЈB,13Ј 2.8, 15Ј-HB), 3.50–
3.65 (1H, m, CHACHBOSi), 3.79 (1H, d, J9Ј,10Ј 10.5, 9Ј-H), 3.83–
4.07 (1H, m, CHACHBOSi), 4.0 (1H, d, JA,B 10.7, CHACHB-
OAc), 4.30 (1H, d, JB,A 10.7, CHACHBOAc), 5.96 (1H, ddd,
J14Ј,13Ј 10.4, J14Ј,15ЈA 5.6, J14Ј,15ЈB 2.8, 14Ј-H), 6.20 (1H, dd, J13Ј,14Ј
10.4, J13Ј,15ЈB 2.8, 13Ј-H), 7.33–7.39 (6H, m, Ar-H) and 7.64–
7.73 (4H, m, Ar-H); m/z (CI, CH4) 663 (MHϩ, 63%) and 647
(M Ϫ CH3, 100).
(2R,4R,2ЈR,6ЈS,8ЈS,9ЈS,11ЈR,1ЉS)- and (2R,4R,2ЈS,6ЈS,8ЈS,
9ЈS,11ЈR,1ЉS)-4-{8-[1-(tert-Butyldiphenylsilyloxymethyl)-
propyl]-9,11-dimethyl-1,7-dioxaspiro[5.5]undec-4-en-2-yl}-2-
ethyl-2-hydroxypent-1-yl acetate 24
A solution of methyl acetals 23 (48 mg, 0.069 mmol) in dry
pentane (9 ml) and ethyl acetate (1 ml) was stirred with Lindlar
catalyst (2 mg) and potassium carbonate (20 mg) at room tem-
perature under a balloon of hydrogen for 1 h. Removal of the
catalyst by filtration through a short pad of Celite followed by
removal of the solvent at reduced pressure, afforded a colour-
less oil. This was redissolved in dichloromethane (10 ml) and
treated with pyridinium toluene-p-sulfonate (1 mg) at room
temperature for 0.5 h. Evaporation of the solvent at reduced
pressure afforded a pale yellow oil which was purified by flash
chromatography using hexane–ethyl acetate (3:1) as eluent to
afford the title compound 24 (40 mg, 87%) as a mixture of
diastereomers (Found: C, 72.0; H, 8.9. C40H60O6Si requires C,
72.3; H, 9.1%); νmax (film)/cmϪ1 3446 (OH), 3070w (Ar-H),
3050w (᎐CH), 2929s, 2856s (C-H) and 1745s (C᎐O); δ (400
(2ЈS,4ЈR,5ЈR,7ЈS,9ЈS,10ЈS,12ЈR,1ЉS)-{9-[1-(tert-Butyldiphenyl-
silyloxymethyl)propyl]-2-ethyl-4,10,12-trimethyl-1,6,8-trioxa-
dispiro[4.1.5.3]pentadec-13-en-2-yl}methyl acetate 40
A sample of lactone 39 (which contained 17% of lactone 17)
was converted to bis-spiroacetal 40 using the procedures
described above for the conversion of lactone 17 to bis-spiro-
acetal 25a. Bis-spiroacetal 40 was isolated as a colourless oil
(Found: MHϩ, 663.4077. C40H58O6Si requires MH, 663.4081);
δH (400 MHz; CDCl3) 0.67 (3H, t, J 7.6, 2Ј-CH2CH3), 0.81–0.94
(12H, m, 4 × CH3), 1.05 (9H, s, t-Bu), 1.00–2.09 (12H, m,
4 × CH2, 3 × CHMe, CHEt), 2.06 (3H, s, COCH3), 2.18 (1H,
ddd, J15ЈA,15ЈB 17.2, J15ЈA,14Ј 4.8, J15ЈA,13Ј 1.4, 15Ј-HA), 2.27 (1H,
ddd, J15ЈA,15ЈB 17.2, J15ЈB,14Ј 4.4, J15ЈB,13Ј 2.0, 15Ј-HB), 3.57 (1H, dd,
JA,B 10.4, JA,1Љ 6.0, CHACHBOSi), 3.68 (1H, dd, JB,A 10.4, JB,1Љ
᎐
᎐
H
t
MHz; CDCl3) 0.75–0.89 (15H, m, 5 × CH3), 1.06 (9H, s, Bu),
1.20–1.97 (14H, m, 4 × CH, 5 × CH2), 2.04–2.10 (3H, m,
COCH3), 3.07–4.11 (5H, m, CH2OSi, CH2OAc, 8Ј-H), 5.42–
5.45 (1H, m, 5Ј-H), 5.85–5.90 (1H, m, 4Ј-H), 7.35–7.42 (6H, m,
Ar-H) and 7.62–7.71 (4H, m, Ar-H); m/z (CI, CH4) 665 (MHϩ,
12%).
386
J. Chem. Soc., Perkin Trans. 1, 2001, 379–389

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7.2, CHACHBOSi), 3.79 (1H, d, J9Ј,10Ј 10.8, 9Ј-H), 3.93 (2H, s
CH2OAc), 5.56 (1H, ddd, J13Ј,14Ј 10.0, J13Ј,15ЈA 1.6, J13Ј,15ЈB 1.6,
13Ј-H), 5.92 (1H, ddd, J14Ј,13Ј 10.0, J14Ј,15ЈA 4.8, J14Ј,15ЈB 4.4,
14Ј-H), 7.32–7.43 (6H, m, Ar-H) and 7.63–7.67 (4H, m, Ar-H).
(36.2 g, 83%) as a colourless oil, bp 120–122 ЊC/15 mm Hg (lit.30
120–122 ЊC/15 mmHg).
5-Chloro-3-methylpentan-2-one 36
A mixture of 2-acetyl-2-methyl-γ-butyrolactone 35 (36.2 g, 255
mmol), hydrochloric acid (87 ml of a 32% solution, 761 mmol)
and distilled water (103 ml) was carefully heated until all gas
evolution had ceased. The reaction mixture was distilled and
100 ml of distillate collected after which water (75 ml) was
added and a further 60 ml of distillate collected. The organic
layer was separated and the aqueous layer extracted with ether
(3 × 100 ml). The combined organic layers were dried over
calcium chloride and the solvent evaporated to afford the title
compound 36 (30.5 g, 89%) as a colourless oil, bp 69–71 ЊC/19
mmHg (lit.30 70 ЊC/19 mm Hg).
(2ЈR,4ЈR,5ЈR,7ЈS,9ЈS,10ЈS,12ЈR,1ЉS)-{9-[1-(tert-Butyldiphenyl-
silyloxymethyl)propyl]-2-ethyl-4,10,12-trimethyl-1,6,8-trioxa-
dispiro[4.1.5.3]pentadec-13-en-2-yl}methanol 26
To a solution of ester 25a (10 mg, 0.016 mmol) in methanol
(3 ml) was added potassium carbonate (10 mg). The mixture
was stirred at room temperature under nitrogen for 1.5 h. The
suspension was then filtered and the solvent evaporated to give
a yellow oil which was purified by flash chromatography using
hexane–ethyl acetate (19:1) as eluent to afford the title com-
pound 26 (5 mg, 53%) as a colourless oil (Found: MHϩ,
621.3955. C38H56O5Si requires MH, 621.3975); νmax (film)/cmϪ1
3443s (OH); δH (400 MHz; CDCl3) 0.69 (3H, t, J 7.6, 2Ј-
CH2CH3), 0.81–0.87 (9H, m, 4Ј-Me, 12Ј-Me, 1Љ-CH2CH3), 0.96
(3H, d, J 6.0, 10Ј-Me), 1.06 (9H, s, t-Bu), 1.06–1.68 (10H, m,
3 × CH2, 3 × CHMe, CHEt), 1.95–2.09 (2H, m, 3’-CH2), 2.22
(1H, ddd, J15ЈA,15ЈB 16.8, J15ЈA,14Ј 6.0, J15ЈA,13Ј 0.8, 15Ј-HA), 2.40
(1H, ddd, J15ЈA,15ЈB 16.8, J15ЈB,14Ј 2.8, J15ЈB,13Ј 2.8, 15Ј-HB), 3.37–
3.56 (3H, m, CH2OH, CH2OH), 3.59 (1H, dd, JA,B 10.0, JA,1Љ
6.0, CHACHBOSi), 3.70 (1H, dd, JB,A 10.0, JB,1Љ 7.6, CHACHB-
OSi), 3.86 (1H, d, J9Ј,10Ј 10.4, 9Ј-H), 5.49 (1H, ddd, J13Ј,14Ј 10.2,
J13Ј,15ЈB 2.8, J13Ј,15ЈA 0.8, 13Ј-H), 5.87 (1H, ddd, J14Ј,13Ј 10.2, J14Ј,15ЈA
6.0, J14Ј,15ЈB 2.8, 14Ј-H), 7.33–7.43 (6H, m, Ar-H) and 7.64–7.70
(4H, m, Ar-H); m/z (CI, CH4) 621 (MHϩ, 45%), 603 (M Ϫ OH,
100), 543 (M Ϫ Ph, 35) and 279 (65).
1-Acetyl-1-methylcyclopropane 37
Chloride 36 (30.5 g, 227 mmol) was added to a solution of
sodium hydroxide (14.0 g, 350 mmol) in water (18 ml) and the
reaction mixture heated under reflux for 2 h. Water (32 ml) was
added and heating continued for an additional 1.5 h before the
water–ketone mixture was distilled until all the organic layer
was removed from the reaction mixture. The organic layer of
the distillate was separated and the aqueous layer saturated
with solid potassium carbonate. The aqueous layer was
extracted with ether and the combined organic layers dried over
magnesium sulfate and then fractionally distilled to afford the
title compound 37 (13.0 g, 58%) as a colourless liquid, bp 120–
123 ЊC (lit.30 bp 121–124 ЊC).
(2ЈR,4ЈR,5ЈR,7ЈS,9ЈS,10ЈS,12ЈR,1ЉS)-{9-[1-(tert-Butyldiphenyl-
silyloxymethyl)propyl]-2-ethyl-4,10,12-trimethyl-1,6,8-trioxa-
dispiro[4.1.5.3]pentadec-13-en-2-yl}methanal 27
1-(1Ј-Methylcyclopropyl)ethanol 38
A solution of ketone 37 (6 g, 61.2 mmol) in anhydrous ether
(60 ml) was added dropwise to a stirred mixture of lithium
aluminium hydride (2.37 g, 62.5 mmol) in anhydrous ether (215
ml) at 0 ЊC under nitrogen. The reaction mixture was stirred at
this temperature for 2 h then quenched with saturated sodium
sulfate (8 ml). The precipitate was filtered off and washed
several times with ether. The combined ether extracts were dried
over sodium sulfate and the solvent removed at reduced pres-
sure to afford a colourless oil. Further purification by flash
chromatography using pentane–ether (4:1) as eluent afforded
the title compound 38 (6.05 g, 99%) as a colourless oil (Found:
M Ϫ Hϩ, 99.0809. C6H12O requires M Ϫ H, 99.0804); νmax (film)/
cmϪ1 3354br (OH), 2971s, 2876s, 1454s, 1375s, 1106s, 1073s,
1012s and 927s; δH (200 MHz; CDCl3) 0.25–0.42 (4H, m, CH2)
1.01 (3H, s, 1Ј-Me), 1.17 (3H, d, J2,1 6.4, H-2), 1.68 (1H, br s,
OH) and 3.09 (1H, q, J1,2 6.4, CHOH); δC (50 MHz; CDCl3)
10.6, 12.3 (CH2, C-2Ј, C-3Ј), 17.1 (CH3, C-1Љ), 19.4 (CH3, C-2),
21.1 (quat., C-1Ј) and 74.5 (CH, C-1); m/z (EI) 99 (M Ϫ H,
100%), 85 (M Ϫ CH3, 15), 69 (M Ϫ CH3O, 17), 55 (M Ϫ
C2H5O, 20) and 43 (M Ϫ CH3CO, 18).
To a solution of alcohol 26 (5 mg 0.008 mmol) in dichloro-
methane (2 ml) was added N-methylmorpholine N-oxide (1.4
mg, 0.012 mmol) and powdered 4 Å molecular sieves (2 mg).
The mixture was stirred at room temperature for 10 min, cooled
to 0 ЊC then tetra-n-propylammonium perruthenate (ca. 0.14
mg, 4 × 10Ϫ4 mmol) added. The reaction mixture was stirred
at room temperature for 3 h, filtered through Celite and the
solvent evaporated to give an oil which was purified by flash
chromatography using hexane–ethyl acetate (19:1) as eluent to
give the title compound 27 (4 mg, 80%) as an unstable colour-
less oil (Found: MHϩ, 619.3745. C38H54O5Si requires MH,
619.3819); νmax (film)/cmϪ1 1732s (C᎐O); δH (400 MHz; CDCl3)
᎐
0.68 (3H, t, J 7.6, 2Ј-CH2CH3), 0.80 (3H, d, J 6.7, 10Ј-Me or
12Ј-Me), 0.81 (3H, d, J 6.5, 10Ј-Me or 12Ј-Me), 0.87 (3H, t,
J 7.5, 1Љ-CH2CH3), 0.92 (3H, d, J 6.4, 4Ј-Me), 1.05 (9H, s, t-Bu),
1.17–2.06 (12H, m, 4 × CH2, 3 × CHMe, CHEt), 2.31–2.33
(2H, m, 15Ј-HA, 15Ј-HB), 3.57 (1H, dd, JA,B 10.2, JA,1Љ 6.0,
CHACHBOSi), 3.66 (1H, dd, JB,A 10.2, JB,1Љ 9.0, CHACHBOSi),
3.67 (1H, d, J9Ј,10Ј 10.3, 9Ј-H), 5.57 (1H, ddd, J13Ј,14Ј 10.1, J13Ј,15ЈA
2.0, J13Ј,15ЈB 2.0, 13Ј-H), 5.92 (1H, ddd, J14Ј,13Ј 10.1, J14Ј,15ЈA 4.6,
J14Ј,15ЈB 4.6, 14Ј-H), 7.35–7.41 (6H, m, Ar-H), 7.63–7.66 (4H, m,
Ar-H) and 9.72 (1H, s, CHO); m/z (CI, CH4) 619 (MHϩ, 26%)
and 541 (M Ϫ Ph, 28).
(E)-1-Bromo-3-methylpent-3-ene 8
Alcohol 38 (1.46 g, 14.6 mmol) and 2,4,6-trimethylpyridine
(1.98 ml, 14.0 mmol) in anhydrous ether (32 ml) was treated
with lithium bromide (3.29 g, 37.9 mmol) at Ϫ30 ЊC. The
resultant suspension was cooled to Ϫ50 ЊC and phosphorus
tribromide (1.45 ml, 15.3 mmol) added. The reaction mixture
was allowed to warm to 0 ЊC over 1 h and stirred at this tem-
perature for a further 6 h. 2,4,6-Trimethylpyridine (2.3 ml) and
water (10 ml) were added and the aqueous layer extracted with
ether (4 × 15 ml). The combined organic extracts were washed
with saturated sodium bicarbonate (10 ml), brine (10 ml) and
dried over sodium sulfate. Removal of solvent afforded the title
compound 8 (1.17 g, 50%) as a colourless oil that was used
without further purification in the next step (Found: Mϩ,
162.0052. C6H11Br requires M, 162.0045); νmax (film)/cmϪ1
2954s, 2919s, 2861s, 1449s, 1384s, 1267s, 1201s, 1138s and
2-Acetyl-2-methyl-ꢀ-butyrolactone 35
2-Acetyl-γ-butyrolactone 34 (39.3 g, 307 mmol) in anhydrous
benzene (200 ml) was added dropwise to a stirred suspension of
sodium metal (8 g, 348 mmol) in benzene (300 ml) containing
methanol (1.5 ml) under nitrogen. The reaction mixture was
stirred overnight, heated under reflux for 3 h then methyl iodide
(115.8 g, 800 mmol) added. The reaction mixture was heated
under reflux for 4 h, then left stirring overnight at room tem-
perature. Sodium iodide was removed by filtration and washed
several times with ethyl acetate. Evaporation of the combined
filtrates afforded a pale yellow oil that was purified by distil-
lation under reduced pressure to afford the title compound 35
J. Chem. Soc., Perkin Trans. 1, 2001, 379–389
387

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1020s; δH (200 MHz; CDCl3) 1.60 (3H, d, J5,4 6.5, H-5), 1.61
(3H, s, H-1Ј), 2.53 (2H, t, J2,1 7.5, H-2), 3.42 (2H, t, J1,2 7.5, H-1)
and 5.32 (1H, q, J4,5 6.5, H-4); δC (50 MHz; CDCl3) 13.4 (CH3,
C-5), 15.2 (CH3, C-1Ј), 31.7 (CH2, C-1), 42.9 (CH2, C-2), 121.2
(CH, C-4) and 132.6 (quat., C-3); m/z (CI, CH4) 163 (MHϩ,
100%), 135 (M Ϫ C2H3, 10) and 119 (M Ϫ C3H7, 21).
(1H, ddd, J14,13 10.1, J14,15 6.3, J14,15 3.3, H-14), 7.33–7.41
(6H, m, Ar-H) and 7.64–7.68 (4H, m, Ar-H); m/z (LSIMS)
703 (MHϩ, 90%), 685 (M Ϫ OH, 100), 645 (M Ϫ C4H9, 38),
589 (M Ϫ C7H13O, 73), 518 (12), 460 (19), 429 (15) and
391 (47).
(2R,4R,5R,7S,9S,10S,12R,1ЈS,4ЈS,5ЈS,1ЉS)- and (2R,4R,5R,
7S,9S,10S,12R,1ЈR,4ЈR,5ЈR,1ЉS)-9-[1-(tert-Butyldiphenylsilyl-
oxymethyl)propyl]-2-(4,5-epoxy-1-hydroxy-4-methylhexan-1-
yl)-2-ethyl-4,10,12-trimethyl-1,6,8-trioxadispiro[4.1.5.3]penta-
dec-13-ene 30, 31
(E)-(2R,4R,5R,7S,9S,10S,12R,1ЈS,1ЉS)- and (E)-(2R,4R,5R,
7S,9S,10S,12R,1ЈR,1ЉS)-9-[1-(tert-Butyldiphenylsilyloxy-
methyl)propyl]-2-ethyl-2-(1-hydroxy-4-methylhex-4-en-1-yl)-
4,10,12-trimethyl-1,6,8-trioxadispiro[4.1.5.3]pentadec-13-ene
28, 29 [erythro and threo]
Freshly prepared dimethyldioxirane31 (0.5 ml) was added to a
solution of alcohol 28 (2.4 mg, 0.03 mmol) and potassium
carbonate (1 mg) in acetone (0.5 ml) at 0 ЊC. The reaction mix-
ture was stirred for 1 h at 0 ЊC and the solvent removed under
reduced pressure to afford a colourless oil. Purification by flash
chromatography using hexane–ethyl acetate (20:1) containing a
trace of triethylamine as eluent to afford a 1:1 mixture of title
compounds 30 and 31 (2.1 mg, 86%) as a colourless oil (Found:
MHϩ, 719.4713. C44H66O6Si requires MH, 719.4706); νmax
(film)/cmϪ1 3456 (OH), 2947s, 2914s, 2858s, 1458s, 1379s, 1107s
(C-O), 1079s (C-O), 1070s (C-O), 955s (C-O), 944s (C-O) and
915s (C-O); δH (400 MHz; CDCl3) 0.62, 0.64* (3H, t, J2Љ,1Љ 7.6,
2Љ-Me), 0.83 (3H, d, J 6.8, 12-Me), 0.89 (3H, d, J 6.8, 10-Me),
0.90 (3H, t, J 7.0, 3ٞ-Me), 1.01 (3H, d, J 6.8, 4-Me), 1.06, 1.07*
A suspension of magnesium powder (100 mg, 4.35 mmol) in
ether (0.75 ml) was activated by stirring under argon for 12 h.
Bromide 8 (10 mg, 0.06 mmol) was then added to initiate
formation of the alkyl metal reagent. To this, the Barbier mix-
ture, a solution of bromide 8 (5 mg, 0.03 mmol) and aldehyde
27 (3.5 mg, 0.006 mmol) in ether (0.5 ml) was added dropwise
with gentle heating. The reaction mixture was heated gently
under reflux for 2 h, cooled to room temperature then quenched
with ice–water (0.5 ml). The mixture was extracted with ether
(3 × 10 ml) and dichloromethane (3 × 10 ml) and the combined
organic extracts dried over potassium carbonate. The solvent
was removed under reduced pressure to afford a yellow oil
which was purified by flash chromatography using hexane–
ether (20:1) containing a trace of triethylamine as eluent to
afford the following.
(i) (E)-(2R,4R,5R,7S,9S,10S,12R,1ЈS,1ЉS)-9-[1-(tert-Butyl-
diphenylsilyloxymethyl)propyl]-2-ethyl-2-(1-hydroxy-4-methyl-
hex-4-en-1-yl)-4,10,12-trimethyl-1,6,8-trioxadispiro[4.1.5.3]-
pentadec-13-ene 28 [erythro] (2.4 mg, 70%) as a colourless oil
(Found: MHϩ, 703.4739. C44H66O5Si requires MH, 703.4757);
νmax (film)/cmϪ1 3467 (OH), 2928s, 2856s, 1461s, 1428s, 1379s,
1262s (C-O), 1112s (C-O), 1078s (C-O), 955s, 937s and 824s;
δH (400 MHz; CDCl3) 0.63 (3H, t, J2Љ,1Љ 7.6, 2Љ-Me), 0.82 (3H, d,
J 6.8, 12-Me), 0.85 (3H, d, J 7.2, 10-Me), 0.88 (3H, t, J 7.6,
3ٞ-Me), 0.97 (3H, d, J 6.8, 4-Me), 1.00 (3H, d, J 6.4, 6Ј-Me),
1.06 (9H, s, tBu), 1.26 (3H, s, 4Ј-Me), 1.20–2.35 (16H, m, H-3A,
H-3B, H-4, H-10, H-11ax, H-11eq, H-12, H-2ЈA, H-2ЈB, H-3ЈA,
H-3ЈB, H-1ЉA, H-1ЉB, H-1ٞ, H-2ٞA, H-2ٞB), 2.23 (1H, dd, Jgem
16.8, J15,14 6.4, H-15A), 2.43 (1H, ddd, Jgem 16.8, J15,14 2.8, J15,13
2.8, H-15B), 3.55 (1H, dd, Jgem 10.2, J1٣,1ٞ 6.0 Hz, H-1٣B), 3.59
(1H, dd, J1Ј,2ЈA 8.0, J1Ј,2ЈB 2.5, H-1Ј), 3.71 (1H, dd, Jgem 10.2, J1٣,1ٞ
8.0, H-1٣A), 3.81 (1H, s, OH), 3.87 (1H, d, J9ax,10ax 10.4, H-9ax),
5.18 (1H, q, J5Ј,6Ј 6.4, H-5Ј), 5.49 (1H, dd, J13,14 9.9, J13,15 2.2,
H-13), 5.87 (1H, ddd, J14,13 9.9, J14,15 6.4, J14,15 3.2, H-14), 7.35–
7.39 (6H, m, Ar-H) and 7.64–7.68 (4H, m, Ar-H); m/z (LSIMS)
703 (MHϩ, 90%), 685 (M Ϫ OH, 100), 645 (M Ϫ C4H9, 38),
589 (M Ϫ C7H13O, 73), 460 (M Ϫ C14H26O3, 19), 429 (15) and
391 (47).
t
(9H, s, Bu), 1.26 (3H, s, 4Ј-Me), 1.23–1.28 (1H, m, 6Ј-Me),
1.20–2.35 (16H, m, H-3A, H-3B, H-4, H-10, H-11ax, H-11eq,
H-12, H-2ЈA, H-2ЈB, H-3ЈA, H-3ЈB, H-1ЉA, H-1ЉB, H-1ٞ, H-2ٞA,
H-2ٞB), 2.23 (1H, dd, Jgem 17.2, J15,14 6.0, H-15A), 2.43, 2.44*
(1H, ddd, Jgem 17.4, J15,14 3.1, J15,13 3.1, H-15B), 3.53–3.60 (2H,
m, H-1Ј, H-1٣B), 3.71, 3.72* (1H, dd, Jgem 10.4, J1٣,1ٞ 8.0,
H-1٣A), 3.81, 3.82* (1H, s, OH), 3.87, 3.91* (1H, d, J9ax,10ax
10.2, H-9ax), 3.84–3.89 (1H, m, H-5Ј), 5.48, 5.49* (1H, dd, J13,14
10.3, J13,15 2.7, H-13), 5.85–5.89 (1H, m, H-14), 7.33–7.41 (6H,
m, Ar-H) and 7.64–7.67 (4H, m, Ar-H); m/z (LSIMS) 719
(MHϩ, 93%), 701 (M Ϫ OH, 100), 661 (M Ϫ C4H9, 21), 643
(M Ϫ C3H7O2, 28), 590 (22), 544 (8) and 480 (9).
(2R,4R,5R,7S,9S,10S,12R,2ЈS,5ЈR,1ЉS,1ٞS)- and (2R,4R,5R,
7S,9S,10S,12R,2ЈR,5ЈS,1ЉR,1ٞS)-9-[1-(tert-Butyldiphenylsilyl-
oxymethyl)propyl]-2-ethyl-4,10,12-trimethyl-2-[5-methyl-5-(1-
hydroxyethyl)tetrahydro-2-furyl]-1,6,8-trioxadispiro[4.1.5.3]-
pentadec-13-ene 32, 33
Pyridinium toluene-p-sulfonate (1 mg) was added to a solution
of a 1:1 mixture of epoxides 30 and 31 (2 mg, 0.003 mmol) in
dichloromethane (0.5 mL) at 0 ЊC. After stirring for 4 h at room
temperature, the solvent was evaporated and the residue puri-
fied by flash chromatography using hexane–ethyl acetate (9:1)
containing a trace of triethylamine as eluent. Further purifi-
cation by high performance liquid chromatography [Whatman
Partisil 5 (4.6 mm ID × 250 mm)] using hexane–ethyl acetate
(93:7) containing a trace of triethylamine as eluent to afford
the following compounds.
(i) (2R,4R,5R,7S,9S,10S,12R,2ЈS,5ЈR,1ЉS,1ٞS)-9-[1-(tert-
Butyldiphenylsilyloxymethyl)propyl]-2-ethyl-4,10,12-trimethyl-
2-[5-methyl-5-(1-hydroxyethyl)tetrahydro-2-furyl]-1,6,8-trioxa-
dispiro[4.1.5.3]pentadec-13-ene 32 (retention time = 36 min)
as a colourless oil (0.6 mg, 30%) (Found: MHϩ, 719.4684.
C44H66O6Si requires MH, 719.4706); νmax (film)/cmϪ1 3464
(OH), 2938s, 2861s, 1463s, 1393s, 1200s (C-O), 1094s (C-O),
1073s (C-O), 1044s (C-O), 1005s (C-O), 982s (C-O), 943s (C-O)
and 890s (C-O); δH (400 MHz; CDCl3) 0.67 (3H, t, J2ٞ,1ٞ 7.6,
2ٞ-Me), 0.84 (3H, d, J 6.0, 12-Me), 0.86 (3H, t, J 7.8, 3٣-Me),
0.87 (3H, d, J 7.2, 10-Me), 0.98 (3H, d, J 6.4, 4-Me), 1.06 (9H, s,
tBu), 1.09 (3H, d, J2Љ,1Љ 6.4, 2Љ-Me), 1.26 (3H, s, 5Ј-Me), 1.15–
2.50 (16H, m, H-3A, H-3B, H-4, H-10, H-11ax, H-11eq, H-12,
H-3ЈA, H-3ЈB, H-4ЈA, H-4ЈB, H-1ٞA, H-1ٞB, H-1ЉЉ, H-2٣A,
H-2٣B), 2.14 (1H, dd, Jgem 17.0, J15,14 6.2, H-15A), 2.39 (1H,
ddd, Jgem 16.4, J15,14 3.0, J15,13 3.0, H-15B), 3.50 (1H, br s, OH),
(ii)
(E)-(2R,4R,5R,7S,9S,10S,12R,1ЈR,1ЉS)-9-[1-(tert-
Butyldiphenylsilyloxymethyl)propyl]-2-ethyl-2-(1-hydroxy-4-
methylhex-4-en-1-yl)-4,10,12-trimethyl-1,6,8-trioxadispiro-
[4.1.5.3]pentadec-13-ene 29 [threo] (0.5 mg, 15%) as a colour-
less oil (Found: MHϩ, 703.4739. C44H66O5Si requires MH,
703.4757); νmax (film)/cmϪ1 3467 (OH), 2928s, 2856s, 1461s,
1428s, 1379s, 1262s (C-O), 1112s (C-O), 1078s (C-O), 955s,
(C-O), 937s (C-O) and 824s (C-O-C); δH (400 MHz; CDCl3)
0.70 (3H, t, J2Љ,1Љ 7.6, 2Љ-Me), 0.82 (3H, d, J 6.8, 12-Me), 0.85
(3H, d, J 6.4, 10-Me), 0.86 (3H, t, J 7.6, 3ٞ-Me), 0.96 (3H, d,
J 5.8, 6Ј-Me), 0.98 (3H, d, J 6.8, 4-Me), 1.06 (9H, s, tBu), 1.26
(3H, s, 4Ј-Me), 1.20–2.10 (16H, m, H-3A, H-3B, H-4, H-10,
H-11ax, H-11eq, H-12, H-2ЈA, H-2ЈB, H-3ЈA, H-3ЈB, H-1ЉA, H-1ЉB,
H-1ٞ, H-2ٞA, H-2ٞB), 2.22 (1H, dd, Jgem 16.8, J15,14 6.0, H-15A),
2.40 (1H, ddd, Jgem 16.6, J15,14 3.1, J15,13 3.1, H-15B), 3.36 (1H,
dd, J1Ј,2ЈA 10.4, J1Ј,2ЈB 2.0, H-1Ј), 3.60 (1H, dd, Jgem 10.0, J1٣,1ٞ
6.0, H-1٣B), 3.58–3.63 (1H, m, OH), 3.71 (1H, dd, Jgem 10.0,
J1٣,1ٞ 7.6, H-1٣A), 3.86 (1H, d, J9ax,10ax 10.0, H-9ax), 5.23 (1H, q,
J5Ј,6Ј 5.8, H-5Ј), 5.49 (1H, dd, J13,14 10.1, J13,15 2.2, H-13), 5.87
388
J. Chem. Soc., Perkin Trans. 1, 2001, 379–389

View Article Online
5 J. Tone, R. Shibatawa, H. Maeda, K. Inoue, S. Ishiguro,
3.57 (1H, Jgem 10.2, J1Љٞ,1٣ 5.4, H-1ЉٞB), 3.70 (1H, dd, Jgem 10.2,
J1Љٞ,1٣ 8.0, H-1ЉٞA), 3.77 (1H, q, J1Љ,2Љ 6.4, H-1Љ), 3.85 (1H, d,
J9ax,10ax 10.8, H-9ax), 4.11 (1H, dd, J2Ј,3Јa 7.0, J2Ј,3Јb 7.0, H-2Ј),
5.48 (1H, dd, J13,14 9.7, J13,15 2.4, H-13), 5.85 (1H, ddd, J14,13
9.7, J14,15 6.5, J14,15 2.7, H-14), 7.34–7.41 (6H, m, Ar-H) and
7.64–7.67 (4H, m, Ar-H); m/z (LSIMS) 719 (MHϩ, 100%),
701 (M Ϫ OH, 60), 661 (M Ϫ C4H9, 30), 589 (32), 407 (20) and
309 (22).
W. P. Cullen, J. B. Routien, L. R. Chappell, C. E. Moppett,
M. J. Jefferson and W. D. Celmer, 18th Intersociety Conference on
Antimicrobial Agents Chemotherapy, Atlanta, GA, Oct 2–4, 1978.
6 J. W. Westley, R. H. Evans, L. H. Sello, N. Troupe, C.-M. Liu,
J. F. Blount, R. G. Pitcher, T. H. Williams and P. A. Miller,
J. Antibiot., 1981, 34, 139.
7 M. M. Faul and B. E. Huff, Chem. Rev., 2000, 100, 2407.
8 For a review see: M. A. Brimble and F. A. Fares, Tetrahedron, 1999,
55, 7661.
9 Y. Kishi, S. Hatakeyama and M. D. Lewis, in Frontiers of Chemistry,
ed. K. J. Laidler, Pergamon, Oxford, 1982, p. 287.
10 K. Horita, Y. Oikawa and O. Yonemitsu, Chem. Pharm. Bull., 1989,
37, 1698.
11 K. Horita, S. Nagato, Y. Oikawa and O. Yonemitsu, Chem. Pharm.
Bull., 1989, 37, 1705.
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14 R. C. D. Brown and P. J. Kocienski, Synlett, 1994, 415.
15 R. C. D. Brown and P. J. Kocienski, Synlett, 1994, 417.
16 P. J. Kocienski, R. C. D. Brown, A. Pommier, M. Procter and
B. Schmidt, J. Chem. Soc., Perkin Trans. 1, 1998, 9.
17 M. A. Brimble and G. M. Williams, J. Org. Chem., 1992, 57, 5818.
18 P. R. Allen, M. A. Brimble and F. A. Fares, J. Chem. Soc., Perkin
Trans. 1, 1998, 2403.
(ii) (2R,4R,5R,7S,9S,10S,12R,2ЈR,5ЈS,1ЉR,1ٞS)-9-[1-(tert-
Butyldiphenylsilyloxymethyl)propyl]-2-ethyl-4,10,12-trimethyl-
2-[5-methyl-5-(1-hydroxyethyl)tetrahydro-2-furyl]-1,6,8-trioxa-
dispiro[4.1.5.3]pentadec-13-ene 33 (retention time = 12 min) as
a colourless oil (0.6 mg, 30%); νmax (film)/cmϪ1 3462 (OH),
2934s, 2863s, 1466s, 1389s, 1205s (C-O), 1091s (C-O), 1073s
(C-O), 1042s (C-O), 1009s (C-O), 980s (C-O), 942s (C-O) and
892s (C-O); δH (400 MHz; CDCl3) 0.68 (3H, t, J2ٞ,1ٞ 6.4, 2ٞ-Me),
0.81 (3H, d, J 6.4, 12-Me), 0.85 (3H, t, J 7.4, 3٣-Me), 0.89 (3H,
t
d, J 7.6, 10-Me), 0.95 (3H, d, J 6.8, 4-Me), 1.05 (9H, s, Bu),
1.04–1.06 (3H, m, 2Љ-Me), 1.25 (3H, s, 5Ј-Me), 1.11–2.43 (18H,
m, H-3A, H-3B, H-4, H-10, H-11ax, H-11eq, H-12, H-3ЈA,
H-3ЈB, H-4ЈA, H-4ЈB, H-1ٞA, H-1ٞB, H-1٣, H-2٣A, H-2٣B,
H-15A, H-15B), 3.50 (1H, br s, OH), 3.57 (1H, Jgem 10.4, J1٣,1٣
6.0, H-1ЉٞB), 3.65–3.72 (2H, m, H-1Љ, H-1ЉٞA), 3.79 (1H, d,
J9ax,10ax 9.6, H-9ax), 4.05–4.09 (1H, m, H-2Ј), 5.52 (1H, d, J13,14
10.4, H-13), 5.87–5.92 (1H, m, H-14), 7.33–7.41 (6H, m, Ar-H)
and 7.63–7.69 (4H, m, Ar-H); m/z (LSIMS) 719 (MHϩ, 100%),
701 (M Ϫ OH, 63), 661 (M Ϫ C4H9, 35), 589 (29), 407 (23) and
309 (25).
19 M. A. Brimble and H. Prabaharan, J. Chem. Soc., Perkin Trans. 1,
1999, 2795.
20 For an earlier communication see: P. A. Allen, M. A. Brimble and
H. Prabaharan, Synlett, 1999, 295.
21 T. Nakata, G. Schmid, B. Vranesic, M. Okigawa, T. Smith-Palmer
and Y. Kishi, J. Am. Chem. Soc., 1978, 100, 2933.
22 R. E. Ireland, R. C. Anderson, R. Badoud, B. J. Fitzsimmons,
G. J. McGarvey, S. Thaisrivongs and C. S. Wilcox, J. Am. Chem.
Soc., 1983, 105, 1988.
Acknowledgements
23 H. C. Kolb, M. S. Van Nieuwenhze and K. B. Sharpless, Chem. Rev.,
1994, 94, 2483.
24 M. A. Brimble and H. Prabaharan, Tetrahedron, 1998, 54, 2113.
25 M. A. Brimble and M. K. Edmonds, Tetrahedron, 1995, 51, 9995.
26 C. S. Chin, B. Lee, S. Kim and J. Chun, J. Chem. Soc., Dalton Trans.,
1991, 443.
We thank the Australian Research Council and the University
of Sydney for financial support.
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