A convergent synthesis of the [4.4]-spiroacetal-γ-lactones cephalosporolides e and F

Article abstract of DOI:10.1016/j.tet.2010.11.107

A short convergent synthesis of the fungal metabolites cephalosporolides E and F is reported. The key step makes use of a chelation-controlled Mukaiyama aldol reaction to access the key acyclic spiroacetal precursor with the required syn stereochemistry.

Full text of DOI:10.1016/j.tet.2010.11.107

Tetrahedron 67 (2011) 995e1001
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
A convergent synthesis of the [4.4]-spiroacetal-
cephalosporolides E and F
g
-lactones
,
c
,
a
,
,
,
,c
Margaret A. Brimble a , Orla C. Finch c, Amanda M. Heapya c, John D. Fraser b c, Daniel P. Furkert a
,
*
,
c
Patrick D. O’Connor a
a Department of Chemistry, University of Auckland, 23 Symonds Street, Auckland 1142, New Zealand
b Department of Molecular Medicine and Pathology, University of Auckland, 85 Park Rd, Grafton, Auckland 1142, New Zealand
c Maurice Wilkins Centre for Molecular Biodiscovery, University of Auckland, Private Bag 92019, Auckland 1142, New Zealand
a r t i c l e i n f o
a b s t r a c t
Article history:
A short convergent synthesis of the fungal metabolites cephalosporolides E and F is reported. The key
step makes use of a chelation-controlled Mukaiyama aldol reaction to access the key acyclic spiroacetal
precursor with the required syn stereochemistry.
Received 24 September 2010
Received in revised form 12 November 2010
Accepted 30 November 2010
Available online 7 December 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Mukaiyama aldol reaction
Cephalosporolide
Total synthesis
Natural products
1. Introduction
almost 20 years after their initial isolation, cephalosporolides E and
F were independently isolated from the fungus Cordyceps militaris
Cephalosporolides E (1a) and F (1b) were first isolated from the
fungus Cephalosporium aphidicola by Ackland et al. in 1985.1 At this
time only the relative stereochemistry was assigned, however re-
cently the absolute stereochemistry was established as 3S,4S,6S,9R
for cephalosporolide E and 3S,4S,6R,9R for cephalosporolide F by
asymmetric synthesis of the enantiomeric compounds.2 The syn-
thesis of the natural products containing the correct stereochem-
istry has also recently been achieved by Fernandes et al.3 In 2004,
together with a proposed furan metabolite.4 In 2005, the biological
linear precursor to cephalosporolides E and F, (þ)-bassianolone (2)
was isolated from the fungus Beauveria bassiana and it was also
shown that (þ)-bassianolone could be converted to
a di-
astereomeric mixture of cephalosporolide E and F by treatment
with silica (Fig. 1).5 (þ)-Bassianolone was shown to exhibit signif-
icant antimicrobial activity, completely inhibiting the growth of
Staphylococcus aureus and Candida albicans.5
H
Me
O
O
4
3
9
6
O
O
OH
H
OH
H
H
SiO2
O
O
cephalosporolide E (1a)
Me
Me
O
O
O
O
HO
(+)-bassianolone (2)
H
Me
O
6
O
9
4
3
O
O
H
cephalosporolide F (1b)
Fig. 1. (þ)-Bassianolone (2) undergoes silica-catalysed cyclisation to give cephalosporolides E (1a) and F (1b).5
* Corresponding author. E-mail address: m.brimble@auckland.ac.nz (M.A. Brimble).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.11.107

996
M.A. Brimble et al. / Tetrahedron 67 (2011) 995e1001
Fig. 2. Natural products containing the tricyclic
b,
g
-fused-[4.4]-spiroacetal-
g
-lactone structural motif.6e8
H
H
H
The interesting tricyclic
b,g-fused-[4.4]-spiroacetal-g-lactone
Me
Me
O
O
O
O
structural motif present in cephalosporolides E (1a) and F (1b) is
also found in five other natural products (Fig. 2). Ascospiroketal B
(3), isolated in 2007 from the marine fungus Aschochyta sali-
corniae,6 differs from the cephalosporolides (1) by the presence of
geminal methyl, hydroxymethylene disubstitution at the position
O
O
O
O
H
1b
1a
O
a
to the g-lactone and an elaborate tail of undefined stereochem-
O
O
istry at C-9 in the spiroacetal. Penisporolides A (4) and B (5), also
isolated in 2007, from the marine derived fungus Penicillium sp. also
possess the same ring system.7 Penisporolides A and B both contain
Me
OTBS
OTBS
8
geminal dimethyl groups at the position
a to the g-lactone with
penisporolide A containing a 50-hydroxyheptyl side chain at C-9
whilst penisporolide B contains a 30-oxohexyl substituent at C-9.
Finally, cephalosporolides H (6) and I (7),8 were also isolated in
2007 from the marine derived fungus Penicillium sp. Both com-
modified Fukuyama
reaction + reduction
Fukuyama
reaction
O
H
Me
ZnI
Me
O
O
pounds contain a geminal dimethyl group at the position
lactone. Cephalosporolide H bears a saturated heptyl chain at C-9
and cephalosporolide I contains a butanoic acid side chain at C-9.
a to the g-
OTBS
OTBS
EtS
OTBS
10
11
9
Scheme 1. Retrosynthesis of cephalosporolides E (1a) and F (1b), using a Fukuyama
reaction.9,10
2. Results and discussion
b,g
-unsaturated methyl ester 12,11 the substrate required for the key
Sharpless asymmetric dihydroxylation12 that allowed installation of
the key stereocentres at C-3 and C-4 (Scheme 2). Sharpless asym-
metric dihydroxylation using (DHQ)2Phal, followed by in situ lac-
tonisation directly afforded lactone 13 in 86% yield with >95% ee.13
Protection of the secondary alcohol 13 followed by removal of the
benzyl group by hydrogenation afforded primary alcohol 14. Oxi-
dation to the carboxylic acid using TEMPO14 and conversion to the
desired thioester 10 then proceeded optimally using DIC, ethane-
thiol and HOBt in dichloromethane. The formation of side products,
presumably resulting from E1cB elimination of the secondary OTBS
group and E1cB opening of the lactone ring, originating by depro-
Our initial retrosynthesis for cephalosporolides E (1a) and F (1b)
(Scheme 1) hinged on accessing linear precursor 8. It was intended
that the [4.4]-spiroacetal be assembled in the final step via acid-
catalysed deprotection and cyclisation of protected ketone 8. Ke-
tone 8 in turn would be accessed via Fukuyama reaction9 between
alkyl zinc iodide 9 and thioester 10 that bears the preformed
g-lactone functionality. Disappointingly, the initial Fukuyama
coupling reaction proved unsuccessful in our hands, however
a modified Fukuyama reaction10 between alkyne 11 and thioester
10 afforded ketone 8 after reduction of the resultant alkyne.
Applying the retrosynthesis summarised in Scheme 1, the com-
mon thioester intermediate 10 was prepared in nine steps starting
from butane-1,4-diol. Butane-1,4-diol was converted to known
tonation
a to the thioester, contributed to the moderate yields
obtained for this step.
Scheme 2. Modified Fukuyama reaction and attempted global TBS deprotection of 8. Reagents and conditions: (a) (DHQ)2Phal, K3Fe(CN)6, K2CO3, MeSO2NH2, OsO4, tBuOH/H2O, 0 ꢀC,
86%, >95% ee; (b) TBSCl, NEt3, DMAP, CH2Cl2, rt, 3 days, 72%; (c) H2 (60 psi), Pd/C, EtOH, rt, 6 h, 95%; (d) TEMPO, NaClO2, NaOCl, MeCN, pH 6.7 phosphate buffer, 35 ꢀC, 3 h, 95%; (e)
DIC, HOBt, EtSH, CH2Cl2, 0 ꢀC/rt, 52%; (f) CuI (2.2 equiv), PdCl2(dppf) (0.1 equiv), P(2-furyl)3 (0.25 equiv), DMF, NEt3, alkyne 11, 34%; (g) Pd/C, H2, EtOAc, 60 psi, 2 h, 75%.

M.A. Brimble et al. / Tetrahedron 67 (2011) 995e1001
997
Initial attempts to access saturated ketone 8 directly, by reaction
of thioester 10 with zinc iodide 9 using the Fukuyama reaction9
were unsuccessful. Alternatively, TBS protected alkyne 11 was
coupled with thioester 10 using a modified Fukuyama strategy10 to
provide ynone 15 albeit in only 34% yield. Complete reduction of
the alkyne moiety afforded the desired cyclisation precursor, ke-
enantiomeric excess of the HKR was established at a later stage by
chiral HPLC analysis of methyl ketone 17 (vide infra). Epoxide 20
was opened at the terminal position by the addition of an allyl
cuprate reagent and the newly-formed secondary alcohol treated
with sodium hydride and benzyl bromide to afford benzyl ether 21
(60% for two steps). Terminal olefin 21 was then subjected to
Wacker oxidation (PdCl2, CuCl, O2)18 to afford methyl ketone 17 in
93% ee as determined by chiral HPLC analysis.
tone 8. Due to the sensitivity of keto-g-lactone 8, all attempts to
effect double TBS deprotection to form (þ)-bassianolone (2) only
afforded complex mixtures of undesired products.
With methyl ketone 17 in hand, attention turned to the synthesis
of the aldol coupling partner, namely aldehyde 18 (Scheme 5). Al-
dehyde 18 was prepared in four steps from (S)-malic acid 22. The
Analogous compounds were synthesised using a methox-
ymethyl (MOM) protecting group strategy in place of OTBS, how-
ever the final acid-catalysed deprotection and cyclisation to afford
(þ)-bassianolone (2) or cephalosporolides E (1a) or F (1b) proved
unrewarding. To circumvent these problems, an alternative syn-
thetic strategy was devised in which the two secondary hydroxyl
protecting groups could be removed under neutral conditions with
the sensitive lactone functionality installed in the final stages of the
synthesis. It was thus anticipated that cephalosporolides E (1a) and
F (1b) could be obtained as a separable mixture of diastereomers
upon debenzylation, in situ spirocyclisation, followed by lactoni-
sation of the acyclic precursor 16 (Scheme 3). The 3,4-syn stereo-
base sensitive b-hydroxy ester 23 dictated the use of acid-catalysed
benzyl protection conditions, hence alcohol 23 was treated with
benzyl trichloroacetimidate in the presence of TfOH to afford benzyl
ether 24.19 The best results were achieved by reaction of alcohol
23 with freshly prepared benzyl trichloroacetimidate20 in the
presence of a catalytic quantity (10 mol %) of TfOH for 2 days at room
temperature. Chelation-controlled reduction of 24 using DIBAL
(2.5 equiv) in the presence of MgBr2$OEt2 at ꢁ8 ꢀC selectively
reduced the methyl ester
a to the neighbouring alkoxy group thus
affording alcohol 25 exclusively. The use of more than 2.5 equiv of
DIBAL resulted in undesired reduction of the second methyl ester.
Direct formation of aldehyde 18 byconducting the reaction at ꢁ90 ꢀC
using 1.0 equiv of DIBAL did not proceed cleanly and only a mixture
of alcohol 25 and aldehyde 18 was observed.21 Oxidation of primary
alcohol 25 proved to be problematic, however aldehyde 18 was
finally obtained using a TEMPO-catalysed oxidation procedure; PCC,
Swern, DMP and IBX oxidation conditions were all unsuccessful. The
chemistry in
b-hydroxyketone 16 would be installed by syn
selective Mukaiyama aldol reaction15 between the silyl enol ether
derivative of methyl ketone 17 with aldehyde 18.16
H
Me
O
O
O
O
O
highly sensitive nature of similar
a-alkoxy aldehydes has previously
H
been reported by other groups.22
1
OH
Me
OMe
OBn
OBn
O
16
O
O
OMe
Me
H
Me
Scheme 5. Synthesis of aldol coupling partner aldehyde 18. Reagents and conditions:
(a) MeOH, AcCl, rt, 18 h, 80%; (b) benzyl trichloroacetimidate, CH2Cl2, cyclohexane,
TfOH, rt, 24 h, 74%; (c) DIBAL-H, (2.5 equiv), CH2Cl2, MgBr2$Et2O, ꢁ78 ꢀC/0 ꢀC, 2 h,
53%; (d) TEMPO, TCIA, NaHCO3, ꢁ5 ꢀC, 1 h, 70%.
OBn
18
O
OBn
17
Scheme 3. Revised retrosynthesis of cephalosporolides E (1a) and F (1b).
Armed with aldol coupling partners 17 and 18, attention turned
to the key stereoselective aldol reaction (Scheme 6).15 After initial
failure to effect a direct aldol reaction using LDA or LHMDS, the TMS
enol ether 26 was prepared by exposure of ketone 17 to TMSOTf in
the presence of triethylamine.23 Use of TMSCl under a variety of
conditions was unsuccessful. Gratifyingly, subsequent Mukaiyama
The synthesis of methyl ketone 17 began with hydrolytic kinetic
resolution (HKR) of propylene oxide 19 (Scheme 4).17 Treatment of
terminal epoxide 19 with the (R,R)-cobalt salen complex A17 pro-
vided enantioenriched (R)-epoxide 20 that could easily be sepa-
rated from the (S)-diol by distillation at atmospheric pressure. The
H
H
N
O
N
Co
O
tBu
tBu
Me
tBu
tBu
A
O
Me
a
Me
b, c
Me
d
Me
O
O
OBn
OBn
20
19
21
17
Scheme 4. Synthesis of methyl ketone 17. Reagents and conditions: (a) (R,R)-salen CoII complex A, AcOH (2.1 equiv), H2O (0.55 equiv); 0 ꢀC/rt, 12 h, 48% (max 50%); (b) CuI, THF,
allylmagnesium bromide (1 M in Et2O), ꢁ30 ꢀC, 4 h; (c) NaH, THF, BnBr, TBAI, rt, 15 h; 60% (two steps); (d) PdCl2, CuCl, DMF, O2, rt, 4 h, 71%.

998
M.A. Brimble et al. / Tetrahedron 67 (2011) 995e1001
O
OH
OTMS
Me
CH2
O
OMe
a
b
Me
Me
Me
OBn
O
OBn
H
O
O
OBn
OBn
16
26
17
H
H
H
H
Me
Me
Me
O
OH
O
O
O
O
c
d
O
O
O
O
OMe
H
1b
1a
27
Scheme 6. Synthesis of cephalosporolides E (1a) and F (1b). Reagents and conditions: (a) TMSOTf, NEt3, CH2Cl2, 30 min, 0 ꢀC; (b) aldehyde 18, CH2Cl2, MgBr2$Et2O, 2 h,
ꢁ78 ꢀC/0 ꢀC, 30%; (c) Pd/C, H2, MeOH, 60 psi, 12 h; (d) Amberlyst-15, CH2Cl2, rt, 12 h, 86% (two steps), 1a:1b (3:2).
aldol reaction with aldehyde 18 proceeded under chelation control
in the presence of MgBr2$OEt2 at ꢁ78 ꢀC in dichloromethane to
afford 3,4-syn alcohol 16 in >95% de (no other diastereomers were
observed by 1H NMR) in moderate yield. Aldol product 16 proved
stable to the aldol reaction conditions and careful purification by
flash chromatography buffered with 0.25% triethylamine did not
a Bruker AV300 spectrometer operating at 300 MHz for the 1H
nuclei and 75 MHz for the 13C nuclei or a Bruker DRX400 spec-
trometer operating at 400 MHz for the 1H nuclei and 100 MHz for
the 13C nuclei. All chemical shifts are recorded in parts per million
(ppm) relative to tetramethylsilane (
chloroform ( 7.26 ppm or 77.0 ppm). Coupling constant J values
are given in Hertz (Hz).
d 0.00 ppm) or deuterated
d
d
effect lactone formation or elimination to the a,b-unsaturated ke-
tone. High pressure hydrogenation was required to effect clean
double debenzylation with concomitant in situ spiroketalisation,
affording the desired [4.4]-spiroketal 27 as an inseparable (1:1)
mixture of diastereomers. Finally acid-catalysed lactonisation was
effected by exposure of hydroxy ester 27 to Amberlyst-15 affording
4.1.1. (4S,5S)-4-(tert-Butyldimethylsilyloxy)-5-(20-hydroxyethyl)di-
hydrofuran-2(3H)-one 14. To stirred solution of alcohol 13
a
(542 mg, 2.29 mmol) in CH2Cl2 (12 mL) at room temperature was
added triethylamine (1.60 mL, 11.4 mmol), tert-butyldimethylsilyl
chloride (1.21 g, 8.02 mmol) and 4-(N,N-dimethylamino)pyridine
(55 mg, 0.46 mmol). After 24 h, the reaction mixture was quenched
by the addition of 1 M HCl (50 mL) and diluted with CH2Cl2 (50 mL).
The layers were separated, the aqueous fraction extracted with
CH2Cl2 (3ꢂ50 mL) and the combined organic extracts dried over
MgSO4. The solvent was evaporated under reduced pressure and
the resultant crude residue purified by flash column chromatog-
raphy using a gradient elution of hexane/ethyl acetate (9:1/4:1) as
eluent to afford the corresponding silyl ether (576 mg, 72%) as
g-lactones (1) as a 3:2 mixture of diastereomers, thereby com-
pleting the synthesis of cephalosporolides E and F. The two [4.4]-
spiroacetal diastereomers were carefully separated by flash column
chromatography, affording pure samples of cephalosporolides E
and F.
3. Conclusion
In conclusion, we have successfully synthesised 3S,4S,6S,9R-
(þ)-cephalosporolide E (1a) and 3S,4S,6R,9R-(ꢁ)-cephalosporolide
F (1b) in 12 steps using a diastereoselective Mukaiyama aldol re-
action to establish the syn-stereocentres in the spirocyclisation
a colourless liquid. Rf (20% EtOAc/hexanes) 0.42; [
a
]
20 ꢁ33.5 (c 1.30
D
in CHCl3); vmax (cmꢁ1): 2952, 2929, 2858, 1779 (C^O), 1362, 1255,
1203, 1159, 1095, 1076; dH (400 MHz; CDCl3; Me4Si): 0.05 (3H, s,
SiCH3), 0.06 (3H, s, SiCH3), 0.88 (9H, s, SitBu), 1.88e1.96 (1H, m, H-
10a), 2.06e2.14 (1H, m, H-10b), 2.42 (1H, dd, J 17.3,1.0 Hz, H-3a), 2.72
(1H, dd, J 17.3, 5.3 Hz, H-3b), 3.65 (2H, dd, J 7.6, 4.7 Hz, H-20), 4.38
(1H, ddd, J 5.3, 4.0, 1.0 Hz, H-4), 4.47 (1H, d, J 11.7 Hz, CH2Ar), 4.55
(1H, d, J 11.7 Hz, CH2Ar), 4.61e4.64 (1H, dt, J 6.9, 4.0 Hz, H-5),
7.27e7.36 (5H, m, AreH); dC (100 MHz; CDCl3; Me4Si): ꢁ5.2 (CH3,
SiCH3), ꢁ4.8 (CH3, SiCH3), 17.9 (C, SitBu), 25.6 (CH3, SitBu), 29.6 (CH2,
C-10), 39.8 (CH2, C-3), 66.4 (CH2, C-20), 69.8 (CH, C-4), 73.2 (CH2,
CH2Ar), 81.9 (CH, C-5), 127.7 (CH, AreH), 127.7 (CH, AreH), 128.4
(CH, AreH), 138.1 (C, Ar), 175.4 (C]O, C-2); m/z (EI, CIþ, NH3):
351.1987 (MHþ, C19H31O4Si requires 351.1992), 368 (MNHþ4 , 0.5%),
351 (MHþ, 2%), 218 (2), 145 (6), 131 (4), 105 (11), 101 (9), 105 (19), 91
(CH2Ph, 100), 77 (8), 75 (11).
precursor 16. The sensitive [4.4]-spiroacetal-g-fused lactone ring
system was introduced in the final steps of the synthesis. This
synthetic strategy should prove amenable to the synthesis of other
members of this structural class of natural products.
4. Experimental
4.1. General methods
All reactions were carried out in oven-dried glassware, which
was further dried under high vacuum whilst heating with a heat
gun. Reactions were carried out under an atmosphere of argon or
nitrogen dried by passing through a cylinder of calcium chloride.
Solvents were dried under standard conditions. Thin layer chro-
matography was carried out using Merck 0.2 mm silica gel 60 F254
aluminium plates. Flash column chromatography was carried out
To a stirred solution of the above silyl ether (550 mg, 1.57 mmol)
in freshly distilled ethanol (10 mL) was added palladium on carbon
(10 wt %, 10 mg, 0.08 mmol). The reaction mixture was stirred
vigorously under an atmosphere of hydrogen. After 2.5 h, the re-
action mixture was filtered through a plug of Celite and washed
through with a solution of hexane/ethyl acetate (3:2) (150 mL). The
solvent was evaporated under reduced pressure and the resultant
crude residue purified by flash column chromatography using
using 40e63
mm, 230e430 mesh silica gel with the solvent in-
dicated. Mass spectra were obtained on a VG-70SE spectrometer.
Prominent fragments are recorded as m (n) where m is the mass to
charge ratio and n is the percentage abundance relative to the base
peak. Infrared spectra were obtained on a PerkineElmer Spectrum
One Universal ATR Sampling Accessory Fourier Transform IR
spectrometer, neat, over a crystal plate or using a PerkineElmer
Spectrum 1000 series Fourier Transform IR spectrometer as a thin
film between sodium chloride plates. Absorption maxima are
expressed in wavenumbers (cmꢁ1). Optical rotations of chiral
compounds were obtained using a PerkineElmer 341 polarimeter
in the solvent indicated. NMR spectra were recorded on either
hexane/ethyl acetate (2:3) as eluent to afford the title compound 14
20
(389 mg, 95%) as a colourless solid. Mp 57e59 ꢀC; [
a]
ꢁ35.4 (c
D
2.00 in CHCl3); vmax (cmꢁ1): 3422 (OH), 2956, 2930, 2887, 2858,
1776 (C]O), 1362, 1255, 1161, 1065; dH (400 MHz; CDCl3; Me4Si):
0.03 (6H, s, SiCH3), 0.83 (9H, s, SitBu), 1.75e1.83 (1H, m, H-10a),
1.96e2.05 (1H, m, H-10b), 2.37e2.42 (2H, m, H-3a, OeH), 2.72 (1H,
dd, J 17.3, 5.0 Hz, H-3b), 3.75 (2H, dd, J 7.0, 5.0 Hz, H-20), 4.41 (1H,

M.A. Brimble et al. / Tetrahedron 67 (2011) 995e1001
999
ddd, J 5.0, 3.6, 0.8 Hz, H-4), 4.59 (1H, dt, J 9.6, 3.6 Hz, H-5); dC
(75 MHz; CDCl3; Me4Si): ꢁ5.2 (CH3, SiCH3), ꢁ4.9 (CH3, SiCH3), 17.8
(C, SitBu), 25.5 (CH3, SitBu), 31.8 (CH2, C-10), 39.7 (CH2, C-3), 58.8
(CH2, C-20) 69.8 (CH, C-4), 82.2 (CH, C-5), 175.7 (C]O, C-2); m/z (EI,
CI, NH3): 261.1524 (MHþ, C12H25O4Si requires 261.1522), 278
(MNHþ4 , 16%), 261 (MHþ, 22%), 203 (21), 173 (20), 161 (27), 157 (24),
131 (43), 129 (39), 111 (30), 92 (19), 75 (100).
alkyne 11 (39 mg, 0.214 mmol). The mixture was heated to 50 ꢀC
and stirred for 3 h. The reaction was cooled to room temperature,
quenched by the addition of brine (3 mL) and diluted with diethyl
ether (5 mL). The layers were separated and the aqueous layer
extracted with diethyl ether (3ꢂ10 mL). The combined organic
extracts were dried over MgSO4, the solvent evaporated under re-
duced pressure and the resultant crude brown residue purified by
flash column chromatography using hexane/ethyl acetate (4:1) as
4.1.2. S-Ethyl 2-((2S,3S)-3-(tert-butyldimethylsilyloxy)-5-oxotetrahy-
drofuran-2-yl)ethanethioate 10. To a stirred solution of alcohol 14
(1.30 g, 5.00 mmol) in acetonitrile (30 mL) and aqueous phosphate
buffer (25 mL, pH 6.7, 1 mol Lꢁ1) at room temperature was added
2,2,6,6-tetramethylpiperidin-1-oxyl (109 mg, 0.70 mmol). The
reaction mixture was warmed to 35 ꢀC and solutions of sodium
chlorite (1.81 g, 20 mmol) in water (14 mL) and sodium hypochlorite
eluent to afford the title compound 15 (16 mg, 34%) as a colourless
20
liquid. Rf (10% EtOAc/hexanes) 0.42; [
a]
þ24.5 (c 0.75 in CHCl3);
D
vmax (cmꢁ1): 2955, 2929, 2857, 2214 (C^C), 1787 (lactone C]O),
1678 (ynone C]O), 1254, 1149, 809, 777; dH (400 MHz; CDCl3;
Me4Si): 0.04 (3H, s, SiCH3), 0.08 (3H, s, SiCH3), 0.11 (3H, s, SiCH3),
0.14 (3H, s, SiCH3), 0.88 (9H, s, SitBu), 0.90 (9H, s, SitBu), 1.46 (3H, d, J
6.6 Hz, H-60), 2.44 (1H, dd, J 17.8, 3.6 Hz, H-3a), 2.74 (1H, dd, J 17.8,
5.2 Hz, H-3b), 3.14 (2H, dd, J 5.8, 4.3 Hz, H-10), 4.59e4.62 (1H, m, H-
4), 4.66 (1H, q, J 6.6 Hz, H-50), 4.84e4.89 (1H, m, H-5); dC (100 MHz;
CDCl3; Me4Si): ꢁ5.3 (CH3, SiCH3), ꢁ5.0 (CH3, SiCH3), ꢁ4.7 (CH3,
SiCH3), ꢁ4.7 (CH3, SiCH3), 17.9 (C, SitBu), 18.1 (C, SitBu), 24.4 (CH3, C-
60), 25.6 (3ꢂCH3, SitBu), 25.8 (3ꢂCH3, SitBu), 39.1 (CH2, C-10), 43.8
(CH2, C-3), 58.8 (CH, C-50), 68.9 (CH, C-4), 79.7 (CH, C-5), 81.8 (C, C-
40), 95.0 (C, C-30), 174.7 (C]O, C-2), 183.3 (C]O, C-20);m/z (EI, CI,
NH3): 441.2496 (MHþ, C22H41O5Si2 requires 441.2493), 458 (MNHþ4 ,
28%), 441 (MHþ, 21%), 383 (100), 313 (20), 309 (18), 255 (30), 209
(9), 171 (14), 90 (16), 73 (68).
(360 mL) in water (8 mL) were added simultaneously over 2 h. The
reaction was stirred for 4 h, diluted with water (15 mL) and diethyl
ether (30 mL), and the pH adjusted to 9 with NaOH (2 mol Lꢁ1). The
reaction was quenched by pouring into saturated Na2S2O3, cooled to
0
ꢀC and stirred for 20 min. The layers were separated, the organic
layer discarded, the aqueous layer adjusted to pH 3 using 2 M HCl
and the mixture extracted with diethyl ether (3ꢂ50 mL). The com-
bined organic extracts were washed with water (30 mL) and brine
(30 mL). The solvent was evaporated under reduced pressure to
afford the corresponding carboxylic acid (1.30 g, 95%) as a colourless
solid. Rf (60% EtOAc/hexanes) 0.20; mp 83e88 ꢀC; [
a]
D
20 þ3.3 (c 1.73
in CHCl3); vmax (cmꢁ1): 2930, 2928, 2857, 1784 (lactone C]O), 1729
(acid C]O), 1186, 1158, 1042, 834, 774; dH (300 MHz; CDCl3; Me4Si):
0.11 (3H, s, SiCH3), 0.13 (3H, s, SiCH3), 0.89 (9H, s, SitBu), 2.48 (1H, dd, J
17.5, 1.4 Hz, H-40a), 2.77 (1H, dd, J 17.5, 5.5 Hz, H-40b), 2.92 (2H, d, J
6.9 Hz, H-2), 4.62 (1H, ddd, J 5.5, 4.0, 1.4 Hz, H-30), 4.81 (1H, td, J 6.9,
4.0 Hz, H-20); dC (75 MHz; CDCl3; Me4Si): ꢁ5.2 (CH3, SiCH3), ꢁ4.6
(CH3, SiCH3), 17.6 (C, SitBu), 25.3 (CH3, SitBu), 33.1 (CH2, C-2), 39.0
(CH2, C-40), 68.8 (CH, C-30) 80.1 (CH, C-20), 175.1 (C]O, C-50), 175.2
(C]O, C-1); m/z (EI, CI, NH3): 292.1578 (MNHþ4 , C12H26NO5Si requires
292.1580), 292 (MNHþ4 , 100%), 275 (MHþ, 22%), 257 (11), 234 (7), 217
(19), 173 (5), 160 (7), 129 (6), 92(19), 74 (31).
4.1.4. (4S,5S)-4-(tert-Butyldimethylsilyloxy)-5-((R)-50-(tert-butyldi-
methylsilyloxy)-20-oxohexyl)dihydrofuran-2(3H)-one 8. To a solu-
tion of ynone 15 (15 mg, 0.034 mmol) dissolved in ethyl acetate
(5 mL) was added palladium on carbon (5 mg, 10 wt %, 0.04 mmol).
The mixture was subjected to 60 psi H2 for 16 h until negligible
starting material was presented by TLC analysis. The reaction
mixture was filtered through a plug of Celite then washed with
ethyl acetate (20 mL) and diethyl ether (20 mL). The solvent was
evaporated under reduced pressure and the resultant crude yellow
residue purified by flash column chromatography using hexane/
ethyl acetate (4:1) as eluent to afford the title compound 8 (10 mg,
To a stirred solution of the above acid (50 mg, 0.18 mmol),
75%) as a colourless liquid. Rf (20% EtOAc/hexanes) 0.40; [
a
]
20 ꢁ3.8
D
1-hydroxybenzotriazole (28 mg, 0.18 mmol) and ethanethiol (20
0.27 mmol) in CH2Cl2 (2 mL) cooled to 0 ꢀC was added 1,3-diiso-
propylcarbodiimide (30 L, 0.18 mmol). The reaction mixture was
mL,
(c 0.50 in CHCl3); vmax (cmꢁ1): 2956, 2929, 2857, 1784 (C]O), 1715
(C]O), 1254, 1093, 1030, 836, 775; dH (400 MHz; CDCl3; Me4Si):
0.01 (3H, s, SiCH3), 0.03 (3H, s, SiCH3), 0.05 (3H, s, SiCH3), 0.06 (3H, s,
SiCH3), 0.85 (9H, s, SitBu), 0.88 (9H, s, SitBu), 1.12 (3H, d, J 6.0 Hz, H-
60),1.67e1.72 (2H, m, H-40), 2.40e2.48 (2H, m, H-30), 2.55e2.58 (1H,
m, H-3a), 2.73 (1H, dd, J 17.6, 5.6 Hz, H-3b), 2.95e2.98 (2H, m, H-10),
3.81e3.85 (1H, m, H-50), 4.57e4.59 (1H, m, H-4), 4.80e4.84 (1H, m,
H-5); dC (100 MHz; CDCl3; Me4Si): ꢁ5.3 (CH3, SiCH3), ꢁ4.8 (CH3,
SiCH3), ꢁ4.7 (CH3, SiCH3), ꢁ4.4 (CH3, SiCH3), 17.9 (C, SitBu), 18.1 (C,
SitBu), 23.5 (CH3, C-60), 25.6 (CH3, SitBu), 25.8 (CH3, SitBu), 32.9 (CH2,
C-40), 39.2 (CH2, C-10), 39.4 (CH2, C-3), 41.2 (CH2, C-30), 67.4 (CH, C-
4), 69.2 (CH, C-50), 80.6 (CH, C-5), 174.9 (C]O, C-2), 208.6 (C]O, C-
20);m/z (EI, CI, NH3): 445.2797 (MHþ, C22H45O5Si2 requires
445.2806), 445 (MHþ, 42%), 387 (48), 369 (14), 329 (10), 313 (90),
295 (12), 255 (100), 171 (16), 132 (11), 75 (38).
m
allowed to warm to room temperature and stirred for 12 h after
which the mixture was filtered through a short plug of silica. The
solvent was evaporated and the crude residue purified by flash
column chromatography using hexane/ethyl acetate (9:1) as eluent
to afford the title compound 10 (30 mg, 52%) as a colourless liquid. Rf
(20% EtOAc/hexanes) 0.45; [
a
]
20 ꢁ3.6 (c 1.30 in CHCl3); vmax (cmꢁ1):
D
2957, 2931, 2888, 2859, 1783 (C]O), 1682 (C]O), 1471, 1408, 1298,
1261; dH (300 MHz; CDCl3; Me4Si): 0.02 (3H, s, SiCH3), 0.05 (3H, s,
SiCH3), 0.86 (9H, s, SitBu), 1.23 (3H, t, J 7.3 Hz, SCH2CH3), 2.40 (1H,
dd, J 17.3, 1.0 Hz, H-40a), 2.72 (1H, dd, J 17.3, 5.2 Hz, H-40b), 2.87 (2H,
q, J 7.3 Hz, SCH2CH3), 3.05 (2H, d, J 6.8 Hz, H-2), 4.54 (1H, ddd, J 5.2,
3.9,1.0 Hz, H-30), 4.83 (1H, td, J 6.8, 3.9 Hz, H-20); dC (75 MHz; CDCl3;
Me4Si): ꢁ5.3 (CH3, SiCH3), ꢁ4.8 (CH3, SiCH3), 14.5 (CH3, SEt), 17.8 (C,
SitBu), 23.3 (CH2, SEt), 25.5 (3ꢂCH3, SitBu), 39.2 (CH2, C-40), 42.4
(CH2, C-2), 69.2 (CH, C-30), 80.3 (CH, C-20), 174.5 (C]O, C-50), 195.9
(C]O, C-1); m/z (EI, CI, NH3): 319.1402 (MHþ, C14H27OSSi requires
319.1399), 336 (MNHþ4 , 51%), 319 (MHþ, 22%), 261 (100), 257 (55),
157 (9), 129 (14), 119 (21), 97 (9), 78 (12), 74 (41).
4.1.5. (S)-Dimethyl malate 23. Acetyl chloride (8.21 mL, 116 mmol)
was added to methanol (150 mL) at room temperature followed
after 10 min by (S)-malic acid (25 g, 186 mmol). The solution was
stirred at room temperature for 18 h before the volatile compo-
nents were evaporated under reduced pressure. The resultant
residue was purified by flash column chromatography using
CH2Cl2/MeOH (95:5) as eluent to afford the title compound 23
(22.67 g, 80%) as a yellow oil. The spectroscopic data was in
agreement with those reported in the literature.24 Rf (5% MeOH/
4.1.3. (4S,5S)-4-(tert-Butyldimethylsilyloxy)-5-((R)-50-(tert-butyl-
dimethylsilyloxy)-20-oxohex-30-ynyl)dihydrofuran-2(3H)-one 15. To
a stirred solution of thioester 10 (34 mg, 0.107 mmol), copper iodide
(45 mg, 0.24 mg), P(2-furyl)3 (6 mg, 0.027 mmol), PdCl2(dppf)
CH2Cl2) 0.51; [
a
]
20 þ1.6 (c 0.80 in CHCl3); lit.24
[
a
]
25 þ3.1 (c in 0.80,
D
D
(9 mg, 0.011 mmol) and triethylamine (150
mL) in dry N,N-dime-
CHCl3); dH (300 MHz; CDCl3; Me4Si) 2.72 (2H, dd, J 16.4, 4.4 Hz, H-
thylformamide (750 L) at room temperature was added neat
m
3), 3.35 (1H, br s, OH), 3.61 (3H, s, C-4OMe), 3.67 (3H, s, C-1OMe),

1000
M.A. Brimble et al. / Tetrahedron 67 (2011) 995e1001
4.42 (1H, dd, J 6.3, 4.4 Hz, H-2); dC (75 MHz; CDCl3; Me4Si) 38.4
(CH2, C-3), 51.9 (CH3, C-4OMe), 51.6 (CH3, C-1OMe), 67.2 (CH, C-2)
170.9 (C]O, C-4), 173.6 (C]O, C-1).
ꢁ56.3 (c 0.70 in CHCl3); dH (300 MHz; CDCl3; Me4Si) 2.55e2.74 (2H,
m, H-2), 3.60 (3H, s, OMe), 4.09e4.17 (1H, m, H-3), 4.51 (1H, d, J
11.4 Hz, CH2Ph), 4.60 (1H, d, J 11.4 Hz, CH2Ph), 7.25e7.36 (5H, m,
PheH) 9.64 (1H, s, H-4); dC (75 MHz; CDCl3; Me4Si) 35.6 (CH2, C-2),
51.9 (CH3, OMe), 73.0 (CH2, CH2Ph) 79.5 (CH, C-3), 127.6 (CH, PheH),
127.7 (CH, PheH), 128.3 (CH, PheH), 2ꢂ128.4 (CH, PheH), 136.8 (C,
Ph), 170.4 (C]O, C-1), 201.8 (C]O, C-4).
4.1.6. (S)-Dimethyl 2-(benzyloxy)succinate 24. Benzyl 2,2,2-tri-
chloroacetimidate (16.3 g, 65.0 mmol) was added to a solution of
(S)-dimethyl malate 23 (7.00 g, 43.0 mmol) in CH2Cl2 (35 mL) and
cyclohexane (60 mL). Triflic acid (0.97 mL, 6.48 mmol) was then
added dropwise. The mixture was stirred at room temperature for
24 h. The mixture was filtered and the filtrate was washed with
(aq) NaHCO3 (50 mL) and extracted with CH2Cl2 (3ꢂ50 mL). The
combined extracts were dried over Na2SO4 and evaporated under
reduced pressure. The resultant crude yellow residue was purified
by flash column chromatography using hexane/ethyl acetate (4:1)
as eluent to afford the title compound 24 (11.52 g, 74%) as a yellow
oil. The spectroscopic data was in agreement with those reported in
4.1.9. (R)-Propylene oxide 20. (R,ReN,N) Bis-(3,5-di-tert-butylsali-
cylidene)-1,2-cyclohexanediaminocobalt(II) (242 mg, 0.40 mmol)
was dissolved in toluene (5 mL) and acetic acid (240 mL, 4.2 mmol)
was added dropwise. The resultant solution was stirred at room
temperature open to air for 30 min resulting in a colour change
from orange-red to dark brown. The solution was concentrated in
vacuo to yield a crude brown solid. The cobalt(III) complex was
dissolved in propylene oxide (11.6 g, 14 mL, 200 mmol), cooled to
the literature.19 Rf (20% EtOAc/hexanes) 0.33; [
a
]
20 ꢁ43.5 (c 1.60 in
0
ꢀC then water (1.98 mL, 110 mmol) was added dropwise over
5 min. The reaction was allowed to warm to room temperature and
stirred overnight. (R)-Propylene oxide 25 was isolated by distilla-
tion at 36 ꢀC at atmospheric pressure (5.6 g, 48%).15
D
20
CHCl3); lit.19
[a
]
ꢁ63.0 (c 1.60 in CHCl3); dH (300 MHz; CDCl3;
D
Me4Si) 2.72e2.76 (2H, m, H-3) 3.60 (3H, s, C-4OMe), 3.69 (3H, s, C-
1OMe), 4.38e4.41 (1H, m, H-2), 4.53 (1H, d, J 11.5 Hz, CH2Ph), 4.76
(1H, d, J 11.5 Hz, CH2Ph) 7.29e7.32 (5H, m, Ph); dC (75 MHz; CDCl3;
Me4Si) 37.4 (CH2, C-3), 51.6 (CH3, C-4OMe), 51.8 (CH3, C-1OMe),
72.7 (CH, C-2) 74.3 (CH2, CH2Ph) 2ꢂ127.7 (CH, PheH), 127.9 (CH,
PheH), 2ꢂ128.2 (CH, PheH) 137.0 (C, Ph) 170.3 (C]O, C-4) 171.6
(C]O, C-1).
4.1.10. (R)-5-Benzyloxyhex-1-ene 21. Copper(I) iodide (1.14 g,
6.00 mmol) was gently heated under nitrogen until it turned light
yellow. THF (100 mL) was added and the resultant solution cooled
to ꢁ30 ꢀC after which 1 M allylmagnesium bromide in Et2O (60 mL,
60 mmol) was added dropwise. The reaction was stirred for 5 min
after which (R)-propylene oxide 20 (2.5 g, 43 mmol) in THF (15 mL)
was added and the mixture allowed to stir for 4 h at ꢁ30 ꢀC NH4Cl
(aq) was added and the mixture extracted with EtOAc, dried over
Na2SO4 and evaporated under reduced pressure to give (R)-hex-5-
en-2-ol as a yellow oil, which was used without further purification.
To a solution of NaH (2.82 g, 70 mmol) in dry THF (180 mL) was
added (R)-hex-5-en-2-ol in THF (25 mL) and the reaction mixture
was stirred at room temperature for 30 min. Benzyl bromide
(7.75 mL, 65 mmol) and tetra-n-butylammonium iodide (75 mg,
0.2 mmol) were then added and stirring continued at room tem-
perature for 15 h. The reaction was then quenched with (aq) NH4Cl
(50 mL), extracted with EtOAc (3ꢂ50 mL), dried over Na2SO4 and
evaporated under reduced pressure. The residue was purified by
flash column chromatography using hexane/ethyl acetate (9.9:0.1)
as eluent to afford the title compound 21 (5.08 g, 60%) as a yellow
oil. The spectroscopic data was in agreement with those reported in
4.1.7. (S)-Methyl 3-(benzyloxy)-4-hydroxybutanoate 25. To a solu-
tion of diester 24 (1.00 g, 3.96 mmol) in CH2Cl2 (50 mL) was added
MgBr2$OEt2 (1.15 g, 4.48 mmol) and the resultant mixture was
stirred at room temperature for 1 h. The solution was then cooled to
ꢁ78 ꢀC and DIBAL-H (9.92 mL of 1.0 M solution in toluene,
9.92 mmol) was added dropwise over 90 min via syringe pump.
After complete addition followed by stirring for 30 min at ꢁ78 ꢀC,
the reaction was allowed to warm to 0 ꢀC then stirred for a further
2 h. Methanol (5 mL) and saturated (aq) Rochelle’s salt solution
(30 mL) were then added and the solution was allowed to warm to
room temperature and stirred for a further 20 min. The reaction
mixture was extracted with CH2Cl2 (3ꢂ50 mL). The organic extracts
were dried over Na2SO4, concentrated under reduced pressure and
the residue purified by flash column chromatography using hex-
ane/ethyl acetate (3:2) as eluent to afford the title compound 25
(0.45 g, 53%) as a yellow oil. Rf (40% EtOAc/hexanes) 0.28; [
a
]
20 ꢁ2.1
D
(c 1.2 in CHCl3) vmax (film)/cmꢁ1 3436, 1730, 1057, 824, 736, 697; dH
(300 MHz; CDCl3; Me4Si) 2.55e2.70 (2H, m, H-2), 3.55e3.65 (2H,
m, H-4), 3.70 (3H, s, OMe), 3.93e3.97 (1H, m, H-3), 4.46 (1H, d, J
11.5 Hz, CH2Ph), 4.57 (1H, d, J 11.5 Hz, CH2Ph), 7.25e7.32 (5H, m,
PheH); dC (75 MHz; CDCl3; Me4Si) 36.4 (CH2, C-2) 51.6 (CH3, C-
1OMe) 63.7 (CH2, C-4) 71.9 (CH, C-3) 76.2 (CH2, CH2Ph) 2ꢂ127.5
(CH, PheH),127.7 (CH, PheH), 2ꢂ128.3 (CH, PheH) 137.9 (C, Ph)
171.7 (C]O, C-1); m/z (EI) 224.0937 (MHþ, C13H18O2 requires
224.1000) 225 (10%), 236 (1), 244 (1), 247 (MNaþ, 100), 248 (15).
the literature.25 Rf (20% EtOAc/hexanes) 0.84; [
a]
20 ꢁ15.7 (c 1.10 in
D
CHCl3); lit.25
[a
]
ꢁ32.9 (c 1.00 in CHCl3); dH (300 MHz; CDCl3;
D
Me4Si) 1.17 (3H, d, J 6.1 Hz, H-6), 1.49e1.53 (1H, m, H-4), 1.67e1.71
(1H, m, H-4), 2.09e2.16 (2H, m, H-3), 3.47e3.52 (1H, m, H-5), 4.44
(1H, d, J 11.7 Hz, CH2Ph), 4.57 (1H, d, J 11.7 Hz, CH2Ph) 4.91e5.01
(2H, m, H-1) 5.76e5.80 (1H, m, C-2), 7.25e7.35 (5H, m, PheH); dC
(75 MHz; CDCl3; Me4Si) 19.5 (CH3, C-6), 29.7 (CH2, C-3), 35.8 (CH2,
C-4), 70.3 (CH2, CH2Ph), 74.2 (CH, C-5), 114.4 (CH2, C-1), 127.4 (CH,
PheH), 127.6 (CH, PheH), 127.7 (CH, PheH), 2ꢂ128.3 (CH, PheH),
138.6 (C, Ph), 139.1 (CH, C-2).
4.1.8. (S)-Methyl 3-(benzyloxy)-4-oxobutanoate 18. To a solution of
alcohol 25 (0.20 g, 0.892 mmol) and TEMPO (1.30 mg, 8.92
m
mol) in
4.1.11. (R)-5-(Benzyloxy)hexan-2-one 17. A solution of alkene 21
(1.00 g, 5.26 mmol) in DMF (7.5 mL) was added to a mixture of PdCl2
(1.00 g, 2.68 mmol) and CuCl (0.67 g, 6.73 mmol) in DMF (15 mL) and
water (5 mL). Oxygen gas was bubbled through the solution. The
reaction was stirred for 4 h then filtered through a plug of silica that
was washed with further EtOAc and the filtrate concentrated under
reduced pressure. The residue was purified by flash column chro-
matography using hexane/ethyl acetate (4:1) as eluent to afford the
title compound 17 (0.76 g, 71%) as ayellowoil. Rf (20% EtOAc/hexanes)
EtOAc (3 mL) was added NaHCO3 (0.225 g, 2.67 mmol). The mixture
was cooled to ꢁ5 ꢀC and a solution of trichloroisocyanuric acid
(0.217 g, 0.938 mmol) in EtOAc (5 mL) was added dropwise over 1 h.
After stirring for 1 h at ꢁ5 ꢀC, NaI (5 mL of 1 M solution in water)
was added. The solution was separated and extracted with EtOAc
(3ꢂ20 mL). The combined organic layers were washed with (10%
aq) Na2SO3 (10 mL) and the aqueous layer further extracted with
EtOAc (3ꢂ20 mL). The combined organic layers were dried over
Na2SO4 and concentrated under reduced pressure to give the title
compound 18 (0.14 g, 70%) as a colourless oil. The spectroscopic
0.40; [
a
]
D
20 ꢁ26.3 (c 1.0 in CHCl3); vmax (film)/cmꢁ1 2969, 1714, 1356,
1093,1063, 743, 697; dH (300 MHz; CDCl3; Me4Si) 1.19 (3H, d, J 6.1 Hz,
H-6), 1.75e1.85 (2H, m, H-3), 2.11 (3H, s, H-1), 2.48e2.54 (2H, m, H-
4), 3.49e3.55 (1H, m, H-5), 4.37 (1H, d, J 11.7 Hz, CH2Ph), 4.54 (1H, d, J
data was in agreement with those reported in the literature.21 Rf
20
(40% EtOAc/hexanes) 0.30; [
a
]
ꢁ16.7 (c 0.70 in CHCl3); lit.21
[a]
D
D

M.A. Brimble et al. / Tetrahedron 67 (2011) 995e1001
1001
11.7 Hz, CH2Ph), 7.25e7.35 (5H, m, Ph); dC (75 MHz; CDCl3; Me4Si)
19.2 (CH3, C-6), 29.5 (CH3, C-1), 30.1 (CH2, C-4), 39.0 (CH2, C-3), 69.9
(CH2, CH2Ph), 73.4 (CH, C-5), 127.1 (CH, PheH), 127.5 (CH, PheH),
127.7 (CH, PheH), 128.4 (CH, PheH), 128.5 (CH, PheH), 138.5 (C, Ph),
208.1 (C]O, C-2); m/z (EI) 229.1190 (MHþ, C13H18NaO2 requires
229.1199) 229 (MNaþ, 100%), 230 (10), 231 (1).
(film)/cmꢁ1 3498, 2934, 1781, 1375, 1165, 1056, 925, 715; dH
(300 MHz; CDCl3; Me4Si) 1.10 (3H, d, J 6.2 Hz, H-10), 1.31e1.50 (1H,
m, H-8), 2.00e2.05 (1H, m, H-8), 2.07e2.15 (2H, m, H-7), 2.15e2.18
(1H, m, H-5), 2.44 (1H, d, J 14.2 Hz, H-5), 2.67 (1H, d, J 18.8 Hz, H-2),
2.71 (1H, dd, J 7.4, 18.8 Hz, H-2), 4.15e4.21 (1H, m, H-9), 4.86e4.91
(1H, m, H-3), 5.15 (1H, t, J 5.9 Hz, H-4); dC (75 MHz; CDCl3; Me4Si)
20.5 (CH3, C-10), 31.3 (CH2, C-8), 34.1 (CH2, C-7), 37.3 (CH2, C-5), 41.6
(CH2, C-2), 75.1 (CH, C-9), 77.3 (CH, C-3), 83.4 (CH, C-4), 115.1 (C, C-
6), 175.9 (C]O, C-1); m/z (EI) 221.0792 (MHþ, C10H14NaO4 requires
221.0784) 221 (MNaþ, 100%), 222 (20), 223 (1), 224 (10).
4.1.12. (R)-5-(Benzyloxy)-2-trimethylsilyloxyhex-1-ene 26. Et3N (1.11
mL, 8.01 mmol) and TMSOTf (0.73 mL, 4.00 mmol) were added to
a solution of ketone 17 (0.55 g, 2.67 mmol) in CH2Cl2 (10 mL) at 0 ꢀC.
After 30 min the reaction was quenched by the addition of (aq)
NH4Cl (5 mL). The layers were separated and the aqueous layer
extracted with Et2O (3ꢂ10 mL) and dried over Na2SO4. Concentra-
tion under reduced pressure afforded the crude silyl enol ether 26 as
a yellow oil, which was used in the next step without further
purification.
20
4.1.16. Cephalosporolide F (1b). Rf (40% EtOAc/hexanes) 0.15; [a]
D
ꢁ33.9 (c 0.79 in CHCl3); lit.5 [
a
]
D
25 ꢁ33.3 (c 0.79 in CHCl3); vmax (film)/
cmꢁ1 3529, 2969, 1774, 1347, 1152, 1054, 917, 700; dH (300 MHz;
CDCl3; Me4Si) 1.27 (3H, d, J 6.2 Hz, H-10), 1.67e1.76 (1H, m, H-8),
1.99e2.05 (1H, m, H-8), 2.06e2.18 (2H, m, H-7), 2.32 (1H, dd, J 14.8,
2.2 Hz, H-5) 2.51 (1H, dd, J 14.8, 6.8 Hz, H-5), 2.67 (1H, d, J 17.8 Hz, H-
2), 2.74 (1H, dd, J 5.3 Hz,17.8, H-2), 4.11e4.16 (1H, m, H-9), 4.72 (1H, t,
J 5.0 Hz, H-3), 5.06e5.10 (1H, m, H-4); dC (75 MHz;CDCl3; Me4Si) 22.7
(CH3, C-10), 32.4 (CH2, C-8), 36.0 (CH2, C-7), 36.9 (CH2, C-5), 42.1
(CH2, C-2), 76.5 (CH, C-9), 79.9 (CH, C-3), 83.8 (CH, C-4),115.5 (C, C-6),
175.5 (C]O, C1); m/z (EI) 221.0790 (MHþ, C10H14NaO4 requires
221.0784) 221 (MNaþ, 100%), 222 (20), 223 (1), 224 (10).
4.1.13. (3S,4S,9R)-Methyl 3,9 bis(benzyloxy)-4-hydroxy-6-oxodeca-
noate 16. To a solution of aldehyde 18 (0.25 g, 1.12 mmol) in CH2Cl2
(5 mL) was added MgBr2$OEt2 (1.74 g, 6.76 mmol) at ꢁ78 ꢀC. (R)-5-
(Benzyloxy)-2-trimethylsilyloxyhex-1-ene 26 (0.64 g, 2.30 mmol)
in CH2Cl2 (2 mL) was added and the reaction allowed to warm to
0
ꢀC. The reaction was stirred at 0 ꢀC for 2 h after which it was
quenched with pH 7 phosphate buffer (5 mL) and extracted with
CH2Cl2 (3ꢂ20 mL). The organic phases were then washed with
brine (10 mL), dried over MgSO4 and evaporated under reduced
pressure. The residue was purified by flash column chromatogra-
phy using hexane/ethyl acetate (4:1) as eluent to afford the title
compound 16 (0.15 g, 30%) as a colourless oil. Rf (20% EtOAc/hex-
Acknowledgements
Financial support from the Maurice Wilkins Centre for Molec-
ular Biodiscovery (O.F.) is gratefully acknowledged.
anes) 0.11; [
a]
20 ꢁ19.0 (c 1.0 in CHCl3); vmax (film)/cmꢁ1 3457, 2928,
References and notes
D
1713, 1454, 1167, 1068, 736, 697; dH (300 MHz; CDCl3; Me4Si) 1.10
(3H, d, J 6.1 Hz, H-10), 1.63e1.73 (2H, m, H-8) 2.38e2.44 (2H, m, H-
7) 2.45e2.52 (2H, m, H-5), 2.54e2.59 (2H, m, H-2), 3.40e3.45 (1H,
m, H-9), 3.71 (3H, s, C-1OMe), 3.81e3.85 (1H, m, H-3), 4.04e4.06
(1H, m, H-4), 4.25 (2H, m, CH2Ph), 4.43 (2H, m, CH2Ph), 4.52 (1H, d, J
5.7 Hz, OH) 7.20e7.35 (10H, m, PheH); dC (75 MHz; CDCl3; Me4Si)
19.3 (CH3, C-10), 30.1 (CH2, C-8) 34.7 (CH2, C-2) 39.3 (CH2, C-7), 44.5
(CH2, C-5), 51.6 (CH3, OMe), 68.1 (CH, C-4), 70.1 (CH2, CH2Ph), 72.6
(CH2, CH2Ph), 73.7 (CH, C-3), 77.3 (CH, C-9), 127.2 (CH, PheH), 127.3
(CH, PheH), 2ꢂ127.5 (CH, PheH), 127.6 (CH, PheH), 127.7 (CH,
PheH), 127.9 (CH, PheH), 128.1 (CH, PheH), 128.2 (CH, PheH),128.4
(CH, PheH), 136.8 (C, Ph), 137.8 (C, Ph), 172.0 (C]O, C-1), 210.8 (C]
O, C-6); m/z (EI) 451.2105 (Mþ, C25H32NaO6 requires 451.2091) 429
(25%), 446 (30), 451 (MNaþ, 100), 467 (31).
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25
4.1.15. Cephalosporolide E (1a). Rf (40% EtOAc/hexanes) 0.30; [a]
D
20
þ27.3 (c 0.41 in CHCl3); lit.3
[a
]
þ49.2 (c 0.25 in CHCl3); vmax
D