A highly enantioselective total synthesis of (+)-goniodiol

Article abstract of DOI:10.1039/b602805e

A high-yielding enantioselective total synthesis of the bioactive styryllactone (+)-goniodiol has been realised, starting from readily available (S)-glycidol. A key step is an oxygen-to-carbon rearrangement of a silyl enol ether linked via an anomeric cen

Full text of DOI:10.1039/b602805e

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www.rsc.org/obc | Organic & Biomolecular Chemistry
A highly enantioselective total synthesis of (+)-goniodiol
Edward W. Tate,a Darren J. Dixonb and Steven V. Ley*c
Received 23rd February 2006, Accepted 9th March 2006
First published as an Advance Article on the web 27th March 2006
DOI: 10.1039/b602805e
A high-yielding enantioselective total synthesis of the bioactive styryllactone (+)-goniodiol has been
realised, starting from readily available (S)-glycidol. A key step is an oxygen-to-carbon rearrangement
of a silyl enol ether linked via an anomeric centre, facilitating the rapid and diastereoselective
construction of this functionalised system.
methodologies: generation of oxygenated lactones via furan
Introduction
oxidation;15 glycoside-templated synthesis;16–19 chiral induction via
enantiopure chromium aryl complexes;20,21 anomeric oxygen-to-
carbon rearrangements;22 enantioselective enzymatic oxidation of
naphthalene derivatives;23,24 and ring-closing metathesis.25–27
We have developed a general method for the introduction of
carbon linked substituents adjacent to the heteroatom in pyranyl
and furanyl ring systems via Lewis acid mediated oxygen-to-
carbon rearrangements of a variety of different anomerically
linked carbon centred nucleophiles.28–35 Anomeric oxygen-to-
carbon rearrangement has proved a useful methodology in our
recent total syntheses of members of several natural product
classes, including the annonaceous acetogenins.36–38 (+)-Goniodiol
represents an excellent target to further test the scope of the
method, and we have previously communicated our preliminary
results from this total synthesis.39 Here we report in full our
enantioselective total synthesis of compound 1.
Studies on natural products isolated from Asian trees of the
genus Goniothalamus have led to the discovery of several classes
of compounds with interesting biological properties, including
acetogenins,1–3 alkaloids4 and styryllactones.5,6 (+)-Goniodiol 1,
a styryllactone, (Fig. 1) was isolated in 1985 from petroleum ether
extracts of the leaves and twigs of Goniothalamus sesquipedalis.7
More recently, it has been shown by McLaughlin et al. to have
potent and selective cytotoxic activity against A-549 human
lung carcinoma,8 and closely related bioactive derivatives have
been found in a number of other Goniothalamus species.9–11 For
example, goniodiol 7-monoacetate isolated from G. amuyon in
1991 by Wu et al. has potent activity against leukaemia, human
melanoma, and CNS carcinoma, though interestingly not against
lung carcinoma.12 The biosynthesis of the styryllactones has been
proposed to incorporate a phenylpropanyl moiety in the processive
polyketide assembly sequence.13
The approach utilises as a key step the rearrangement of an
anomerically linked silyl enol ether nucleophile to introduce the
5,6,7-oxygenation pattern and the phenyl ring present in (+)-
goniodiol. This strategy represents a significant departure from
previously reported routes, each of which focus on ring closure and
homologation methodology rather than exploiting the chemistry
of an anomeric centre. Key stages in our retrosynthetic analysis
of (+)-goniodiol are shown in Scheme 1. The overall strategy
is convergent, with a fragment containing what will become the
right-hand portion of (+)-goniodiol introduced directly onto a
ring system with sufficient functionality to allow subsequent
conversion to the oxygenated lactone. This concise route requires
control of the cis/trans selectivity about a THP ring system
bearing a stereochemical handle that acts as a latent lactone
functionality at C-1. A protected oxymethyl functionality is ideal
for this purpose—the bulk of the protecting group provides trans-
stereocontrol in the rearrangement, and its oxidative degradation
can provide a lactol or lactone suitable for elaboration to the nat-
ural product. Other noteworthy features include generation of the
rearrangement substrate from a readily available starting material,
and selective reduction of a hydroxyketone to the C-6, C-7 diol.
Fig. 1 (+)-Goniodiol, showing the conventional numbering of the carbon
skeleton.
(+)-Goniodiol and its congeners have excited considerable
interest amongst synthetic organic chemists—they are relatively
small and densely functionalised molecules, making them ideal
targets for testing new synthetic methodology. Furthermore,
their interesting and varied bioactivity makes them potential
drug leads and chemical genetic research tools.14 The six major
routes reported to date towards (+)-goniodiol and its con-
geners have exemplified the use of the following key synthetic
aBiological and Biophysical Chemistry Section, Department of Chemistry,
Imperial College London, London, UK SW7 2AZ. E-mail: e.tate@
imperial.ac.uk; Fax: +44 20 7594 1139; Tel: +44 20 7594 5720
bDepartment of Chemistry, The University of Manchester, Manchester, UK
M13 9PL. E-mail: Darren.Dixon@man.ac.uk; Fax: +44 161 2754939;
Tel: +44 161 2751426
Results and discussion
The synthesis commences from commercially available S-(−)-
glycidol (Scheme 2). Treatment with tert-butyldiphenylsilyl-
chloride, triethylamine and DMAP gave the protected alcohol
cDepartment of Chemistry, University of Cambridge, Lensfield Road,
Cambridge, UK CB2 1EW. E-mail: svl1000@cam.ac.uk; Fax: +44 1223
336442; Tel: +44 1223 336398
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We therefore adopted a two step solution to the problem:
alkylation with a-bromo N,N-methylmethoxy acetamide in the
presence of KHMDS afforded 81% yield of the exclusively cis
anomerically-linked Weinreb amide 5 (Scheme 3). This interesting
and remarkable stereoselectivity has been further developed for the
generation of chiral water equivalents.41–43 Subsequent treatment
with phenylmagnesium bromide in THF at −30 ◦C then led to
the phenyl ketone 6 in 97% yield,44 which was converted into a
single trimethylsilyl (TMS) enol ether 7 on exposure to TMSOTf
◦
(1.2 eq.) and triethylamine (1.4 eq.) at −30 C. TMS enol ether
7 was assigned cis/Z stereochemistry by analogy to our previous
work on anomerically linked silyl enol ethers.45
Scheme 1 Key stages in the retrosynthetic analysis of (+)-goniodiol.
Scheme 3 Reagents and conditions: (a) KHMDS, THF, −78 ◦C then
2-bromo-N-methoxy-N-methylacetamide (81% + 16% unreacted 4); (b)
PhMgBr, THF, −30 ◦C (97%); (c) 1.2 eq. TMSOTf, 1.4 eq. Et3N, CH2Cl2,
−78 ◦C to −30 ◦C; (d) 0.1 eq. TMSOTf, CH2Cl2, −30 ◦C (85% over two
steps); (e) (i) THF, PPh3, DEAD, AcOH, 0 ◦C; (ii) NaOMe, MeOH (69%
over two steps).
Scheme 2 Reagents and conditions: (a) TBDPSCl, DMAP, triethylamine,
◦
On exposure to catalytic TMSOTf at −30 C 7 was smoothly
=
CH2Cl2, r.t., 3d (86%); (b) 1.2 eq. CH2 CH(CH2)2MgBr, 0.1 eq. Li2CuCl4,
converted to a separable mixture of the exclusively trans a-hydroxy
ketones 8 and 9 (8 : 9 = 1 : 1) in 85% overall combined yield from
6.† The relative conformation of 8 and 9 was assigned by analogy
to the NMR spectra of related isomers from our previous study
where the configuration was unambiguously demonstrated by X-
ray crystallography methods; this preliminary assignment was
later proven correct upon completion of the total synthesis. In light
of our previous work where we had observed C-6 diastereomeric
ratios of up to 3 : 1 in favour of the desired erythro-isomer, it was
both surprising and disappointing to find that in the present case
no control was observed at the C-6 alcohol.45
THF, −30 ◦C (100%); (c) O3, CH2Cl2, −78 ◦C, then PPh3, r.t. (100%);
(d) base, bromoacetophenone.
2 in 86% yield, to which the subsequent addition of but-3-
enylmagnesium bromide in the presence of catalytic dilithium
copper(II) chloride40 proceeded with exclusive attack at the less
substituted end of the epoxide, to afford the corresponding alkenol
3 in quantitative yield. Ozonolysis of this material followed by
reductive work-up afforded lactol 4 in 100% yield. Unfortunately
however, all attempts to alkylate the anion of 4 with bromoace-
tophenone in order to furnish the requisite anomerically linked
ketone resulted in degradation; evidently the acidity of the a-
protons in bromoacetophenone is such that they are deprotonated
by the lactol alkoxide.
† Attempts to perform this reaction with a tert-butyldimethylsilyl (TBS)
group on the oxymethyl substituent met with concurrent deprotection.
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Attempts to improve the selectivity at this position by changing
the silicon protecting group on the pendent hydroxylmethyl group
and enol ether substituent (TES, TBS) or by varying the Lewis acid
(TBSOTf, TESOTf, SnCl4, BF3.Et2O) were unsuccessful, whilst
experiments aimed at improving kinetic control by performing the
rearrangement reaction at a lower temperature resulted in decom-
position. Given that the equatorially positioned TBDPSOCH2
group is presumably too remote from the a-hydroxy position to
affect the stereochemistry directly, it remains unclear why the
change from the alkyl chain used in previous studies to the more
bulky TBDPS protected oxymethyl group results in a decrease in
selectivity at the hydroxy position a to the ketone. Fortunately,
we found that the undesired diastereoisomer 9 could be inverted
by acetic acid under Mitsunobu conditions46 to provide 8 in 69%
yield after basic hydrolysis of the intermediate acetate (Scheme 3).
The overall yield for 8 including this recovered material was high
(77%), and permitted the rapid generation of large quantities of 8
for use in subsequent steps.
The stereochemistry present at C-7 of (+)-goniodiol was
introduced via a highly diastereoselective reduction of the ketone
moiety of 8 (>95% d.e.) using two equivalents of NaBH4 in
MeOH at 0 ◦C to give diol 10 in quantitative yield (Scheme 4).47
Subsequent reaction with 2,2-dimethoxypropane in acetone with
catalytic camphorsulfonic acid gave the protected diol 11 in 99%
yield, and NOE studies on 11 permitted confident assignment of
the desired diol stereochemistry.
Scheme
5
Reagents and conditions: (a) 10% TBAF, THF (99%);
(b) DMSO, oxalyl chloride, Et3N, CH2Cl2, −78 ◦C (93%); (c) (i) NaO2Cl,
KHPO4, 2-methyl-2-butene, H2O/tBuOH (1 : 2); (ii) 2 eq. Pb(OAc)4, 2 eq.
pyridine, THF, r.t. (68% over two steps).
formed in the latter route could be unstable, leading to potential
problems during ozonolysis. Thus, oxidation of 12 to aldehyde 13
using the Swern protocol49 in 93% yield, was followed by exposure
to NaO2Cl, KHPO4 and 2-methyl-2-butene in 1 : 2 water/tBuOH50
to give the corresponding acid, which was used in the following
step without further purification (Scheme 5). Exposure to lead
tetraacetate51 in the presence of pyridine in tetrahydrofuran at
room temperature afforded the anomeric acetate 14 as a 2 : 1
mixture of anomers. Considering the diverse range of potential
fragmentations and alternative couplings available to the radical
and ionic intermediates in this reaction, we were pleased to observe
the formation of 14 in excellent overall yield from 13.
Deacetylation of 14 with 0.5 eq. of NaOMe in MeOH was
followed by oxidation with catalytic tetra-n-propylammonium
perruthenate (TPAP)52 in the presence of N-methyl-morpholine
N-oxide (NMO) to give the lactone 15 in 97% overall yield
(Scheme 6). Attempts to introduce the a,b-unsaturation into
the lactone system in one step by heating with benzeneselenic
anhydride53 were unsuccessful. However, we found that this
transformation could be achieved efficiently in two steps via
sequential treatment with lithium diisopropylamide and PhSeBr
to give an epimeric mixture of selenides 16, followed by oxidative
elimination with H2O2 resulting in oxygenated lactone 17 in 82%
yield over the two steps.54 Final deprotection of the C-6, C-7 diol
with 50% aqueous acetic acid at 80 ◦C for 30 minutes gave the
natural product (+)-goniodiol 1 in 97% yield. All physical data for
the synthetic sample of 1 were in excellent agreement with those
reported for the natural product.7
Scheme 4 Reagents and conditions: (a) 2 eq. NaBH4, MeOH, 0 ◦C
(100%); (b) 2,2-dimethoxypropane, acetone, cat. camphorsulfonic acid
(99%). The inset figure shows key observed NOE signals used to assign
diol stereochemistry.
The sequence to convert the tert-butyldiphenylsilyl protected
alcohol of 11 into the a,b-unsaturated lactone of the natural
product was initiated by treatment with TBAF to release the free
alcohol 12 in 99% yield (Scheme 5). We considered two potential
strategies for converting 12 to a d-lactone: oxidation to the acid
followed by a radical degradation with concurrent anomeric
oxidation or an ionic strategy via activation and elimination of
the alcohol to form an exo–enol ether, which could be ozonolysed
directly to the lactone.
Conclusions
The route to (+)-goniodiol described here once again illustrates the
utility of anomeric oxygen-to-carbon rearrangements in natural
product total synthesis. It provides rapid access to a densely
functionalised molecule, starting from a commercially available
starting material, which was subsequently converted to the desired
product in 21% overall yield. The synthesis described above is likely
In the event, the former route was selected as there is some
literature precedent for such an anomeric oxidative degradation
process.48 Furthermore, it was considered that the enol ether
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plate from dichloromethane. Proton NMR spectra were recorded
in CDCl3, on Bruker AC-200, Bruker DPX-200, Bruker AM-400,
Bruker DPX-400 or Bruker DPX-600 spectrometers, at 200, 400 or
600 MHz, with residual chloroform as the internal reference (dH =
7.26 ppm). 13C NMR spectra were recorded in CDCl3 on the same
spectrometers at 50, 100 or 150 MHz, with the central peak of
chloroform as the internal reference (dC = 77.0 ppm). Mass spectra
and accurate mass data were obtained on a Micromass Platform
LC-MS, Kratos MS890MS or Bruker BIOAPEX 4.7 T FTICR
spectrometer, and at the EPSRC Mass Spectrometry Service, by
electron ionisation, chemical ionisation or fast atom/ion bom-
bardment techniques. GC analysis was performed on a Hewlett
Packar◦d 5890 S◦eries II Gas Chromatograph [80 ◦C (10 min) then
to 180 C (at 5 C min−1), then 10 min at 180 ◦C]. DEPT135 and
two-dimensional (COSY, HMQC, HMBC) NMR spectroscopy
were used, where appropriate, to aid in the assignment of signals
in the proton and 13C NMR spectra.
Syntheses
(R)-tert-Butyloxiranylmethoxydiphenylsilane (2)55. To a stirred
solution of S-(−)-glycidol (5.0 g, 68.0 mmol) in dichloromethane
(150 mL) was added triethylamine (15.1 mL, 109.0 mmol), tert-
butyldiphenylsilyl chloride (19 mL, 75.0 mmol) and dimethy-
laminopyridine (2.5 g, 20.4 mmol), and the reaction mixture stirred
for 3 days. 1.5 N HCl (100 mL) was added, the organic layer
separated, and the aqueous layer extracted with dichloromethane
(2 × 100 mL). The combined organics were washed with satu-
rated aqueous bicarbonate solution (150 mL) followed by brine
(100 mL), dried (MgSO4), filtered, and the solvent removed in
vacuo to leave a slightly yellow oil. Purification by flash column
chromatography, eluting with 5% to 10% diethyl ether–petroleum
ether (bp 40–60 ◦C), gave 2 (18.4 g, 86%) as a colourless oil.
[a]D29 (CHCl3, c 2.1) = +2.5; mmax (thin film)/cm−1 3070, 2858,
1589, 1472, 1428, 1390, 1361, 1254; dH (400 MHz; CDCl3):
7.75–7.73 (4H, m, Ph), 7.49–7.41 (6H, m, Ph), 3.90 (1H, dd, J
11.8 and 3.1, CHHCHCH2OSi), 3.76 (1H, dd, J 11.8 and 4.7,
CHHCHCH2OSi), 3.18–3.14 (1H, m, CHCH2OSi), 2.77 (1H, t, J
4.3, CHHOSi), 2.66–2.63 (1H, m, CHHOSi), 1.12 (9H, C(CH3)3);
dC (100 MHz; CDCl3): 135.7 (Ph), 135.6 (Ph), 133.3 (Ph, quat.),
129.8 (Ph), 127.8 (Ph), 127.7 (Ph), 64.4 (CH2CHCH2OSi), 52.3
(CHCH2OSi), 44.4 (CH2OSi), 27.0 (C(CH3)3), 19.3 (C(CH3)3).
Scheme 6 Reagents and conditions: (a) (i) 0.5 eq. NaOMe, MeOH; (ii)
5 mol% TPAP, 1.5 eq. NMO, CH2Cl2, r.t. (97% over two steps); (b) LDA,
THF, −78 ◦C then 2 eq. PhSeBr; (c) CH2Cl2/30% H2O2(aq) (2 : 1), 0 ◦C,
10 min (82% over two steps); (d) 50% AcOH(aq), 80 ◦C, 30 min (97%).
to prove a versatile strategy for the construction of analogues of
(+)-goniodiol via straightforward variation of the substituent on
the ketone used in the rearrangement reaction, and will also allow
the synthesis of related families of styryllactones to be approached.
Experimental
General methods
All reactions were carried out under an atmosphere of argon,
and those not involving aqueous reagents were carried out
in oven-dried glassware, cooled under vacuum. Diethyl ether
and tetrahydrofuran were distilled over sodium benzophenone;
dichloromethane, methanol and toluene were distilled over cal-
cium hydride. All other solvents and reagents were used as
supplied, unless otherwise stated. Flash column chromatography
was carried out using Merck Kieselgel (230–400 mesh). Analytical
thin layer chromatography was performed on glass plates pre-
coated with Merck Kieselgel 60 F254, and visualised under ultra-
violet irradiation, or by staining with aqueous acidic ammonium
molybdate(IV) or acidic potassium manganate(VII). Melting points
were recorded using a Reichert hot stage apparatus, and are
uncorrected. Boiling points were obtained during distillation,
unless otherwise noted. Microanalyses were performed in the
microanalytical laboratories at the Department of Chemistry,
Lensfield Road, Cambridge. Optical rotations were measured at
29 ◦C on an Optical Activity AA-1000 polarimeter, and are given
in 10−1 deg cm2 g−1; concentration (c) is in g per 100 mL. Infrared
spectra were obtained on Perkin-Elmer 983G or FTIR 1620
spectrometers, from a thin film deposited onto a sodium chloride
(R)-1-(tert-Butyldiphenylsilanyloxy)-hept-6-en-2-ol (3)56. To a
stirred s◦olution of 2 (2.0 g, 6.41 mmol) in tetrahydrofuran (10 mL)
at −30 C was added a solution of dilithium tetrachlorocuprate
in tetrahydrofuran (0.1 M, 6.41 mL) followed by a solution of
butenylmagnesium bromide in tetrahydrofuran (0.5 M, 15.4 mL).
After 15 min the reaction mixture was quenched by the addition of
saturated aqueous ammonium chloride solution (5 mL), distilled
water added (10 mL), and the mixture extracted with diethyl
ether (3 × 15 mL). The combined organic extracts were dried
(MgSO4), filtered and the solvent removed in vacuo to leave a
yellow oil. Purification by flash column chromatography, eluting
with 12% diethyl ether–petroleum ether (bp 40–60 ◦C) gave the
title compound (2.4 g, 100%) as a colourless oil. Found: C, 75.14;
H, 8.71%. C23H32O2Si requires: C, 74.95; H, 8.75%. [a]2D9 (CHCl3,
c 3.0) = +10.0; mmax (thin film)/cm−1 3565 (br), 3071, 3051, 2931,
2858, 1640, 1589, 1472, 1428, 1261, 1113; dH (400 MHz; CDCl3):
7.71–7.69 (4H, m, Ph), 7.48–7.39 (6H, m, Ph), 5.85–5.75 (1H, m,
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CHCH2), 5.03–4.94 (2H, m, CHCH2), 3.76–3.67 (2H, m, CHOH
and CHHOSi), 3.52 (1H, dd, J 10.0 and 7.5, CHHOSi), 2.54
(1H, d, J 3.3, OH), 2.09–2.05 (2H, m, CH2), 1.58–1.38 (4H, m,
2 × CH2), 1.11 (9H, C(CH3)3); dC (100 MHz; CDCl3): 138.6 (Ph),
135.6 (Ph), 133.3 (Ph, quat.), 133.2 (Ph, quat.), 129.8 (CHCH2),
114.7 (CHCH2), 71.8 (CHOH), 68.1 (CH2O), 33.7 (CH2), 32.3
(CH2), 26.9 and 26.8 (C(CH3)3), 24.8 (CH2), 19.3 (C(CH3)3); m/z
(EI) 311 (62%, M − C4H9), 199 (100%); Found (EI): M − C4H9
311.1466. C19H23O2Si requires 311.1467.
in dimethyl sulfoxide (7 mL) and treated with NaOAc (1.0 g,
8.0 mmol) at 25 ◦C for 1 h. The mixture was diluted with
diethyl ether (10 mL), washed with water (3 × 10 mL), and the
organic layer dried (MgSO4), filtered and the solvent evaporated
in vacuo to leave pure 5 (1.15 g, 81%) as a colourless oil. [a]D29
(CHCl3, c 1.6) = +43.8; mmax (thin film)/cm−1 3071, 2940, 1677,
1427, 1390, 1112, 1040; dH (400 MHz; CDCl3): 7.70–7.68 (4H,
m, Ph), 7.43–7.35 (6H, m, Ph), 4.59–4.47 (3H, m, OCHO and
OCH2CON), 3.78 (1H, dd, J 10.0 and 5.7, CHHOSi), 3.65–3.58
(5H, m, CHHOSi, CHOCHO and NCH3), 3.16 (3H, s, OCH3),
2.02–1.85 (2H, m, CH2), 1.62–1.42 (3H, m, CHH and CH2),
1.24–1.11 (1H, m, CHH), 1.06 (9H, s, C(CH3)3); dC (100 MHz;
CDCl3): 170.7 (CON), 135.5 (Ph), 133.6 (Ph, quat.), 129.6 (Ph),
127.6 (Ph), 101.5 (OCHO), 76.8 (CHOCHO), 66.9, 65.6, 61.2
(OCH3), 32.2 (NCH3), 30.9 (CH2), 27.1 (CH2), 26.8 (C(CH3)3),
21.5 (CH2), 19.2 (C(CH3)3). m/z (FAB) 494 (100%, MNa+);
Found (FAB): 494.2350 (MNa+). C26H37O5SiNNa: 494.2339.
(R)-6-(tert-Butyldiphenylsilanyloxymethyl)-tetrahydropyran-2-ol
(4). To
a stirred solution of 3 (1.9 g, 5.16 mmol) in
dichloromethane (150 mL) at −78 ◦C was added sodium
bicarbonate (0.3 g), and O3 (1.5 L s−1) bubbled through
until the reaction mixture became light blue (about 30 min).
Triphenylphosphine (1.65 g, 6.2 mmol) was added to the reaction
mixture, which was allowed to warm to ambient temperature
and stirred for 16 h. The solvent was removed in vacuo to
leave a slightly creamy oil which was purified by flash column
chromatography, eluting with 10% to 40% diethyl ether–petroleum
ether (bp 40–60 ◦C), to give 4 (1.9 g, 100%), as a 3 : 2 mixture
of anomers, as a colourless oil. Found: C, 71.03; H, 8.20%.
C22H30O3Si requires: C, 71.31; H, 8.16%. [a]2D9 (CHCl3, c 3.0) =
−1.5; mmax (thin film)/cm−1 3400 (br), 2930, 2857, 1726, 1461,
1428, 1274, 1113; dH (400 MHz; CDCl3): 9.75 (1H of trace
tautomeric aldehyde, br s, CH2CHO), 7.69–7.59 (4H major and
minor, m, Ph), 7.44–7.31 (6H major and minor, m, Ph), 5.27 (1H
minor, br s, OCHO), 4.69–4.64 (1H major, m, OCHO), 4.10–4.03
(1H minor, m, CHOCHO), 3.80–3.46 (3H major and 2H minor,
m, CH2OSi major and minor and CHOCHO major), 2.88 (1H
major, d, J 6.0, OH), 2.42 (1H minor, d, J 1.8, OH), 1.89–1.11
(6H major and 6H minor, m, 3 × CH2), 1.07 (9H, C(CH3)3);
dC (100 MHz; CDCl3): 135.7 (Ph), 135.6 (Ph), 129.6 (quat. Ph,
major and minor), 127.7 (Ph), 127.6 (Ph), 96.3 and 91.8 (CHOH,
major and minor), 76.8 and 69.4 (CHOCHO, major and minor),
67.5 and 67.0 (CH2OSi, major and minor), 32.6 and 30.0 (CH2
major and minor), 29.1 and 27.9 (CH2 major and minor), 27.7
and 27.3 (CH2 major and minor), 26.9 (C(CH3)3), 22.7 and 19.3
(C(CH3)3); m/z (EI) 313 (7%, M − C4H9), 91 (100%). Found
(EI) M − C4H9 313.1258. C18H21O3Si requires 313.1260.
(R,R)-2-(6ꢀ -tert-Butyldiphenylsilanyloxymethylpyranyloxy)-1-
phenylethanone (6). To a stirred solution of 5 (1.0 g, 2.12 mmol) in
tetrahydrofuran (10 mL) at −30 ◦C was added dropwise a solution
of phenylmagnesium bromide in diethyl ether (3.0 M, 1.41 mL).
After 30 min the reaction mixture was quenched by the addition
of saturated aqueous ammonium chloride (3 mL), extracted with
diethyl ether (2 × 10 mL), the combined organics washed with
brine (20 mL), dried (MgSO4), filtered and the solvent evaporated
in vacuo to leave a yellow oil. Purification of this oil by flash
column chromatography, eluting with 15% ether–petroleum ether
◦
(bp 40–60 C) isolated 6 (1.0 g, 97%) as a colourless oil. [a]D29
(CHCl3, c 2.0) = +39.8; mmax (thin film)/cm−1: 3070, 2931, 2856,
1703, 1428, 1155, 1112, 1038; dH (400 MHz; CDCl3): 7.93–7.87
(2H, m, Ph), 7.73–7.67 (3H, m, Ph), 7.58–7.31 (10H, m, Ph), 5.07
(1H, d, J 7.0, CHHCOPh), 4.94 (1H, d, J 7.0, CHHCOPh), 4.61–
4.59 (1H, m, OCHO), 3.82 (1H, dd, J 10.2 and 5.9, CHHOSi),
3.69–3.57 (2H, m, CHOCHO and CHHOSi), 2.01–1.16 (6H, m,
3 × CH2), 1.08 (9H, SiC(CH3)3); dC (100 MHz; CDCl3): 195.9
(COPh), 135.9 (Ph), 135.6 (Ph, quat.), 135.1 (Ph, quat.), 134.8 (Ph),
128.7 (Ph), 127.9 (Ph), 127.7 (Ph), 127.6 (Ph), 101.7 (OCHO), 76.9
(CHOCHO), 69.9 (OCH2COPh), 66.9 (CH2OSi), 31.0 (CH2), 27.2
(CH2), 26.8 (C(CH3)3), 21.6 (CH2), 19.3 (C(CH3)3). m/z (FAB) 511
(100%, MNa+); Found (FAB): 511.2317 (MNa+).C30H36O4SiNa:
511.2281.
(R,R)-N-Methoxy-N-methyl-2-(6ꢀ-tert-butyldiphenylsilanyloxy-
methylpyranyloxy)-acetamide (5). To a stirred solution of 4
(1.1 g, 3.0 mmol) in tetrahydrofuran (7.0 mL) at −78 ◦C was
added dropwise a solution of potassium hexamethyldisilylamide
in toluene (0.5 M, 6.3 mL), and the reaction mixture sucessively
warmed to 0 ◦C and cooled to −78 ◦C. After the dropwise
addition of a solution of freshly distilled 2-bromo-N-methoxy-N-
methylacetamide (0.8 g, 4.5 mmol) in tetrahydrofuran (3.0 mL)
the mixture was stirred at −78 ◦C for 2 h and quenched by
the addition of a saturated aqueous solution of ammonium
chloride (5 mL). Water was added (10 mL), the mixture
extracted with diethyl ether (2 × 20 mL), the combined organics
washed with brine (30 mL), dried (MgSO4), filtered and the
solvent evaporated in vacuo to leave a yellow oil. Purification
of this oil by flash column chromatography, eluting with
50% to 100% ether–petroleum ether (bp 40–60 ◦C) isolated
unreacted 4 (0.18 g, 16%) and 5 contaminated with unreacted
Z-(2R, 2ꢀR)-Trimethyl-[1-phenyl-2-(6ꢀ-tert-butyldiphenylsilanyl-
oxymethylpyran-2ꢀ-yloxy)-vinyloxy]-silane (7). To a stirred solu-
tion of 6 (2.70 g, 5.57 mmol) in dichloromethane (10 mL) at
−78 ◦C was added Et3N (1.10 mL, 7.80 mmol) followed by
dropwise addition of TMSOTf (1.21 mL, 6.70 mmol), and the
mixture allowed to warm to −30 ◦C. The reaction mixture was
quenched by the rapid addition of saturated aqueous NaHCO3
(5 mL), extracted with dichloromethane (2 × 10 mL), the organic
extracts washed with brine (10 mL), dried (Na2SO4), filtered and
the volatile organics removed in vacuo to give crude 7 as a yellow
oil. dH (400 MHz; CDCl3): 7.76–7.60 (2H, m, Ph), 7.47–7.12 (3H,
m, Ph), 7.58–7.31 (10H, m, Ph), 6.78 (1H, s, OCHCPh), 4.78–4.72
(1H, m, OCHO), 3.83–3.77 (1H, m, CHHOSi), 3.73–3.67 (2H,
m, CHOCHO and CHHOSi), 2.00–1.52 (6H, m, 3 × CH2), 1.01
(9H, C(CH3)3), 0.29 (9H, s, Si(CH3)3); dC (100 MHz; CDCl3): 137.0
(quat.), 135.7 (Ph), 135.6 (Ph), 134.1 (quat.), 133.0 (quat.), 129.7
(Ph), 123.7 (Ph), 123.6 (Ph), 101.8 (OCHO), 77.2 (CHOCHO),
2-bromo-N-methoxy-N-methylacetamide. The mixture of
5
and 2-bromo-N-methoxy-N-methylacetamide was dissolved
1702 | Org. Biomol. Chem., 2006, 4, 1698–1706
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66.7 (CH2OSi), 30.7 (CH2), 27.0 (CH2), 26.8 (C(CH3)3), 21.4
(CH2), 19.3 (C(CH3)3), 0.70 (Si(CH3)3).
chromatography, eluting with 5%–50% diethyl ether–petroleum
ether (bp 40–60 ◦C), to give 8 (0.49 g, 69%) as a colourless oil.
Spectroscopic data for 8 were identical to those reported above.
(2S, 2ꢀR, 6ꢀR)-2-Hydroxy-2-(6ꢀ -tert-butyldiphenylsilanyloxy-
methylpyranyl)-1-phenylethanone (8) and (2R, 2ꢀR, 6ꢀR)-2-hydroxy-
2-(6ꢀ-tert-butyldiphenylsilanyloxymethylpyranyl)-1-phenylethanone
(9). The crude oil (7) was dissolved in dichloromethane (5 mL),
cooled to −30 ◦C, and TMSOTf (0.10 mL, 0.56 mmol) added
dropwise. After 10 min the reaction mixture was quenched with
aqueous NaOH (10%, 10 mL), extracted with dichloromethane
(2 × 10 mL), the organic extracts washed with brine (10 mL),
dried (MgSO4), filtered, and the solvent evaporated in vacuo to
give a yellow oil; proton NMR spectroscopy showed an 8 : 9 ratio
of 1 : 1 (by integration of the signals in the 400 MHz proton
NMR spectrum at dH = 4.90 (8) and 5.17 (9)). Purification of
this oil by flash column chromatography, eluting with 20% diethyl
ether–petroleum ether (bp 40–60 ◦C) isolated 8 and 9 (2.30 g,
85%) as a colourless oil. Repeated medium pressure flash column
chromatography, eluting with 20% diethyl ether–petroleum ether
(bp 40–60 ◦C) isolated first 9 (1.14 g, 42%), and then 8 (1.13 g,
42%) as colourless oils. Data for 8: [a]2D9 (CHCl3, c 1.6) = −6.75;
mmax (thin film)/cm−1 3471 (br), 3070, 2929, 1738, 1693, 1598, 1471,
1266, 1110; dH (600 MHz; CDCl3): 7.88–7.33 (15H, m, Ph), 5.17
(1H, dd, J 7.1 and 4.2, CHOH), 4.04–4.01 (1H, m, OCH2CH),
3.89 (1H, dt, J 8.6 and 4.2, CHCHOH), 3.68 (1H, dd, J 10.4
and 6.2, OCHH), 3.63 (1H, d, J 7.1, OH), 3.57 (1H, dd, J 10.4
and 6.7, OCHH), 1.75–1.32 (6H, m, CH2CH2CH2), 1.02 (9H, s,
(CH3)3Si); dC (150 MHz; CDCl3): 200.2 (COPh), 135.5 (Ph,
quat.), 134.9 (Ph), 133.5 (Ph, quat.), 133.4 (Ph, quat.), 133.3 (Ph),
129.6 (Ph), 128.5 (Ph), 128.3 (Ph), 127.7 (Ph), 127.6 (Ph), 76.1
(CHOH), 73.3 (CHOCHCH), 72.8 (CHCHOH), 63.3 (CH2OSi),
26.8 (C(CH3)3), 26.4 (CH2), 24.8 (CH2), 19.1 (C(CH3)3), 18.4
(CH2); m/z (FAB) 511 (63%, MNa+), 354 (62%), 197 (100%);
Found (FAB): MNa+ 511.2265. C30H36O4SiNa: 511.2281. Data
for 9: [a]2D9 (CHCl3, c 1.1) = −23.3◦; mmax (thin film)/cm−1 3467 (br),
3068, 2937, 1680, 1598, 1471, 1265, 1111; dH (600 MHz; CDCl3):
7.80–7.33 (15H, m, Ph), 4.90 (1H, dd, J 6.2 and 3.3, CHOH),
3.93–3.90 (1H, m, CHCHOH), 3.86 (1H, m, OCH2CH), 3.73
(1H, d, J 6.2, OH), 3.46 (1H, dd, J 10.1 and 7.5, OCHH), 3.26
(1H, dd, J 10.1 and 5.3, OCHH), 1.79–1.51 (6H, m, 3 × CH2),
0.97 (9H, s, (CH3)3Si). dC (150 MHz; CDCl3): 200.3 (COPh),
135.6 (Ph), 135.5 (Ph), 134.6 (Ph, quat.), 133.8 (Ph), 133.7 (Ph,
quat.), 133.5 (Ph, quat.), 129.7 (Ph), 128.7 (Ph), 127.7 (Ph), 76.0
(CHOH), 73.4 (CHOCHCH), 73.3 (CHCHOH), 64.1 (CH2OSi),
26.8 (C(CH3)3), 25.5 (CH2), 24.5 (CH2), 19.2 (C(CH3)3), 18.4
(CH2); m/z (FAB) 511 (70%, MNa+), 354 (54%), 197 (100%);
Found (FAB) MNa+ 511.2317. C30H36O4SiNa requires 511.2281.
(4R, 5R, 2ꢀR, 6ꢀR)-2-(6ꢀ-tert-Butyldiphenylsilanyloxymethyl-
pyranyl)-1-phenylethane-1,2-diol (10). To a stirred solution of
8 (0.45 g, 0.92 mmol) in methanol (5 mL) at 0 ◦C was added
sodium borohydride (0.07 g, 1.84 mmol). After 1 min the reaction
was quenched by the addtion of distilled water (1 mL), and the
reaction mixture extracted with diethyl ether (3 × 10 mL). The
combined organic extracts were washed with brine (10 mL), dried
(MgSO4), filtered and the solvent removed in vacuo to leave 10
(0.45 g, 100%) as a colourless oil. [a]2D9 (CHCl3, c 0.37) = −4.3;
mmax (thin film)/cm−1 3452 (br), 3070, 2934, 2857, 1428, 1261,
1112; dH (600 MHz; CDCl3): 7.71–7.68 (6H, m, Ph), 7.67–7.21
(9H, m, Ph), 4.93–4.92 (1H, OCHCHOH), 4.02–3.98 (1H, m,
CHCH2OSi), 3.89–3.83 (2H, m, CHHOSi and OCHCHOH),
3.72–3.64 (2H, m, OCHCHOH and CHOHPh), 3.54 (1H, dd, J
10.7 and 5.8, CHHOSi), 2.80 (1H, d, J 6.1, CHOHPh), 1.68–
1.12 (6H, 3 × CH2), 1.09 (9H, s, C(CH3)3); dC (150 MHz;
CDCl3): 141.4 (Ph, quat.), 135.6, 135.5, 133.4 (Ph, quat.), 133.3
(Ph, quat.), 129.8 (Ph), 128.3 (Ph), 127.8 (Ph), 127.7 (Ph), 127.3
(Ph), 126.0 (Ph), 76.4 (CHOHCHOHPh), 75.6 (COHPh), 73.8
(CHCH2OSi), 70.0 (CHCHOHCHOH), 63.1 (CH2OSi), 26.8
(CH2), 26.7 (C(CH3)3), 25.0 (CH2), 19.1 (C(CH3)3), 18.2 (CH2);
m/z (FAB) 513 (3%, MNa+), 147 (100%). Found (FAB): MNa+
513.2448. C30H38O4SiNa requires 513.2437.
(4R, 5S, 2ꢀR, 6ꢀR)-2,2-Dimethyl-5-(6ꢀ-tert-butyldiphenylsilanyl-
oxymethylpyranyl)-4-phenyl-[1,3]dioxolane (11). To a stirred so-
lution of 10 (0.45 g, 0.92 mmol) in acetone (6 mL) was added 2,2-
dimethoxypropane (1 mL, 8.2 mmol) and ( )-camphorsulfonic
acid (0.02 g). After 30 min the reaction was quenched by the
addition of triethylamine (0.2 mL), and the volatile components
removed in vacuo to leave a slightly yellow oil. Purification of
this oil by flash column chromatography, eluting with 12% diethyl
ether–petroleum ether (bp 40–60 ◦C) isolated 11 (0.47 g, 99%) as a
colourless oil. [a]D29 (CHCl3, c 0.83) = −15.0; mmax (thin film)/cm−1
2934, 2856, 1589, 1460, 1378, 1218, 1111, 1052; dH (600 MHz;
CDCl3): 7.64–7.62 (4H, m, Ph), 7.43–7.35 (6H, m, Ph), 7.30–7.26
(2H, m, Ph), 7.20–7.16 (3H, m, Ph), 5.06 (1H, d, J 6.9, CHPh), 4.37
(1H, t, J 6.9, CHCHPh), 3.93–3.90 (1H, m, CHCH2OSi), 3.53–
3.51 (2H, m, CH2OSi), 3.34–3.31 (1H, br q, J 5.9, CHCHCHPh),
1.63 (3H, s, CH3), 1.61–1.52 (2H, m, SiOCH2CHCH2), 1.47
(3H, s, CH3), 1.45–1.21 (2H, m, CH2CH2CH2), 1.10–1.07 (2H,
m, CH2CHCH), 1.03 (9H, s, C(CH3)3); dC (150 MHz; CDCl3):
135.6 (Ph), 133.7 (Ph, quat.), 129.6 (Ph, quat.), 129.5 (Ph,
quat.), 128.0 (Ph), 127.9 (Ph), 127.6 (Ph), 127.5 (Ph), 108.9
(CCH3), 79.6 (CHCHPh), 79.4 (CHPh), 71.9 (SiOCH2CH), 70.1
(CHCHCHPh), 63.7 (SiOCH2), 26.9 (CH3), 26.8 (C(CH3)3), 26.2
(CH2CHCH), 25.4 (CH2CHCH2), 25.1 (CH3), 19.2 (C(CH3)3),
17.8 (CH2CH2CH2); m/z (FAB) 530 (34%, MNa+), 276 (100%).
Found (FAB) MNa+ 530.2873. C33H42O4SiNa requires 530.2852.
Conversion of (9) to (8). To a stirred solution of 9 (0.71 g,
1.45 mmol), acetic acid (0.11 mL, 1.89 mmol) and triphenylphos-
phine (0.50 g, 1.89 mmol) in tetrahydrofuran (10 mL) at 0 ◦C was
added diethyl azodicarboxylate (0.3 mL, 1.89 mmol) dropwise via
syringe. The reaction mixture was allowed to warm to ambient
temperature and stirred for 16 h, diluted with diethyl ether
(10 mL), washed with distilled water (3 × 20 mL), and the volatile
components removed in vacuo to leave a yellow oil which was
dissolved in methanol (5 mL) and stirred at ambient temperature.
A solution of sodium methoxide (2.0 M, 0.010 mL) was added, and
the reaction mixture stirred for 30 min and the solvent removed
in vacuo to leave a yellow oil which was purified by flash column
(4R, 5S, 2ꢀR, 6ꢀR)-2,2-Dimethyl-5-(6ꢀ-hydroxymethylpyranyl)-4-
phenyl[1,3]dioxolane (12). 11 (0.42 g, 0.80 mmol) was dissolved in
a stirred solution of tetra-n-butylammonium fluoride in tetrahy-
drofuran (1.0 M, 8 mL). After 2 h the solvent was removed in
vacuo, and the brown residue purified by flash column chromato-
graphy, eluting with 30% to 100% diethyl ether–petroleum ether
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◦
(bp 40–60 C) isolated 12 (0.23 g, 99%) as a colourless oil. [a]D29
from 13) as a colourless oil. Data for 14 (isolated as a 2 : 1 mixture
of anomers): [a]D29 (CHCl3, c 1.0) = −116.0; mmax (thin film)/cm−1
2982, 2938, 1746, 1456, 1371, 1241, 1166, 1061, 1038, 1008; dH
(600 MHz; CDCl3): 7.39–7.26 (5H, m, Ph), 6.13 (1H major, br s,
CHOAc), 5.46 (1H minor, dd, J 9.3 and 1.9, CHOAc), 5.19 (1H
major, d, J 6.9, CHPh), 5.13 (1H minor, d, J 6.5, CHPh), 4.26
(1H minor, t, J 6.4, CHCHPh), 4.18 (1H major, dd, J 6.8 and 1.8,
CHCHPh), 3.51–3.46 (1H major, m, CHCHCHPh), 3.25–3.20
(1H minor, m, CHCHCHPh), 2.09 (3H minor and 3H major, s,
COCH3), 1.85 (3H major and 3H minor, s, COCH3), 1.69–0.97
(6H major and 6H minor, m, 3 × CH2); m/z (FAB) 344 (88%,
MNa+), 149 (100%); Found (FAB) MNa+ 342.1535. C18H24O5Na
requires 343.1522.
(CHCl3, c 0.87) = −46.0; mmax (thin film)/cm−1 3451 (br), 2937,
1457, 1372, 1217, 1104, 1046; dH (400 MHz; CDCl3): 7.42–7.26
(5H, m, Ph), 5.16 (1H, d, J 6.9, CHPh), 4.48 (1H, t, J 7.0,
CHCHPh), 3.90–3.84 (1H, m, CHCH2OSi), 3.58–3.47 (2H, m,
and CHCHCHPh), 3.33 (1H, dd, J 11.3 and 3.7, CHHOSi), 1.88
(1H, br s, OH), 1.66 (3H, s, CH3), 1.62–1.51 (2H, m, CH2), 1.49
(3H, s, CH3), 1.40–1.26 (2H, m, CH2), 1.18–1.03 (2H, m, CH2);
dC (100 MHz; CDCl3): 137.5 (Ph, quat.), 128.3 (Ph), 127.7 (Ph),
127.5 (Ph), 108.9 (CCH3), 79.1 (CHPh), 77.4 (CHCHPh), 72.0
(OHCH2CH), 69.3 (CHCHCHPh), 62.3 (CH2OH), 27.0 (CH3),
25.8 (CH2), 25.5 (CH2), 25.1 (CH3), 18.3 (CH2); m/z (FAB)
315 (100%, MNa+); Found (FAB) MNa+ 315.1589. C17H24O4Na
requires 315.1573.
(6R, 4ꢀS, 5ꢀR)-6-(2ꢀ,2ꢀ-Dimethyl-5ꢀ-phenyl-[1ꢀ,3ꢀ]dioxolan-4ꢀ-yl)-
pyran-2-one (15). To a stirred solution of 14 (0.10 g, 0.313 mmol)
in methanol (2 mL) was added a solution of sodium methoxide in
methanol (0.5 M, 0.02 mL). After 10 min the reaction mixture was
diluted with diethyl ether (20 mL) and the solution filtered through
a silica plug, eluting with diethyl ether, and the solvent removed in
vacuo to leave the lactol as a colourless oil which was used without
further purification. Following the protocol of Ley et al.,57 this
colourless oil was dissolved in dichloromethane (2 mL) and stirred
(2R, 6R, 4ꢀS, 5ꢀR)-6-(2ꢀ,2ꢀ-Dimethyl-5ꢀ-phenyl-[1ꢀ,3ꢀ]dioxolan-4ꢀ-
yl)-pyran-2-carbaldehyde (13). To a stirred solution of oxalyl
chloride (0.084 mL) in dichloromethane (20 mL) at −78 ◦C
was dropwise added a solution of dimethyl sulfoxide (0.148 mL)
in dichloromethane (10 mL). After 30 min a solution of 12
(100 mg, 0.34 mmol) in dichloromethane (5 mL) was added
◦
dropwise, and the reaction mixture stirred at −78 C for 60 min
before triethylamine (0.39 mL) was added and the reaction
mixture allowed to warm to ambient temperature. The reaction
mixture was extracted with dichloromethane (3 × 20 mL) and
the combined organic extracts washed with brine (20 mL), dried
(MgSO4), filtered and the solvent removed in vacuo to leave
a colourless oil. Purification by flash column chromatography,
eluting with 30% diethyl ether–petroleum ether (bp 40–60 ◦C),
isol◦ated 13 (0.092 g, 93%) as a white crystalline solid (mp 76–
78 C). [a]2D9 (CHCl3, c 1.0) = +4.0; mmax (thin film)/cm−1 2938,
1727, 1454, 1378, 1219, 1116, 1052, 1014; dH (400 MHz; CDCl3):
9.17 (1H, d, J 0.6, CHO), 7.39–7.27 (5H, m, Ph), 5.21 (1H, d,
J 6.9, CHPh), 4.31 (1H, t, J 6.3, CHCHPh), 4.11 (1H, d, J 4.9,
CHCHO), 3.35–3.30 (1H, m, CHCHCHPh), 1.92–1.88 (1H, m,
CHH), 1.70 (3H, s, CH3), 1.65–1.52 (1H, m, CHH), 1.51 (3H, s,
CH3), 1.49–0.99 (4H, m, 2 × CH2); dC (100 MHz; CDCl3): 206.0
(CHO), 137.5 (Ph, quat.), 128.1 (Ph), 128.0 (Ph), 127.5 (Ph), 109.2
(CCH3), 81.0 (CHPh), 79.0 (CHCHPh), 78.9 (CHCHO), 73.2
(CHCHCHPh), 26.8 (CH3), 26.5, 25.2 (CH3), 23.5 (CH2), 19.2;
m/z (FAB) 290 (55%, M+); Found (FAB) 290.1527 (M+). C17H22O4
requires 290.1518.
˚
at ambient temperature. 4 A molecular sieves (0.2 g) were added
followed by N-methylmorpholine N-oxide (0.055 g, 0.47 mmol)
and tetra-n-propylammonium perruthenate (0.006 g, 0.016 mmol).
After 10 min the reaction mixture was filtered through Celite
(eluting with diethyl ether) and the solvent was removed in vacuo to
leave a brown oil. Purification by flash column chromatography,
eluting with 50% diethyl ether–petroleum ether (bp 40–60 ◦C),
isolated 15 (0.084 g, 97% from 14) as a colourless oil. Found:
C, 69.53; H, 7.17%. C16H20O4 requires C, 69.54; H, 7.30%. [a]D29
(CHCl3, c 0.54) = −51.9; mmax (thin film)/cm−1 2960, 2940, 1735,
1456, 1380, 1244, 1159, 1055; dH (400 MHz; CDCl3): 7.47–7.45
(2H, m, Ph), 7.37–7.34 (2H, m Ph), 7.32–7.29 (1H, m, Ph), 5.32
(1H, d, J 7.1, CHPh), 4.28 (1H, dd, J 7.1 and 3.4, CHCHPh),
3.88 (1H, dt, J 10.2, 7.0 and 3.5, CHCHCHPh), 2.37–2.30 (2H,
m, OOCCH2), 1.81–1.50 (7H, m, CH3 and 2 × CH2), 1.49 (3H, s,
CH3); dC (100 MHz; CDCl3): 170.7 (COO), 136.1 (Ph, quat.), 128.3
(Ph), 128.2 (Ph), 127.4 (Ph), 80.2 (CHCHPh), 79.3 (CHPh), 77.4
(CHCHCHPh), 34.0 (CCH3), 29.5 (OOCCH2), 26.5 (CH3), 25.2
(CH3), 24.6 (CH2CH), 18.0 (CH2CH2CH2); m/z (FAB) 300 (57%,
MNa+), 154 (100%); Found (FAB): MNa+ 299.12546. C16H20O4Na
requires 299.10162.
(6R, 4ꢀS, 5ꢀR) 6-(2ꢀ,2ꢀ-Dimethyl-5ꢀ-ethyl-[1ꢀ,3ꢀ]dioxolan-4ꢀ-yl)-
pyranyl acetate (14). To a stirred solution of 13 (0.082 g,
(6R, 4ꢀS, 5ꢀR)-6-(2ꢀ,2ꢀ-Dimethyl-5ꢀ-phenyl-[1ꢀ,3ꢀ]dioxolan-4ꢀ-yl)-
3-phenylselanyltetrahydropyran-2-one (16). To a stirred solution
of diisopropylamine (0.12 mL, 0.761 mmol) in tetrahydrofuran
(1.5 mL) at −78 ◦C was added a solution of n-butyllithium in
hexanes (1.6 M, 0.476 mL), and the reaction mixture warmed
to 0 ◦C before cooling to −78 ◦C. 15 (0.070 g, 0.254 mmol) in
tetrahydrofuran (0.5 mL) was added dropwise, and after 30 min
phenylselenenyl chloride (0.146 g, 0.761 mmol) was added. After
60 min the reaction mixture was quenched by the addition of
saturated aqueous ammonium chloride (2 mL), distilled water
(5 mL) was added and the mixture extracted with diethyl ether
(3 × 10 mL). The combined organic extracts were filtered through
a plug of silica (eluting with diethyl ether), and the solvent removed
in vacuo to leave 16 as a slightly orange oil. 16 was obtained
as a 2 : 1 mixture of diastereomers, separable by flash column
t
0.282 mmol) in BuOH (1.5 mL) was added 1,2-dimethoxyprop-
1-ene (0.34 mL, 3.2 mmol) and a solution of sodium perchlorite
(0.226 g) in aqueous monobasic potassium phosphate (1.0 M,
1.7 mL). After 10 min the reaction mixture was diluted with ethyl
acetate (10 mL), washed with distilled water (5 mL), extracted
with ethyl actetate (4 × 10 mL), dried (MgSO4), filtered and the
solvent removed in vacuo to leave the acid as a white powder.
This white powder was stirred in tetrahydrofuran (5 mL), and
pyridine (0.1 mL, 0.846 mmol) added followed by lead tetraacetate
(0.37 g, 0.846 mmol). After 30 min the reaction mixture was filtered
through Celite, washed with tetrahydrofuran, and the solvent
evaporated in vacuo to leave an orange oil. Purification by flash
column chromatography, eluting with 1% triethylamine–19% ethyl
acetate–petroleum ether (bp 40–60 ◦C), isolated 14 (0.061 g, 68%
1704 | Org. Biomol. Chem., 2006, 4, 1698–1706
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chromatography, eluting with 50% diethyl ether–petroleum ether
(bp 40–60 ◦C), partially characterised by proton NMR. Data for
minor (first eluting) isomer: dH (400 MHz; CDCl3): 7.63–7.60 (1H,
m Ph), 7.44–7.41 (1H, m, Ph), 7.37–7.22 (8H, m, Ph), 5.24 (1H, d,
J 4.3, CHPh), 4.23 (1H, dd, J 4.1 and 1.9, CHCHPh), 3.92–
3.88 (1H, m, CHCHCHPh), 3.84–3.82 (1H, m, SeCH), 2.03–
1.90 (2H, m, SeCHCH2), 1.63 (3H, s, CH3), 1.56–1.20 (5H, m,
2 × CH2 and CH3); Data for major (second eluting) isomer:
dH (400 MHz; CDCl3): 7.47–7.22 (10H, m, Ph), 5.33 (1H, d, J
4.7, CHPh), 4.25 (1H, dd, J 3.7 and 1.1, CHCHPh), 4.07–4.02
(1H, m, CHCHCHPh), 3.80 (1H, t, J 4.9, SeCH), 2.24–2.15 (1H,
m, SeCHCHH), 1.77–1.43 (9H, m, 2 × CH3, SeCHCHH, and
CH2CH2CH).
m/z (FAB) 234 (25%, M+), 85 (100%); Found (FAB) M+ 234.0885.
C13H14O4 requires 234.0892.
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