New domino silyl enol ether reactions in the synthesis of a tetrodecamycin fragment

Article abstract of DOI:10.1002/ejoc.200600346

On heating in toluene at 180°C for four days the TMS enol ether 7 underwent a domino acid catalysed rearrangement, Diels-Alder cycloaddition and further rearrangement to give the bicyclic TMS enol ether 17, which was converted into a tetrodecamycin precur

Full text of DOI:10.1002/ejoc.200600346

FULL PAPER
DOI: 10.1002/ejoc.200600346
New Domino Silyl Enol Ether Reactions in the Synthesis of a Tetrodecamycin
Fragment
Jing He,[a] Kirill Tchabanenko,*[a] Robert M. Adlington,[a] Andrew R. Cowley,[a] and
Jack E. Baldwin[a]
Keywords: Silyl enol ethers / Alkene migration / Cycloaddition / Domino reactions
On heating in toluene at 180 °C for four days the TMS enol
ether 7 underwent a domino acid catalysed rearrangement,
Diels–Alder cycloaddition and further rearrangement to give
the bicyclic TMS enol ether 17, which was converted into a
tetrodecamycin precursor 3 in three synthetic steps. Further,
monocyclic silyl enol ethers were consecutively treated with
mCPBA and bromine to give syn α-hydroxy αЈ-bromo
ketones in a one-pot reaction sequence.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2006)
ture of tetrodecamycin combined with its interesting bio-
logical properties have attracted synthetic effort, and syn-
theses of partial structures have been reported.[5,6]
Our initial synthetic plan is presented in Scheme 2. Dis-
connection of the tetracycle into two components leads to
an epoxide-containing decalin fragment 2,[7] which would
Introduction
Reactions of silylated enol ethers possessing bulky alkyl
substituents on silicon with electrophiles were noticed to
proceed through an ene-type mechanism as shown in
Scheme 1.[1,2] For example, the oxonium species B generated
on electrophilic addition to the silyl enol ether A is stabi-
lized not by the loss of the bulky trialkylsilyl group, but by
a proton loss from the adjacent αЈ-position resulting in an
ene-type product – silyl enol ether C.
An extended process, which would involve a direct trans-
formation of the silyl enol ether C to product D would be of
even more interest, as it will lead to an increase in structural
complexity of the substrate; however, examples of such
domino silyl enol ether reactions[3] are few. Herein, we pres-
ent some of our recent findings in this area arising from an
approach to the decalin fragment of tetrodecamycin (1).
Tetrodecamycin (1) is a novel α-(γ-hydroxyacyl)tetronic
acid based polyketide antibiotic isolated from the culture
broth of Streptomyces nashvillensis in 1994 by Takeuchi and
co-workers.[4] It shows distinct activity against Gram-posi-
tive bacteria including methicillin-resistant Staphylococcus
aureus (MRSA) and Bacillus anthracis. The unique struc-
Scheme 2. Initial approach to tetrodecamycin (1).
Scheme 1. Ene-type reactions of silyl enol ethers.
be derived by a stereoselective epoxidation of the allylic
alcohol 3, which itself would be obtained through an intra-
molecular Diels–Alder cycloaddition of the silyl enol ether
4; no cycloadditions of silyl enol ethers of type 4 have been
previously reported in the literature.
[a] Chemistry Research Laboratory, University of Oxford,
Mansfield Road, Oxford, OX1 3TA, United Kingdom
E-mail: Kirill.Tchabanenko@chem.ox.ac.uk
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
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Scheme 3. Synthesis of silyl enol ethers 5, 6, 7 and 8.
Preparation of Diels–Alder Precursors
Model Cycloaddition of the TMS Enol Ether 5
To test our idea we prepared a model silyl enol ether 5
Having synthesised the model silyl enol ether 5, we set
together with analogous silyl enol ethers 6, 7 and 8 by stan- out to perform the cycloaddition. To our surprise, com-
dard sequences of cycloalkene ozonolysis,[8] Grignard ad- pound 5 was stable under a variety of reaction conditions.
dition, Wittig reaction, Dess–Martin oxidation[9] and an en- Reflux in toluene in the presence of mild Lewis acids
olisation/silylation as shown in Scheme 3. After initial (BF3·Et2O or Et2AlCl) led only to the recovery of the start-
attempts to prepare silyl enol ethers in the absence of ing material. However, when heated at 180 °C in toluene in
HMPA led to the isolation of 1:1 mixtures of E and Z silyl a sealed tube in the presence of CSA (cat.), 5 was converted
enol ethers, our attention was drawn by reports of Xie et into two new products. The reaction took four days to reach
al.[10] on the use of HMPA, which destabilizes Ireland’s completion and led to the isolation of two unexpected prod-
chair transition state[11] and leads to selective formation of ucts (Scheme 4); instead of the anticipated decalin, e.g. de-
the kinetic Z-silyl enol ether. The use of LiHMDS and smethyl-3, the bicyclic [3.4.0]nonane products 9 and 10 were
HMPA in our case led to selective formation of the desired obtained. The silyl enol ether 9 was readily converted into
Z-silyl enol ethers 5, 6, 7 and 8, stereochemistries of which the keto form on treatment with dilute HCl in tetra-
were confirmed by NOE analysis.
hydrofuran, from which the relative stereochemistry of the
Scheme 4. Model cycloaddition of enol ether 5.
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New Domino Silyl Enol Ether Reactions in Synthesis of a Tetrodecamycin Fragment
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bicyclic ketone 10 was established by NOE analysis and interesting example of domino silyl enol ether chemistry
confirmed by a single-crystal X-ray crystallography (Fig- where the first isomerisation facilitates a number of further
ure 1)[12] of the product derived from stereoselective re- processes.
duction of the ketone[13] followed by conversion into the
3,5-dinitrobenzoate[14] 11.
Cycloadditions Leading to Decalin Derivatives
Next, our attention centred on the possibility of per-
forming a cycloaddition of a homologue of 5, which would
provide entry into the substituted decalins. Thus the TMS
enol ether 6 possessing an extra methylene group in the
tether was treated under similar conditions [CSA (cat.), tol-
uene, 180 °C, four days], resulting to our delight in the for-
mation of decalins 14 and 15. In situ hydrolysis of the silyl
enol ether form 14 led to a more thermodynamically stable
trans-decalin 15, the structure of which was established by
Figure 1. Crystal structure of 11.
a combination of NMR and X-ray spectroscopy of its crys-
talline derivative, hydrazone 16.[16] Pleasingly, the three con-
Our mechanistic explanation of the observed process is tiguous stereogenic centres of the cycloadduct 14 possess
presented in Scheme 4. Upon being heated, the silyl enol the same relative stereochemistry as in tetrodecamycin (1).
ether 5 undergoes acid-catalysed tautomerisation into the This encouraged us to investigate cycloadditions of silyl
Z,E-silyl enol ether 12, which is set for endo-cycloaddition enol ethers 7 and 8 possessing the extra methyl substituent,
producing the bicyclo[3.4.0]nonane framework of 13.[15] which would provide the complete carbon framework of the
The cycloadduct 13 undergoes yet another acid-catalysed tetrodecamycin fragment (Scheme 5).
rearrangement to give the more thermodynamically stable
tetrasubstituted double bond in the silyl enol ether 9, which sealed tube for four days in the presence of CSA (cat.), the
upon acidification gives a kinetic cis-bicyclononane 10. desired decalin adducts 17 and 18 were formed in good
Thus, when silyl enol ether 7 was heated at 180 °C in a
The inability of 5 to undergo an intramolecular cycload- overall yield, with formation of the ketone 18 attributed
dition directly may be attributed to the fact that HOMO/ to low stability of the TMS enol ether 17 towards acidic
LUMO coefficients disfavour orbital overlap from the silyl conditions. As we were interested in further oxidation of
enol ether 5 as opposed to that from the isomerised form the TMS enol ether 17 to set the tertiary hydroxy group at
12. The first isomerisation is presumably the rate-limiting the ring junction, we investigated the cycloaddition of a
step, the subsequent cycloaddition and final silyl enol ether TBS enol ether 8, which resulted in the formation of the
rearrangement happening much faster. This provides an desired TBS enol ether 19 as a major product (Scheme 6).
Scheme 5. Cyclisation of TMS enol ether 6.
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J. He, K. Tchabanenko, R. M. Adlington, A. R. Cowley, J. E. Baldwin
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Scheme 6. Cyclisations of enol ethers 7 and 8.
Interestingly, despite numerous attempts to optimize the re- which was separated and characterized by observation of
action conditions for selective conversion of the TMS enol NOE enhancements upon irradiation of the hydroxy proton
ether 7 into 17, a substantial amount of the (E)-enone 20 in deuteriated benzene. The stereoselectivity of the oxi-
was always formed. This could be converted into the TBS dation was unexpected, but welcome in the context of tet-
enol ether 21 following Corey’s procedure,[15] whose struc- rodecamycin synthesis. (Our explanation of the observed
ture was confirmed by NOE NMR analysis. This (Z,E)- selectivity is presented in Scheme 9). The TBS enol ether
TBS-enol ether 21 (whose analogue 12 we postulate to be 19, on the contrary, gave the TBS enol ether 24 as the major
an intermediate in the previously described cycloadditions) oxidation product. In this case the TBS enol ether was re-
as expected underwent a fast Diels–Alder reaction when tained by isomerisation rather than conversion to the
heated at 180 °C in the presence of Et2AlCl (cat.). The ketone, as was observed for the TMS derivative 17
product 22 obtained after 4 h could be hydrolysed in quan- (Scheme 7).
titative yield to the ketone 18 or isomerised into 19 on heat-
ing in toluene in the presence of CSA (cat.) (Scheme 6).
This provided experimental evidence for our proposal
(Scheme 4) of an intermediate (Z,E)-silyl enol ether struc-
ture and the endo mode of the cycloaddition.
Furthermore, the treatment of the TBS enol ether 24
with N-bromosuccinimide led to clean formation of the
bromide 25 as a single diastereoisomer accompanied by
TBS migration. Unfortunately, numerous attempts to access
the allylic alcohol 3 by Kishner eliminative reduction[17] of
the α-bromo ketone 25 or its deprotected version 26 met
with failure. The white crystalline solid alcohol 26 allowed
for X-ray analysis, which shows that the more substituted
Completion of the Decalin Fragment 3
Next, we attempted the oxidation of the silyl enol ethers six-membered ring adopts an unusual boat-like conforma-
17 and 19. When treated with mCPBA at –78 °C in dichlo- tion in a trans-fused decalin system. This allows the bulky
romethane the TMS enol ether 17 produced, after protic halogen to adopt a pseudo-equatorial position contributing
work-up, the expected hydroxy ketone 23 as a 9 to 1 mixture no doubt to the difficulty observed in attempted alkene-
of epimers, favouring the desired trans-decalin product 23, forming reactions.
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New Domino Silyl Enol Ether Reactions in Synthesis of a Tetrodecamycin Fragment
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Scheme 7. Oxidation of enol ethers 17 and 19.
Finally, Luche reduction[18] of the hydroxy ketone 23 lished, as in the next step it was converted into a selenide
produced the diol 27 as a single diastereomer. The stereo- followed by an in situ oxidative elimination,[19] resulting in
chemistry of the secondary hydroxy group was not estab- the desired key intermediate, the allylic alcohol
3
(Scheme 8).
Stereoselectivity in the Oxidation of Silyl Enol Ethers 17
and 19
Simple molecular modelling of the silyl enol ether 19 pre-
dicts that epoxidation would occur on the “exo” face (the
same side as the hydrogen at the ring junction) of the mole-
cule to produce a cis-decalin product. In order to account
for the oxidation of 19 into the trans-decalin product 24 we
Scheme 8. Completion of synthesis of 3.
Scheme 9. Postulated formation of 24.
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postulate initial formation of a cis-decalin structure 28,
which is equilibrated into a more stable trans-decalin prod-
uct 24 under nonbuffered acidic conditions via an interme-
diate tertiary allylic cation 29 (Scheme 9). Further evidence
in favour of the intermediate carbocation 29 and its possible
equilibration was obtained in our attempted α,αЈ-function-
alisation of silyl enol ether derivatives of simple cyclic
ketones (see Scheme 10 and Scheme 11).
Scheme 11. Double functionalisation of simple enol ethers.
by means of GCMS. Work-up of the reaction mixture re-
sulted in isolation of the silyloxy ketones 34 and 35. Treat-
ment of both reaction mixtures from 30 and 31 on comple-
tion of the oxidation with bromine at –78 °C followed by
slow warming to room temperature led to the isolation of
a single bromide 37 in both cases. Formation of the same
product starting from two isomeric silyl enol ethers can be
explained by equilibration of the two enol ethers via a
carbocation species 36 and a higher reactivity of the trisub-
stituted silyl enol ether 33 towards bromination. The prod-
ucts of α,αЈ-derivatisation were obtained as single stereoiso-
mers, and the relative stereochemistry was established by
NOE analysis. Our model accounting for the observed ste-
reochemical outcome of the reactions is presented in
Scheme 10. The hydroxy group in the intermediate species
33 adopts an axial position due to the stabilizing anomeric
interaction between the σ* (C–OH) and the π system.[1]
Subsequently approach of bromine from an axial trajectory
results in a relative syn orientation of newly introduced bro-
mine and hydroxy substituents.
Scheme 10. Consecutive oxidation and bromination of silyl enol
ethers 30 and 31.
In a similar manner the silyl enol ethers 38, 39 and 40
were converted into an α-hydroxy-αЈ-bromo derivatives 41,
42 and 43 (Scheme 11). These observations provide sup-
porting evidence for our proposed formation of a stabilized
allylic carbocation 29 during oxidation of the bicyclic silyl
enol ether 19 (Scheme 9).
Double Functionalisation of Simple Cyclic Enolates
Our success in the sequential oxidation and bromination
of the bicyclic silyl enol ether 19 (Scheme 7) prompted us
to investigate the application of the same reaction sequence
to simple monocyclic silyl enol ethers. We were also inter-
ested in development of a one-pot procedure leading to
α,αЈ-disubstituted ketones. Preparations of silyl enol ethers
30, 38 and 40 under kinetic conditions and those of 31 and
39 under thermodynamic conditions were previously re-
Conclusions
We have observed an unusual silyl enol ether isomeris-
ported by Magnus et al.[1] When the 2-methylcyclohexa- ation followed by an intramolecular Diels–Alder cycload-
none derivatives 30 and 31 were treated with mCPBA in dition and further silyl enol ether isomerisation cascade to
DCM at –78 °C, two new silyl enol ethers 32 and 33 were give for example the bicyclic silyl enol ether 17 from the
formed. Unfortunately, we were unable to isolate these un- acyclic silyl enol ether 7. Compound 17 was further trans-
stable hydroxy silyl enol ethers, although we found that for- formed into a key intermediate 3 in our proposed total syn-
mation of the intermediates 32 and 33 could be monitored thesis of tetrodecamycin (1). The mechanism of this inter-
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General Method for Vinyl Grignard Addition and Acetal Hydrolysis:
To a solution of aldehydes (65 mmol) in THF (500 mL) was added
dropwise allylmagnesium chloride (2  in THF, 39.8 mL,
79.6 mmol) at –78 °C. After stirring at low temperature for 3 h the
solution was warmed to room temperature, ammonium chloride
(satd. solution, 200 mL) was added, and the resulting mixture was
extracted with ethyl acetate (3×250 mL). The combined organic
layers were dried with magnesium sulfate, filtered and concentrated
in vacuo. To the pale yellow oily residue was added acetone
(500 mL), water (100 mL) and aqueous HCl (1 , 15 mL), and the
resulting solution was stirred at room temperature for 12 h. Ad-
dition of saturated aqueous sodium hydrogen carbonate (300 mL)
was followed by ethyl acetate extraction (3×100 mL). The organic
extracts were dried (MgSO4) and concentrated. Purification of the
residue by flash chromatography gave aldehydes (70–81% over
three steps) as colourless oils.
esting reaction sequence has been probed. In addition, a
new procedure for a one-pot α-hydroxylation, αЈ-bromina-
tion of silyl enol ethers of cyclic ketones was investigated.
Further work will focus on widening the scope of the cyclic
ketone α,αЈ-bis-derivatisation and completion of the total
synthesis of tetrodecamycin.
Experimental Section
General Experimental: All solvents were distilled before use. All
reagents were used as obtained from commercial sources unless
otherwise stated and were purified by standard techniques.[20] All
reactions were carried out under dry, oxygen-free nitrogen or argon
and in glassware that had been dried at
100 °C overnight unless otherwise stated. Flash column chromatog-
raphy was performed on silica gel (0.125–0.25 mm, 60–120 mesh)
as the stationary phase. Thin-layer chromatography was carried out
on aluminium plates pre-coated with silica (Merck silica gel 60
General Method for Wittig Olefinations: To a solution of aldehydes
(42.5 mmol) in dichloromethane (500 mL) was added (ethoxycar-
bonylethylidene)triphenylphosphorane (18.55 g, 51.2 mmol), and
the reaction mixture was refluxed for 24 h. The solvent was re-
moved in vacuo, and the residue was extracted with diethyl ether/
hexane (1:1, 300 mL, 3×). The combined extracts were concen-
trated and chromatographed over silica gel, eluted with ethyl ace-
tate/petroleum ether (1:9) to give the enolates (65–79%) as colour-
less oils.
F254), which were visualized by quenching of UV fluorescence
(λmax = 254 nm), and/or by staining with 1% w/v potassium per-
manganate in aqueous alkaline solution followed by heating, as
appropriate. Infrared spectra were recorded as thin films between
NaCl plates or as KBr disks with a Perkin–Elmer Paragon 1000
Fourier Transform spectrometer or Bruker Tensor 27 with internal
referencing. Absorption maxima are reported in wavenumbers
General Method for DMP Oxidations of Homoallylic Alcohols:
Dess–Martin reagent (31.40 g, 67.0 mmol) was added in one por-
tion to a solution of allylic alcohols (38.0 mmol) in dry DCM
(400 mL). After 2 h of stirring at room temperature the mixture
was diluted with DCM (200 mL) and subsequently washed with
saturated aqueous Na2S2O3 solution (200 mL), and 5% NaHCO3
solution (200 mL). The combined aqueous layers were extracted
once with DCM (100 mL), and the combined organic extracts were
dried (Na2SO4) and concentrated in vacuo. The residue was chro-
matographed over silica gel (EtOAc/petroleum ether, 1:6) to yield
the ketones as colourless oils (85–90%).
[νmax, cm–1], and only selected peaks are reported. Magnetic reso-
˜
nance spectra were recorded at ambient temperature. Proton mag-
netic resonance spectra (1H NMR) were recorded at 400 and
500 MHz with Bruker DQX 400, Bruker DPX 400 and Bruker
AMX 500 instruments. Coupling constants (J) are reported
to 0.1 Hz. Carbon magnetic resonance spectra (13C NMR) were
recorded at 100.6 and 125.7 MHz with Bruker DQX 400 and
Bruker AMX 500. Chemical shifts (δ) are quoted in parts per mil-
lion (ppm) and are referenced to the residual solvent peak. High
resolution mass spectra were recorded by chemical ionization (CI)
operating at a resolution of 10000 (10% valley). The quoted masses
are accurate to 5 ppm.
General Method for cis-Enolisation of Homoallylic Ketones: To a
stirred solution of homoallylic ketones (10.0 mmol) in dry THF
(100 mL) was added HMPA (1.97 g, 11.0 mmol), and the mixture
was cooled to –78 °C when LiHMDS (1  soln. in THF, 12.0 mL,
12.0 mmol) was added. After 15 min of stirring the enolate was
quenched with freshly distilled TMSCl (1.30 g, 12.0 mol) or
TBSOTf (3.17 g, 12.0 mmol). After being stirred for 1 h, the reac-
tion mixture was warmed to room temperature and poured into
pentane (100 mL) in a separation funnel. The mixture was washed
twice with saturated NaHCO3 (100 mL), once with brine and the
organic layer was dried with anhydrous MgSO4. The solution was
concentrated and chromatographed over silica gel (Et2O/petroleum
ether, 1:100) to yield the (Z)-enol ethers as colorless oils (75–91%).
General Method for Ozonolysis of Cycloalkenes: A 500-mL, three-
necked, round-bottomed flask was fitted with a glass tube to admit
ozone, a tube to output oxygen, a glass stopper and a magnetic
stirring bar and was charged with cycloalkene (75.0 mmol), dichlo-
romethane (250 mL) and methanol (50 mL). The flask was cooled
to –78 °C (acetone/dry ice), and ozone was bubbled through the
solution. When the solution turned blue, ozone addition was
stopped. Oxygen was passed through the solution until the blue
colour was discharged and then the cold bath was removed. The
ozone inlet and outlet tubes were replaced with a stopper and vac-
cine cap, and p-toluenesulfonic acid (1.22 g) was added. The solu-
tion was warmed to room temperature as it was stirred under nitro-
gen for 90 min. Anhydrous sodium hydrogen carbonate (2.15 g,
4 equiv.) was added to the flask, and the mixture was stirred for
15 min, and then dimethyl sulfide (12 mL, 150 mmol) was added.
After stirring for 12 h, the heterogeneous mixture was concentrated
to approximately 50 mL by evaporation. Dichloromethane
(100 mL) was added, and the mixture was washed with water
(75 mL). The aqueous layer was extracted with dichloromethane
(2×100 mL), and the combined organic layers were washed with
water (100 mL). After extracting the aqueous layer with dichloro-
methane (100 mL), the organic layers were dried with anhydrous
magnesium sulfate, filtered and concentrated by rotary evapora-
tion. The crude product (colourless oil) was used without further
purifications in the next step.
TMS Enol Ether 5: The TMS enol ether 5 (490 mg, 75%) was ob-
tained from the corresponding homoallylic ketone (500 mg,
2.23 mmol) as a colourless oil by following the general enolisation
1
method: H NMR (400 MHz, CDCl3): δ = 0.21 (s, 9 H), 1.29 (t, J
= 7.0 Hz, 3 H), 1.44–1.56 (m, 4 H), 2.07 (t, J = 7.4 Hz, 2 H), 2.22
(dt, J = 7.2, 7.1 Hz, 2 H), 4.19 (q, J = 7.0 Hz, 2 H), 4.83 (dd, J =
10.5, 2.0 Hz, 1 H), 5.05 (dd, J = 17.2, 2.0 Hz, 1 H), 5.29 (d, J =
10.5 Hz, 1 H), 5.83 (d, J = 15.5 Hz, 1 H), 6.54 (ddd, J = 17.2, 10.5,
10.5 Hz, 1 H), 6.95 (dt, J = 15.5, 7.0 Hz, 1 H) ppm. 13C NMR
(100.6 MHz, CDCl3): δ = 0.6, 14.3, 26.3, 27.4, 32.0, 36.3, 60.1,
110.6, 111.9, 121.5, 131.5, 148.9, 152.8, 166.7 ppm. MS (CI+):
m/z found MH+ 297.1901 C16H29O3Si requires 297.1886. IR (thin
film): νmax = 2939 (s), 1722 (s), 1650 (s) cm–1.
˜
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TMS Enol Ether 6: The TMS enol ether 6 (1.19 g, 75%) was ob-
tained from the corresponding homoallylic ketone (1.22 g,
1.35 (m, 1 H), 1.56 (m, 1 H), 1.69–1.78 (m, 2 H), 1.83 (m, 1 H),
2.07 (m, 1 H), 2.41–2.48 (m, 3 H), 2.65–2.73 (m, 2 H), 2.81 (dd, J
= 14.4, 7.6 Hz, 1 H), 4.19 (m, 2 H) ppm. 13C NMR (125.7 MHz,
5.14 mmol) as a colourless oil by following the general enolisation
1
method: H NMR (400 MHz, CDCl3): δ = 0.22 (s, 9 H), 1.30 (t, J CDCl3): δ = 14.7, 17.9, 23.4, 27.4, 31.5, 32.3, 42.3, 45.2, 48.0, 51.2,
= 7.1 Hz, 3 H), 1.25–1.38 (m, 2 H), 1.44–1.54 (m, 4 H), 2.06 (t, J
= 7.2 Hz, 2 H), 2.18–2.24 (m, 2 H), 4.19 (q, J = 7.1 Hz, 2 H), 4.82
(dd, J = 10.5, 1.8 Hz, 1 H), 5.00 (dd, J = 17.2, 1.8 Hz, 1 H), 5.29
(d, J = 10.5 Hz, 1 H), 5.82 (dt, J = 15.7, 1.5 Hz, 1 H), 6.55 (ddd,
J = 17.2, 10.5, 10.5 Hz, 1 H), 6.96 (dt, J = 15.7, 7.2 Hz, 1 H) ppm.
13C NMR (100.6 MHz, CDCl3): δ = 0.6, 14.3, 26.6, 27.8, 28.6, 32.1,
36.5, 60.1, 110.4, 111.7, 121.3, 131.6, 149.2, 153.2, 173.4 ppm. MS
(CI+): m/z = found MH+ 311.2032 C17H31O3Si requires 311.2042.
60.8, 174.5, 213.2 ppm. MS (CI+): m/z found MH+ 225.1488
C H O requires 225.1491; IR (thin film): νmax = 1731 (s), 1728
˜
13 21
(s), 1179 (s) cm–1.
3
Reduction of Bicyclic Ketone 10: To a stirred solution of the ketone
10 (110 mg, 0.49 mmol) in dry THF (10 mL) at 0 °C was added a
1  solution of -selectride in THF (0.74 mL, 0.74 mmol,
1.5 equiv.) under nitrogen. After the reaction mixture had been
stirred for 30 min, diethyl ether and water were added. The aqueous
layer was thoroughly extracted with diethyl ether and the combined
extracts were washed successively with 10% hydrochloric acid, satu-
rated aqueous sodium hydrogen carbonate, and brine. The ethereal
solution was then dried (MgSO4) and evaporated to give a residue,
which was purified by flash chromatography (ethyl acetate/petro-
leum ether, 1:7) to give a alcohol (39.6 mg, 36%) as colourless oil.
1H NMR (400 MHz, CDCl3): δ = 0.91 (d, J = 7.2 Hz, 3 H), 1.25
(t, J = 7.1 Hz, 3 H), 1.45 (m, 1 H), 1.54–1.76 (m, 6 H), 1.76–1.85
(m, 1 H), 2.26–2.41 (m, 3 H), 2.47 (m, 1 H), 4.08–4.26 (m, 3 H)
ppm. 13C NMR (100.6 MHz, CDCl3): δ = 14.3, 14.7, 21.1, 22.3,
31.1, 31.2, 35.3, 36.8, 45.0, 46.2, 60.1, 66.6, 174.7 ppm. MS (CI+):
m/z found MH+ 227.1647 C13H23O3 requires 227.1647. IR (thin
IR (thin film): νmax = 2935 (s), 1721 (s), 1650 (m), 1254 (m), 1181
˜
(m), 1044 (m), 847 (s) cm–1.
TMS Enol Ether 7: The corresponding homoallylic ketone (2.52 g,
10.0 mmol) was converted into the titled compound (2.46 g, 79%)
1
by following the general enolisation method: H NMR (400 MHz,
CDCl3): δ = 0.22 (s, 9 H), 1.30 (t, J = 7.1 Hz, 3 H), 1.35 (m, 2 H),
1.42–1.55 (m, 4 H), 1.83 (d, J = 1.3 Hz, 3 H), 2.06 (t, J = 7.4 Hz,
2 H), 2.17 (dt, J = 7.2, 7.1 Hz, 2 H), 4.19 (q, J = 7.1 Hz, 2 H), 4.81
(dd, J = 10.4, 1.9 Hz, 1 H), 5.00 (dd, J = 17.2, 1.9 Hz, 1 H), 5.30
(d, J = 10.7 Hz, 1 H), 6.55 (ddd, J = 17.2, 10.7, 10.4 Hz, 1 H), 6.75
(tq, J = 7.2, 1.3 Hz, 1 H). 13C NMR (100.6 MHz, CDCl3): δ = 0.6,
12.3, 14.3, 26.7, 28.4, 28.9, 36.5, 60.4, 110.4, 111.7, 127.8, 131.6,
142.1, 153.3, 168.2. MS (CI+): m/z found MH+ 325.2200
film): νmax = 3418 (s, br.), 1715 (s), 1462 (m), 1384 (s) cm–1.
˜
C H O Si requires 325.2199. IR (thin film): νmax = 2934 (s), 1710
˜
18 33
(s), 1264 (m) cm–1.
3
Dinitrobenzoate 11: The product of reduction of ketone 10
(39.6 mg, 0.18 mmol) was stirred in pyridine (5 mL) for 30 min and
then treated with 3,5-dinitrobenzoyl chloride (60.4 mg, 0.26 mmol).
The reaction mixture was left to stir overnight. Water was then
added, and the mixture was extracted with diethyl ether. The com-
bined organic fractions were washed with saturated aqueous
CuSO4, water, saturated aqueous NaHCO3 and water, then dried
(MgSO4) and concentrated in vacuo to give the crude product
which was purified on silica gel (DCM/petroleum ether, 2:1) to af-
ford 11 as white prisms (61.3 mg, 83%); m.p. 102–104 °C. 1H NMR
(400 MHz, CDCl3): δ = 1.02 (d, J = 7.07 Hz, 3 H), 1.29 (t, J =
7.07 Hz, 3 H), 1.57 (m, 1 H), 1.65–1.80 (m, 4 H), 1.84–1.92 (m, 2
H), 2.00 (m, 1 H), 2.48 (m, 2 H), 2.59 (m, 2 H), 4.11–4.24 (m, 2
H), 5.64 (m, 1 H), 9.12 (d, J = 2.27 Hz, 2 H), 9.23 (t, J = 2.27 Hz,
1 H) ppm. 13C NMR (100.6 MHz, CDCl3): δ = 14.3, 14.9, 21.3,
23.8, 30.2, 31.0, 32.0, 37.3, 41.4, 46.1, 60.3, 74.2, 122.2, 129.3,
134.4, 148.7, 162.0, 174.1 ppm. MS (CI+): m/z found MH+
TBS Enol Ether 8: The TBS enol ether 8 (167 mg, 91%) was ob-
tained from the corresponding homoallylic ketone (126 mg,
0.5 mmol) as a colourless oil by following the general enolisation
1
method: H NMR (500 MHz, CDCl3): δ = 0.20 (s, 6 H), 1.02 (s, 9
H), 1.35 (t, J = 7.1 Hz, 3 H), 1.40 (m, 2 H), 1.49–1.58 (m, 4 H),
1.88 (s, 3 H), 2.11 (t, J = 7.5 Hz, 2 H), 2.23 (dt, J = 7.3, 7.1 Hz, 2
H), 4.24 (q, J = 7.1 Hz, 2 H), 4.85 (d, J = 10.4 Hz, 1 H), 5.03 (d,
J = 17.0 Hz, 1 H), 5.31 (d, J = 10.7 Hz, 1 H), 6.66 (ddd, J = 17.0,
10.7, 10.4 Hz, 1 H), 6.80 (t, J = 7.3 Hz, 1 H), ppm. 13C NMR
(100.6 MHz, CDCl3): δ = –3.8, 12.3, 14.4, 25.7, 25.8, 26.9, 28.5,
28.6, 29.0, 36.6, 60.5, 110.0, 111.6, 127.9, 131.8, 142.2, 153.4, 168.4
ppm. MS (CI+): m/z MH+ found 367.2688 C21H39O3Si requires
367.2668. IR (thin film): νmax = 2933 (s), 1710 (s), 1257 (m) cm–1.
˜
General Method for Cycloaddition of Silyl Enol Ethers 5,6,7 and
8: A solution of enol ether (0.3 mmol) and freshly recrystallised
camphorsulfonic acid (4 mol-%) in dry toluene (5 mL) was placed
in an argon-filled sealed tube and was heated at 180 °C for 4 d
while being stirred. Cooling and concentration was followed by
flash chromatography (diethyl ether/petroleum ether, 1:10) to yield
the cycloadducts.
227.1659 C20H25N2O8 requires 227.1647. IR (thin film): ν
=
˜
max
1730 (s),1720 (s), 1550 (m), 1347 (m), 1286 (m) cm–1.
Cycloadduct 15: Adduct 15 (65.3 mg, 63%) was obtained from
TMS enol ether 6 (135.0 mg, 0.43 mmol) by following the general
cycloaddition method as a colourless oil: 1H NMR (400 MHz,
CDCl3): δ = 0.91 (d, J = 6.8 Hz, 3 H), 0.98–1.08 (m, 2 H), 1.17–
1.33 (m, 3 H), 1.28 (t, J = 6.8 Hz, 3 H), 1.70–1.74 (m, 1 H), 1.80–
1.82 (m, 1 H), 1.90–2.01 (m, 3 H), 2.26 (dd, J = 10.2, 2.0 Hz, 1 H),
2.60–2.68 (m, 2 H), 2.73 (dd, J = 10.2, 3.4 Hz, 1 H), 4.15–4.20 (m,
2 H) ppm. 13C NMR (100.6 MHz, CDCl3): δ = 14.3, 16.3, 24.7,
25.9, 26.5, 30.1, 30.8, 37.1, 45.7, 50.2, 51.9, 60.3, 175.7, 212.2 ppm.
MS (CI+): m/z MH+ 239.1647 C14H23O3 requires 239.1647. IR
TMS Enol Ether 9: Compound 9 (137.2 mg, 49%) was obtained
from TMS enol ether 5 (280 mg, 0.94 mmol) following the general
cycloaddition method as a colourless oil: 1H NMR (500 MHz,
CDCl3): δ = 0.17 (s, 9 H), 0.95 (d, J = 7.4 Hz, 3 H), 0.99 (m, 1 H),
1.27 (t, J = 7.0 Hz, 2 H), 1.54–1.63 (m, 1 H), 1.68–1.82 (m, 2 H),
2.06–2.24 (m, 3 H), 2.27–2.36 (m, 1 H), 2.40–2.48 (m, 2 H), 2.59
(m, 1 H), 4.18 (m, 2 H) ppm. 13C NMR (125.7 MHz, CDCl3): δ =
0.6, 14.2, 15.4, 23.4, 26.1, 31.1, 33.2, 37.3, 37.6, 49.6, 59.9, 119.7,
139.1, 174.6 ppm. MS (CI+): m/z found MH+ 297.1881 C16H29O3Si
(thin film): νmax = 2934 (s), 2840 (m), 1740 (s), 1712 (m), 1175 (s),
˜
1030 (m) cm–1.
requires 297.1886; IR (thin film): νmax = 1734 (s), 1449 (s), 1252
˜
3,5-Dinitrophenyl Hydrazone 16: To aqueous 3,5-dinitrophenylhy-
drazine (30% in water, 311.1 mg, 1.10 mmol) was added EtOH
(7.8 mL), water (2.3 mL) and concd. H2SO4 (1.5 mL). The resulting
(s), 1180 (s) cm–1.
Bicyclic Ketone 10: Compound 10 (25.6 mg, 12%) was obtained
from TMS enol ether 5 (280 mg, 0.94 mmol) following the general solution was mixed with a solution of ketone 15 (65.3 mg,
cycloaddition method as a colourless oil: 1H NMR (500 MHz,
0.27 mmol) in EtOH (0.73 mL). Hydrazone 16 crystallised on shak-
CDCl3): δ = 1.01 (d, J = 6.7 Hz, 3 H), 1.29 (t, J = 7.1 Hz, 3 H),
ing and was separated by filtration as orange prisms (89.6 mg,
4010
www.eurjoc.org
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2006, 4003–4013

New Domino Silyl Enol Ether Reactions in Synthesis of a Tetrodecamycin Fragment
FULL PAPER
75.4%); m.p. 119–120 °C. 1H NMR (400 MHz, C6D6): δ = 0.90 (d,
J = 7.3 Hz, 3 H), 1.08 (t, J = 7.1 Hz, 3 H), 1.15–1.34 (m, 2 H),
1.47–1.64 (m, 3 H), 1.68–1.73 (m, 2 H), 1.85–1.95 (m, 2 H), 2.05–
2.23 (m, 3 H), 2.35 (dd, J = 10.6, 4.6 Hz, 1 H), 2.47 (dd, J = 14.4,
4.3 Hz, 1 H), 4.02–4.08 (m, 2 H), 7.62 (d, J = 9.5 Hz, 2 H), 7.64
aqueous NaHCO3 solution and extracted with Et2O (3×20 mL).
The combined organic phase was dried with MgSO4, and the sol-
vent was removed in vacuo. The residue was purified by chromatog-
raphy on silica gel (ether/petroleum ether, 1:100) to give the product
1
as a colourless oil (0.310 g, 86%). H NMR (400 MHz, CDCl3): δ
(d, J = 9.5 Hz, 1 H), 11.03 (br. s, 1 H) ppm. 13C NMR (100.6 MHz, = 0.10 (s, 6 H), 0.99 (s, 9 H), 1.29 (t, J = 7.1 Hz, 3 H), 1.37 (m, 2
C6D6): δ = 14.5, 15.4, 26.1, 26.2, 27.5, 32.8, 33.0, 33.8, 41.3, 47.8,
52.4, 60.4, 115.9, 123.6, 145.5, 159.4, 172.9, 173.9 ppm. MS (CI+):
m/z MH+ 419.1930 C20H27N4O6 requires 419.1931 IR (KBr):
H), 1.46 (m, 2 H), 1.73 (d, J = 6.2 Hz, 3 H), 1.82 (s, 3 H), 2.09 (m,
2 H), 2.16 (m, 2 H), 4.19 (q, J = 7.1 Hz, 2 H), 4.63 (t, J = 7.2 Hz,
1 H), 5.71–5.86 (m, 2 H), 6.75 (t, J = 7.4 Hz, 1 H) ppm. 13C NMR
ν
max = 3440 (s), 2963 (s), 1730 (s), 1620 (s), 1338 (m), 1308 (m), (100.6 MHz, CDCl3): δ = –3.7, 12.3, 14.2, 17.6, 18.4, 25.8, 26.0,
˜
1161 (m) cm–1.
28.4, 28.5, 29.4, 60.3, 112.5, 123.9, 126.1, 127.8, 142.3, 148.2, 168.3.
MS (CI+): found MH+ 367.2651 C21H39O3Si requires 367.2668. IR
TMS Enol Ether 17: Compound 17 (61.2 mg, 68%) was obtained
from the triene 7 (90 mg, 0.28 mmol) as a colourless oil by follow-
ing the general cycloaddition method: 1H NMR (400 MHz,
CDCl3): δ = 0.17 (s, 9 H), 0.87 (d, J = 6.82 Hz, 3 H), 1.02–1.15 (m,
2 H), 1.13 (s, 3 H), 1.25 (t, J = 7.17 Hz, 3 H), 1.32–1.42 (m, 2 H),
1.68–1.84 (m, 4 H), 1.96 (m, 1 H), 2.44 (m, 1 H), 2.60 (m, 1 H),
2.84 (m, 1 H), 4.08–4.20 (m, 2 H) ppm. 13C NMR (100.6 MHz,
CDCl3): δ = 0.6, 14.3, 16.2, 20.1, 26.0, 26.3, 26.5, 28.4, 31.0, 34.1,
36.2, 47.1, 60.0, 115.9, 137.9, 176.9 ppm. MS (CI+): found MH+
(thin film): νmax = 2964 (s), 1730 (s), 1550 (s), 1347 (s) cm–1.
˜
TBS Enol Ether 22: A solution of (Z,E)-enol ether 21 (68 mg,
0.19 mmol) in dry toluene (5 mL) and diethylaluminium chloride
(1  solution in THF, 10 µL) was placed in a sealed tube under
argon and heated at 180 °C for 4 h while stirring. Cooling to room
temperature, concentration and flash column chromatography (pe-
troleum ether/diethyl ether, 20:1) afforded the title compound 22
(51.6 mg, 76%) as a colourless oil: 1H NMR (500 MHz, CDCl3): δ
= 0.13 (s, 3 H), 0.14 (s, 3 H), 0.93 (s, 9 H), 0.94 (d, J = 3.13 Hz, 3
H), 1.17 (s, 3 H), 1.27 (t, J = 7.04 Hz, 3 H), 1.68–1.90 (m, 6 H),
2.02–2.36 (m, 5 H), 4.06- 4.25 (m, 2 H), 4.41 (dd, J = 5.48, 1.96 Hz,
1 H) ppm. 13C NMR (125.7 MHz, CDCl3): δ = –3.9, 14.2, 16.2,
18.2, 20.6, 25.9, 26.0, 26.3, 26.4, 28.5, 34.3, 36.2, 38.4, 47.1, 60.1,
115.5, 138.2, 176.9 ppm. MS (CI+): MH+ found 367.2668
325.2193 C H O Si requires 325.2199. IR (thin film): νmax = 2929
˜
18 33
3
(s), 1728 (s), 1253 (m), 1183 (m) cm–1.
Bicyclic Ketone 18: Compound 18 (5.4 mg, 6%) was obtained from
TMS enol ether 7 (90 mg, 0.28 mmol) as a colourless oil by follow-
ing the general cycloaddition method: 1H NMR (400 MHz,
CDCl3): δ = 0.85 (d, J = 6.83 Hz, 3 H), 1.09–1.23 (m, 4 H), 1.27
(t, J = 6.83 Hz, 3 H), 1.45 (s, 3 H), 1.77 (m, 2 H), 2.06 (m, 2 H),
2.14 (dd, J = 13.65, 3.41 Hz, 1 H), 2.16–2.31 (m, 3 H), 2.75 (dd, J
= 13.65, 5.12 Hz, 1 H), 4.11–4.23 (m, 2 H) ppm. 13C NMR
(100.6 MHz, CDCl3): δ = 14.2, 16.8, 18.4, 25.6, 25.7, 26.0, 28.6,
41.2, 43.0, 44.1, 48.3, 49.2, 60.4, 175.5, 211.5 ppm. MS (CI+): found
C H O Si requires 367.2668. IR (thin film): νmax = 2931 (s), 1728
˜
18 33
3
(s), 1257 (m), 1179 (s) cm–1.
Hydroxy Ketone 23: To a stirred solution of TMS cycloadduct 17
(29 mg, 0.09 mmol) in DCM (5 mL) was added a solution of
mCPBA (18 mg, 0.10 mmol) in DCM (5 mL) at –78 °C. The mix-
ture was left to warm to room temperature gradually over 12 h and
then washed with saturated aqueous NaHCO3 (4 mL) and ex-
tracted with DCM (3×5 mL). The crude product was purified by
flash chromatography (diethyl ether/petroleum ether, 1:25) to give
MH+ 253.1803 C H O requires 253.1804. IR (thin film): ν
=
˜
max
15 25
3
1739 (s), 1713 (s), 1270 (m), 1213 (m), 1134 (m) cm–1.
TBS Enol Ether 19: The enol ether 19 (345 mg, 69%) was obtained
from the triene 8 (500 mg, 1.36 mmol) as a colourless oil by follow-
ing the general cycloaddition method: 1H NMR (500 MHz,
CDCl3): δ = 0.16 (s, 6 H), 0.93 (d, J = 6.94 Hz, 3 H), 1.00 (s, 9 H),
1.08–1.15 (m, 1 H), 1.17 (s, 3 H), 1.30 (t, J = 6.75 Hz, 3 H), 1.30
(t, J = 7.25 Hz, 3 H), 1.08–1.14 (m, 1 H), 1.34–1.49 (m, 3 H), 1.56–
1.67 (m, 1 H), 1.72–1.86 (m, 2 H), 1.97–2.05 (m, 1 H), 3.47 (m, 1
H), 2.64 (m, 1 H), 2.95 (m, 1 H), 4.13–4.23 (m, 2 H) ppm. 13C
NMR (100.6 MHz, CDCl3): δ = –3.9, –3.8, 14.3, 16.3, 18.3, 20.2,
26.0, 26.4, 26.5, 28.5, 34.4, 36.3, 38.5, 47.2, 60.1, 115.6, 138.2, 177.0
ppm. MS (CI+): m/z MH+ found 367.2668 C21H39O3Si requires
1
the title compound as a colourless oil (11.5 mg, 43.0%): H NMR
(500 MHz, CDCl3): δ = 0.85 (d, J = 7.2 Hz, 3 H), 1.18–1.40 (m, 3
H), 1.25 (t, J = 7.04 Hz, 3 H), 1.44 (s, 3 H), 1.47–1.85 (m, 6 H),
2.20 (m, 2 H), 2.33 (dd, J = 13.20, 7.03 Hz, 1 H), 2.96 (dd, J =
13.20, 4.30 Hz, 1 H), 4.11 (q, J = 7.04 Hz, 2 H) ppm. 13C NMR
(125.7 MHz, CDCl3): δ = 14.3, 16.7, 19.4, 21.0, 23.6, 26.2, 33.9,
39.3, 41.3, 44.6, 48.8, 60.6, 75.1, 176.3, 212.3 ppm. MS (CI+): m/z
found MH+ 269.1753, C15H25O4 requires 269.1755. IR (thin film):
ν
˜
max = 3485 (s, br.), 1739 (s), 1715 (s), 1236 (m), 1148 (m) cm–1.
Hydroxy Enol Ether 24: To a stirred solution of TBS cycloadduct
19 (402 mg, 1.10 mmol) in DCM (10 mL) was added a solution of
mCPBA (210.5 mg, 1.22 mmol) in DCM (10 mL) at –78 °C. The
mixture was left to warm to room temperature gradually over 12 h,
and then washed with saturated aqueous NaHCO3 (10 mL) and
extracted with DCM (3×10 mL). The crude product was purified
by flash chromatography (diethyl ether/petroleum ether, 1:25) to
give the title compound as a colourless oil (187 mg, 44.5%). 1H
NMR (400 MHz, CDCl3): δ = 0.19 (s, 6 H), 0.88 (d, J = 7.0 Hz, 3
H), 0.92 (m, 1 H), 0.95 (s, 9 H), 1.22–1.30 (m, 2 H), 1.27 (t, J =
7.59 Hz, 3 H), 1.35 (s, 3 H), 1.38–1.43 (m, 1 H), 1.51 (m, 1 H),
1.60–1.82 (m, 4 H), 2.10 (m, 1 H), 2.20 (m, 1 H), 4.08–4.18 (m, 2
H), 4.71 (d, J = 5.6 Hz, 1 H) ppm. 13C NMR (125.7 MHz, CDCl3):
δ = –4.61, –4.23, 14.2, 18.3, 18.9, 19.1, 21.5, 22.5, 25.8, 26.5, 36.4,
39.5, 42.7, 47.8, 60.0, 70.9, 107.5, 151.1, 176.3 ppm. MS (CI+): m/z
MH+ found 383.2622, C21H39O4Si MH+ requires 383.2618. IR
367.2668. IR (thin film): νmax = 2931 (s), 1728 (s), 1257 (m), 1179
˜
(s) cm–1.
trans-Enone 20: Obtained in small quantities as a byproduct of pre-
viously described cycloadditions as a colourless oil: 1H NMR
(400 MHz, CDCl3): δ = 1.25–1.37 (m, 2 H), 1.29 (t, J = 7.2 Hz, 3
H), 1.45 (m, 2 H), 1.62 (m, 2 H), 1.82 (s, 3 H), 1.90 (dd, J = 6.8
and 1.7 Hz, 3 H), 2.17 (m, 2 H), 2.52 (t, J = 7.3 Hz, 2 H), 4.18 (q,
J = 7.2 Hz, 2 H), 6.12 (m, 1 H), 6.74 (m, 1 H), 6.86 (m, 1 H) ppm.
13C NMR (100.6 MHz, CDCl3): δ = 200.5, 168.3, 142.4, 142.0,
131.9, 127.8, 60.4, 39.8, 29.0, 28.5, 28.4, 24.0, 18.2, 14.3, 12.3 ppm.
MS (CI+): found MH+ 253.1805 C15H25O3 requires. IR (thin film):
ν
˜
max = 1720 (s), 1709 (s), 1270 (m) cm–1.
(Z,E)-TBS Enol Ether 21: To a solution of the enone 20 (0.250 g,
0.99 mmol) and tert-butyldimethylsilyl triflate (0.40 g, 1.50 mmol)
in anhydrous THF (20 mL) was added potassium hexamethyldisila-
zide (3 mL, 0.5  in toluene, 1.50 mmol) dropwise at –78 °C under
nitrogen. The resulting solution was stirred at –78 °C for 30 min
and at room temperature for 1 h. The solution was quenched with
(thin film): νmax = 2933 (s), 1726 (s), 1203 (s) cm–1.
˜
Bromo Ketone 25: To a stirred solution of TBS enol ether 24
(83.5 mg, 0.22 mmol) in anhydrous THF (10 mL) was added solu-
Eur. J. Org. Chem. 2006, 4003–4013
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4011

J. He, K. Tchabanenko, R. M. Adlington, A. R. Cowley, J. E. Baldwin
FULL PAPER
tion of N-bromosuccinimide (46.7 mg, 0.26 mmol) in THF (10 mL)
at –78 °C, and the resulting mixture was stirred at –78 °C for 4 h,
warmed to room temperature and poured into a separation funnel
containing ether (15 mL). The mixture was washed with saturated
aqueous NaHCO3 (2×10 mL) and brine (10 mL), dried (MgSO4)
and concentrated. The residue was purified by flash chromatog-
raphy (ether/petroleum ether, 1:100) to give the bromide 25 as a
washed with water (2×5 mL), dried (MgSO4) and concentrated to
give a crude product. Purification by flash chromatography (petro-
leum ether/diethyl ether, 4:1) gave the title compound 3 (11.9 mg,
59%) as a colourless oil: 1H NMR (500 MHz, CDCl3): δ = 1.07 (d,
J = 7.25 Hz, 3 H), 1.23 (s, 3 H), 1.31 (t, J = 6.94 Hz, 3 H), 1.34–
1.40 (m, 2 H), 1.44–1.54 (m, 2 H), 1.60–1.76 (m, 2 H), 1.78 (dd, J
= 12.30, 4.73 Hz, 1 H), 1.85 (ddd, J = 12.30, 5.67, 2.84 Hz, 1 H),
1.94–2.00 (m, 1 H), 2.01–2.11 (m, 2 H), 4.19 (dq, J = 14.50,
6.94 Hz, 2 H), 5.91–5.97 (m, 2 H ) ppm. 13C NMR (100.6 MHz,
CDCl3): δ = 14.3, 16.5, 19.9, 21.8, 24.9, 25.1, 32.5, 37.8, 38.7, 50.0,
60.1, 67.4, 120.0, 139.2, 176.3 ppm. MS (CI+): m/z found MH+
1
pale yellow oil (69.2 mg, 69%). H NMR (400 MHz, CDCl3): δ =
0.21 (s, 3 H), 0.31 (s, 3 H), 0.91 (s, 9 H), 0.98 (d, J = 7.2 Hz, 3 H),
1.25 (t, J = 7.4 Hz, 3 H), 1.40 (s, 3 H), 1.46–1.63 (m, 4 H), 1.80–
1.89 (m, 4 H), 2.31 (dd, J = 11.4, 2.9 Hz, 1 H), 2.45 (qd, J = 7.4,
2.4 Hz, 1 H), 4.12 (q, , 1 H, J = 7.2 Hz, 2 H), 4.27 (d, J = 2.4 Hz) 253.1808 C H O requires 253.1804. IR (thin film): νmax = 3500
˜
15 25
3
ppm. 13C NMR (100.6 MHz, CDCl3): δ = –2.98, –2.47, 14.1, 18.1, (br.), 1726 (s) cm–1.
20.4, 24.0, 25.8, 26.2, 26.3, 30.2, 37.7, 43.1, 47.6, 57.4, 60.6, 74.3,
General Procedure for Sequential Oxidation and Bromination of
85.3, 175.8, 203.8 ppm. MS (CI+): found MH+ 461.1714,
TIPS Enol Ethers: To a solution of the TIPS enolate (0.5 mmol) in
DCM (5 mL) cooled to –78 °C was added dropwise a solution of
mCPBA (94.6 mg, 0.55 mmol) in DCM (3 mL). After 2 h of stirring
at –78 °C, a solution of bromine (88 mg, 0.55 mmol) in DCM
(0.55 mL) was added dropwise. The mixture was stirred at –78 °C
for another 2 h, and then warmed to room temp. Removal of the
solvent under reduced pressure and flash silica gel chromatography
of the residue (Et2O/petroleum ether, 1:50) led to the isolation of
pure α-hydroxy αЈ-bromo ketones.
C H BrO Si [MH+] requires 461.1723. IR (thin film): νmax = 2933
˜
21 38
4
(s), 1750 (s), 1728 (s), 1171 (m) cm–1.
Tertiary Alcohol 26: To a stirred solution of the bromide 25
(63.5 mg, 0.14 mmol) in acetonitrile (1.5 mL) was added fluorosi-
licic acid solution (25% in water, 0.15 mL). After 1 h the reaction
mixture was washed with water, extracted with diethyl ether, dried
(MgSO4), and the solvents were evaporated. Flash chromatography
of the residue gave alcohol 26 as white needles (45.3 mg, 95%); m.p.
147–149 °C. 1H NMR (500 MHz, C6D6): δ = 0.97 (t, J = 7.2 Hz, 3
H), 0.95–1.04 (m, 2 H), 1.27 (d, J = 7.0 Hz, 3 H), 1.29–1.35 (m, 2
H), 1.43 (s, 3 H), 1.40–1.49 (m, 2 H), 1.56 (m, 1 H), 1.71 (dd, J =
12.8, 3.7 Hz, 1 H), 1.78 (d, J = 14.1 Hz, 1 H), 2.32 (m, 1 H), 2.43
(dd, J = 14.5, 2.1 Hz, 1 H), 3.97 (m, 2 H), 5.44 (d, J = 13.5 Hz, 1
H) ppm. 13C NMR (100.6 MHz, CDCl3): δ = 14.2, 17.0, 20.0, 20.6,
23.8, 26.1, 35.4, 43.0, 44.4, 51.4, 60.0, 60.7, 75.2, 175.7, 203.7 ppm.
MS (CI+): m/z found MH+ 347.0856 C15H24BrO4 requires
6-Bromo-2-hydroxy-2-methylcyclohexanone (37): Bromide 37
(82.7 mg, 80%) was produced from the TIPS enol ether 30
(134.0 mg, 0.50 mmol) as a colourless oil by following the general
oxidation and bromination method: 1H NMR (400 MHz, CDCl3):
δ = 1.81–1.89 (m, 2 H), 1.92 (s, 3 H), 2.03–2.12 (m, 2 H), 2.18–2.29
(m, 1 H), 2.36–2.45 (m, 1 H), 2.62–2.69 (m, 1 H), 5.59 (dd, J =
13.4, 6.3 Hz, 1 H) ppm. 13C NMR (100.6 MHz, CDCl3): δ = 23.6,
28.8, 39.4, 43.3, 52.2, 64.9, 196.2 ppm. MS (CI+): m/z found MH+
347.0856. IR (KBr): νmax = 3449 (s, br.), 2938 (s), 1728 (s), 1702
˜
207.0021 C H BrO requires 207.0021. IR (thin film): νmax = 2867
˜
7
12
2
(s), 1259 (m), 1171 (m) cm–1.
(s), 1731 (s), 1447 (m), 1303 (w), 1176 (m), 1073 (m), 731 (m), 666
(m) cm–1.
Diol 27: To a stirred solution of the hydroxy ketone 23 (76 mg,
0.28 mmol) and cerium trichloride heptahydrate (103 mg,
0.3 mmol) in methanol (3 mL) was added sodium borohydride
(13 mg, 0.3 mmol), and the resulting mixture was stirred for 30 min
at room temperature, quenched with satd. aqueous NH4Cl (3 mL)
and extracted with diethyl ether (3×5 mL). The organic extracts
were dried (MgSO4) and evaporated to give a crude product. Purifi-
cation by flash column chromatography (petroleum ether/diethyl
6-Bromo-2-tert-butyl-2-hydroxycyclohexanone (41): Bromide 41
(2.23 g, 68%) was produced from TIPS enol ether 38 (4.11 g,
13.2 mmol) as a colourless oil by following the general oxidation
1
and bromination method. H NMR (400 MHz, CDCl3): δ = 1.24
(s, 9 H), 1.85–1.92 (m, 1 H), 1.98–2.12 (m, 3 H), 2.20–2.32 (m, 1
H), 2.42–2.48 (m, 1 H), 2.58–2.65 (m, 1 H), 5.72 (dd, J = 13.5,
6.0 Hz, 1 H) ppm. 13C NMR (100.6 MHz, CDCl3): δ = 23.7, 30.3,
36.6, 38.9, 39.7, 54.6, 81.7, 194.6 ppm. MS (CI+): m/z found MH+
1
ether, 1.5:1) gave the diol 27 (60 mg, 79%) as a colourless oil: H
249.0494 C10H18BrO2 requires 249.0490. IR (thin film): ν
=
˜
NMR (500 MHz, CDCl3): δ = 1.12 (d, J = 7.25 Hz, 3 H), 1.30, (t,
J = 7.04 Hz, 2 H), 1.32–1.40 (m, 2 H), 1.44 (s, 3 H), 1.47–1.67 (m,
6 H), 1.68–1.85 (m, 2 H), 1.90–2.02 (m, 2 H), 2.37 (ddd, J = 14.50,
6.02, 4.10 Hz, 1 H), 2.46 (ddd, J = 14.50, 5.04, 3.47 Hz, 1 H), 3.54
(dd, J = 3.47, 3.15 Hz, 1 H), 4.16 (q, J = 7.04 Hz, 2 H) ppm. 13C
NMR (100.6 MHz, CDCl3): δ = 14.2, 19.4, 19.6, 21.6, 24.2, 26.4,
31.5, 36.6, 36.8, 37.0, 49.1, 60.0, 73.5, 75.3, 176.9 ppm. MS (CI+):
m/z found MH+ 271.1913, C15H27O4 requires 271.1909. IR (thin
max
2963 (s), 1728 (s), 1448 (m), 1367 (m), 1089 (m) cm–1.
6-Bromo-2-hydroxy-2-phenylcyclohexanone (42): Following the ge-
neral oxidation and bromination method the bromide 42 (2.88 g,
54%) was produced from TIPS enol ether 39 (6.59 g, 19.94 mmol)
as a colourless oil: 1H NMR (400 MHz, CDCl3): δ = 2.03–2.10 (m,
2 H), 2.18–2.25 (m, 1 H), 2.37–2.48 (m, 1 H), 2.53–2.61 (m, 1 H),
2.71–2.78 (m, 2 H), 5.80 (dd, J = 12.8 and 6.0 Hz, 1 H), 7.34–7.40
(m, 3 H), 7.49–7.52 (m, 2 H) ppm. 13C NMR (100.6 MHz, CDCl3):
δ = 19.2, 38.9, 41.1, 52.5, 56.8, 128.0, 128.7, 138.9, 194.6 ppm. MS
(CI+): m/z found MH+ 269.0175 C12H14BrO2 requires 269.0177. IR
film): νmax = 3509 (br.), 2935 (s), 1721 (s), 1389 (s), 1258 (s) cm–1.
˜
Allylic Alcohol 3: To a stirred solution of the diol 27 (21 mg,
0.08 mmol) and o-nitrophenylselenocyanate (20 mg, 0.085 mmol) in
dry chloroform (5 mL) was added tri-n-butylphosphane (20 µL,
0.085 mmol), and the resulting solution was stirred overnight at
room temperature after which TLC showed complete consumption
of the starting material 27. The solution was cooled to –40 °C, pyri-
dine (20 µL) was added followed by an aqueous solution of hydro-
gen peroxide (30%, 0.1 mL). The resulting solution was warmed to
room temperature over a period of 6 h, and a saturated solution
of sodium bisulfite (1 mL) was added. The reaction mixture was
extracted with ethyl acetate (2×10 mL), the organic extracts were
(thin film): νmax = 3445 (w), 2943 (s), 1725 (s), 1464 (m), 1170 (m),
˜
1055 (m) cm–1.
2-Bromo-6-hydroxy-4-methylcyclohexanone (43): Bromide 43
(65.7 mg, 56%) was produced from TIPS enol ether 40 (153.0 mg,
0.57 mmol) as a colourless oil by following the general oxidation
and bromination method. 1H NMR (400 MHz, CDCl3): δ = δH
1.08 (d, J = 6.3 Hz, 3 H), 1.52 (br. s, 1 H), 1.82–1.98 (m, 2 H), 2.31
(m, 1 H), 2.54–2.64 (m, 2 H), 4.55 (t, , 1 H, J = 3.0 Hz, 1 H), 5.49
(dd, J = 13.5, 5.8 Hz) ppm. 13C NMR (100.6 MHz, CDCl3): δ =
4012
www.eurjoc.org
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2006, 4003–4013

New Domino Silyl Enol Ether Reactions in Synthesis of a Tetrodecamycin Fragment
FULL PAPER
195.8, 50.1, 49.2, 47.0, 42.6, 28.4, 20.1 ppm. MS (CI+): m/z found
MH+ 207.0013 C H BrO requires 207.0021. IR (thin film): ν
Bauschke, K. Polborn, Tetrahedron Lett. 2003, 44, 2549–2552;
F. Paintner, L. Allmendinger, G. Bauschke, K. Polborn, Synlett
2002, 1308–1312; F. Paintner, G. Bauschke, M. Kestel, Tetrahe-
dron Lett. 2000, 41, 9977–9980.
=
˜
max
7
12
2
2986 (s), 1729 (s), 1429 (m), 1369 (w), 1070 (m) cm–1.
Supporting Information (see also the footnote on the first page of
this article): 1H and 13C NMR spectroscopic data for all novel com-
pounds.
[6]
[7]
J. M. Warrington, L. Barriault, Org. Lett. 2005, 7, 4589.
Recent publication (ref.[6]) has disclosed an identical initial dis-
connection strategy leading to decalin fragment 2. Our ap-
proach to the decalin fragment is different to the one presented
by L. Barriault et al. ref.[6]
.
Acknowledgments
[8]
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lographic data for this paper. These data can be obtained free
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Received: April 21, 2006
Published Online: June 29, 2006
Eur. J. Org. Chem. 2006, 4003–4013
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4013