Conformational preferences of oxy-substituents in butenolide- tetrahydropyran spiroacetals and butenolide-piperidine spiro-N,O-acetals

Article abstract of DOI:10.1039/c2ob06849d

We describe the synthesis of a series of oxy-substituted butenolide spiroacetals and spiro-N,O-acetals by oxidative spirocyclisation of 2-[(4-hydroxy or 4-sulfonamido)butyl]furans. The axial-equatorial preference of each oxy-substituent is investigated (NMR) by an acid-catalysed thermodynamic relay of configuration between the spiro- and oxy-centres. The axial site is preferred for most oxy-substituents at synthetically useful levels. The potential origins of this preference are discussed in terms of a stabilising gauche effect combined with the influence of solvation. These results have relevance to the synthesis of bis(acetylenic)enol ether spiroacetals including AL-1 and related compounds.

Full text of DOI:10.1039/c2ob06849d

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PAPER
Conformational preferences of oxy-substituents in butenolide–
tetrahydropyran spiroacetals and butenolide–piperidine spiro-N,O-acetals†
Sébastien Naud,a Sarah J. Macnaughton,a Bryony S. Dyson,a Daniel J. Woollaston,a
Jonathan W. P. Dallimoreb and Jeremy Robertson*a
Received 2nd November 2011, Accepted 21st February 2012
DOI: 10.1039/c2ob06849d
We describe the synthesis of a series of oxy-substituted butenolide spiroacetals and spiro-N,O-acetals by
oxidative spirocyclisation of 2-[(4-hydroxy or 4-sulfonamido)butyl]furans. The axial–equatorial
preference of each oxy-substituent is investigated (NMR) by an acid-catalysed thermodynamic relay of
configuration between the spiro- and oxy-centres. The axial site is preferred for most oxy-substituents at
synthetically useful levels. The potential origins of this preference are discussed in terms of a stabilising
gauche effect combined with the influence of solvation. These results have relevance to the synthesis of
bis(acetylenic)enol ether spiroacetals including AL-1 and related compounds.
Introduction
Oxidative spirocyclisation1 of 2-(4-hydroxybutyl)furan deriva-
tives under Lefebvre conditions2 provides efficient access to 1,6-
dioxaspiro[4.5]dec-3-en-2-one intermediates for the synthesis of
natural products containing the 5,6-spiroacetal core (Scheme 1).
Our group has employed this reaction in the context of the lituar-
Scheme 1 Oxidative spirocyclisation of 2-(ω-hydroxyalkyl)furans pro-
vides butenolide spiroacetals.
ines,3 pyrenolide D,4 and sawaranospirolides C and D.5 We con-
sidered whether these spiroacetal butenolides could be
elaborated by epoxidation and alkylidenation to AL-1, the most
potent inhibitor of TPA-induced tumour promotion of a group of
spiroacetal enol ethers from Artemisia lactiflora.6,7 For this syn-
thesis, selection of the correct enantiomer of a mono-protected
diol spirocyclisation substrate (1 or 2, Scheme 2) requires knowl-
edge of the conformational preferences of oxy-substituents at the
3-position of the tetrahydropyranyl ring in this system.
The conformational energy (A-value, −ΔG°) for the acetoxy
substituent in 3-acetoxytetrahydropyran is −0.71 kJ mol−1, cor-
responding to a slight preference of the equatorial conformer
(eq : ax ratio ca. 1.3 : 1).8 However, in the majority of the
reported structures containing the 5,6-spiroacetal motif bearing
only a 3-acyloxy substituent in the THP ring—mainly natural
products similar to AL-19—the acyloxy substituent is axial and,
on the basis that the structures are likely to be the thermodynami-
cally preferred forms, it could be inferred that in these
aDepartment of Chemistry, Chemistry Research Laboratory, University
of Oxford, Mansfield Road, Oxford, OX1 3TA, UK. E-mail:
jeremy.robertson@chem.ox.ac.uk; Fax: +44 1865 285002; Tel:
+44 1865 275660
bSyngenta Limited, Jealotts Hill Research Centre, Bracknell, Berkshire,
RG42 6YA, UK
†CCDC 842957 and 842958. For crystallographic data in CIF or other
electronic format see DOI: 10.1039/c2ob06849d
Scheme 2 The conformational preference of 3-oxy-substituents in
THP–butenolide spiroacetals determines the choice of starting material
and mode of final esterification. [AL-1 and THP numbering indicated].
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compounds the effective A-value is positive. Contrary to this,
Hofer reported the isolation from Artemisia selengensis of an
AL-1 isomer, in which the isovalerate substituent is equatorial;10
however, the configuration of the spiro-centre is inverted in this
compound (5-epi-AL-1) relative to that in AL-1 and the two
natural products may therefore be viewed as ‘anomers’ related
through open cationic intermediates as shown in Scheme 3.
Within this context, we set out to explore whether a 3-oxy-
substituent in the spiroacetal butenolide system exhibits a suffi-
cient bias towards either an axial or equatorial site to set the
absolute stereochemistry of the spiro-centre.11 Such a relay of
stereochemistry should be possible given our experience that the
C(spiro)–O(butenolide) bond shows an essentially complete ten-
dency to be axial; beyond anomeric stabilisation, this is likely
aided by the expected equatorial preference for the –CHvCH–
unit (the A-value of tetrahydropyranyl 2-OAc and 2-CHvCH2
substituents are +2.5 and −9.5 kJ mol−1, respectively).8 In paral-
lel, we also investigated analogous conformational biasing in
butenolide N,O-spiroacetals with potential application to the syn-
thesis of spirocyclic Pandanus alkaloids such as pandamarilac-
tone-1.12
Synthesis of substrates
Volatile alkene 313 (Scheme 4) was dihydroxylated under stan-
dard Upjohn conditions14 and the 2°-alcohol blocked as the
TIPS ether to prevent competitive spirocyclisation by that
hydroxyl group in the next step. Following oxidation, the TIPS-
substituted spiroacetal 5 was obtained as a mixture of axial–
equatorial diastereomers. The ratio of 5ax : 5eq present in the
crude product directly after oxidation, and following chromato-
graphic purification on silica, showed no trend, with significant
variation between experiments. Attempted TIPS-deprotection of
15
the separated isomers with aq. H2SiF6 gave a complex product
mixture containing diastereomers of 5,5- and 5,6-spirocycles.
Under mildly basic conditions, using TBAF, removal of the silyl
group in both diastereomers was effective but in each case the
isolated yield of the alcohols (6) was reduced slightly by the pro-
duction of small amounts of the undesired diastereomers and
5,5-spirocycles during chromatography. The structures of 6ax
and 6eq were confirmed by single crystal X-ray analysis
1
(Fig. 1).16 The appearance of the CHOH resonance in the H
NMR spectra of 6ax and 6eq was not informative; in both
isomers, the resonance appeared at ca. 3.9 ppm as a multiplet.
However the CH2O resonances showed that the dominant con-
formation in solution reflected that indicated in the crystal: for
6ax these resonances appeared at δH 3.85 (dt, J 12.4, 1.9 Hz)
Scheme 3 AL-1 and 5-epi-AL-1, isolated from separate Artemisia
species, are in principle interconvertible by acid catalysis. [R =
CuCCuCMe, R′ = COCH2CHMe2].
Scheme 4 Reagents and conditions: (i) 1 mol% OsO4, NMO, aq. acetone, 20 °C, 16 h (85%); (ii) TBSCl, imidazole, THF, 0 °C, 3 h (89%); (iii)
TIPSOTf, pyridine, CH2Cl2, 0 °C, 0.5 h (99%); (iv) aq. H2SiF6, CH3CN, 0 °C, 0.5 h (72%); (v) MCPBA, CH2Cl2, 0 °C, 2 h then 6.5 mol% TPAP,
NMO, CH2Cl2, 20 °C, 18 h (5ax 29%, 5eq 35%); (vi) TBAF, THF, 20 °C, 14 h (6ax 68%, 6eq 69%); (vii) BnBr, Ag2O, CH2Cl2, 20 °C, 20 h (7ax
59%, 7eq 59%); (viii) AcOH, DCC, DMAP, CH2Cl2, 20 °C, 1 h (8ax 75%, 8eq 80%); (ix) isovaleric acid, DCC, DMAP, CH2Cl2, 20 °C, 12 h (9ax
87%, 9eq 92%).
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and 4.09 (dd, J 12.4, 1.4 Hz) consistent with an equatorial
CHOH; for 6eq these resonances appeared at δH 3.70 (t, J 10.3
Hz) and 3.95 (ddd, J 10.3, 4.9, 2.1 Hz) consistent with an axial
CHOH. Pure samples of each isomer were converted into three
acid-stable derivatives 7–9 in both series for investigation of
thermodynamic conformational–configurational preferences.
For the corresponding N,O-spiroacetal series, oxidative spiro-
cyclisation conditions had first to be established and to that end
two model substrates 10 and 12 were prepared using the routes
shown in Scheme 5. Sulfonamide protection for the nitrogen was
selected because of its compatibility to the Lefebvre conditions
used in the aza-Achmatowicz reaction17,18 and in the hope that
the spirocyclic products might be crystalline, allowing X-ray
crystallographic analysis. Application of the MCPBA oxidation
conditions that had proven reliable in the ω-hydroxyalkyl series
(cf. Scheme 4) were not successful in delivering N,O-spiroacetals
with sulfonamides 10 and 12; these attempts merely generated
small quantities of hydroxybutenolides. Initial success was
achieved with peracetic acid, as in Lefebvre’s original work,2
and the novel N,O-spiroacetals 11 and 13 were produced in low
yield. Later work showed that hydroxy- or methoxybutenolides
produced from these substrates by a variety of oxidation methods
well and, for example, spirocycle 13 was produced in up to 89%
yield.20
Scheme 6 summarises the synthesis of two sulfonamide ana-
logues of spirocyclisation substrates 7 and 9. The routes began
from the readily available, and cheap, food flavourant 3-(2-furyl)
acrolein (14) that was hydrogenated selectively without competi-
tive reduction of the furan ring with Ashfeld’s recently described
procedure.21 This method gave essentially pure product direct
from the reaction and, with dichloromethane as the solvent, the
volatile aldehyde 1522 was isolated without significant loss
during the work-up process. This aldehyde was then converted
into the isovalerate substrate 17 using classical chemistry via the
cyanohydrin. The benzyl substrate (19) proved rather more
elusive and all attempts to effect O-benzylation of alcohol 16
failed. Based on Oriyama’s two-step procedure for the prep-
aration of O-alkylcyanohydrins from dialkyl acetals,23 routes to
dibenzyl acetal 18 were screened. Of these, Bentley’s mild pro-
cedure24 with NCS and thiourea produced the acetal without
competitive decomposition of the furan ring, which had been a
problem using standard acidic conditions. Conversion to the O-
benzyl cyanohydrin could be achieved on a small scale with
TCNE as the catalyst25 but with quantities greater than ca.
200 mg the reaction was accompanied by significant decompo-
sition. Finally, activation of the acetal via the O,P-acetal enabled
1
(including MCPBA or O2 etc.) could be cyclised effectively by
stirring in aq. H2SO4.19 This one-pot, two-step protocol worked
Scheme 5 Reagents and conditions: (i) BuLi, THF, −78 °C, 1 h, 0 °C,
2 h then Br(CH2)3Cl, 20 °C, 16 h (92%); (ii) NaI, butan-2-one, reflux,
4 h (63%); (iii) TsNH2, KOH, DMSO, 50 °C, 1.5 h (79%); (iv) AcOOH,
AcOH, CH2Cl2, 0 °C → 20 °C, 16 h (23%) or MCPBA, CH2Cl2, 20 °C,
16 h then aq. H2SO4 (30%), 20 °C, 16 h (72%); (v) NaCN, DMSO,
80 °C, 5 h (95%); (vi) LiAlH4, Et2O, 20 °C, 0.25 h (97%); (vii) TsCl,
aq. Na2CO3, THF, 20 °C, 6.5 h (86%); (viii) AcOOH, AcOH, CH2Cl2,
0 °C → 20 °C, 16 h (19%) or MCPBA, CH2Cl2, 20 °C, 16 h then aq.
H2SO4 (30%), 20 °C, 16 h (89%).
Fig. 1 Molecular structures of 6ax (upper) and 6eq (lower) from single
crystal X-ray analysis.16
Scheme 6 Reagents and conditions: (i) Cp2TiCl2, Zn, Et3NH+Cl−, CH2Cl2, 20 °C, 1 h (96%); (ii) TMSCN, K2CO3, DMF, 20 °C, 40 min (82%);
(iii) LiAlH4, Et2O, 20 °C, 0.5 h (towards 16 90%, towards 19 85%); (iv) TsCl, Et3N, DMAP, CH2Cl2 0 °C, 1 h (16 94%, 19 81%); (v) isovaleric anhy-
dride, TMSOTf, CH2Cl2, −10 °C, 1 h (80%); (vi) BnOH, 2 mol% thiourea, 5 mol% NCS, 20 °C, 4 h (77%); (vii) TMSCN, TMSOTf, P(o-tolyl)3,
CH2Cl2, 20 °C, 1 h (73%).
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Scheme 7 Reagents and conditions: (i) O2, rose bengal, MeOH, hν,
0 °C, 10 min then Ac2O, pyridine, 20 °C, 15 min (20 99%, 21 77%).
Scheme 9 Reagents and conditions: (i) aq. H2SO4 (40%), 20 °C, 2–5
d (23 27%, 24 79%); (ii) 1 mol% aq. HI, CD3CN, 20 °C, 5 min–24 h
(NMR). [isomer ratios to nearest 5%.]
Fig. 2 O-Cyclisation substrate for pyrenolide D isomers.
Fig. 3 Additional (C–H)σ-(C–OR)σ* and (C–H)σ-(C–OTHP)σ* inter-
actions in 6–9ax.
Spirocyclisation of sulfonamide substrates 20 and 21 was
achieved with H2SO4 as in the model studies (Scheme 9). Clea-
vage of the ester competed during cyclisation of isovalerate sub-
strate (20), which required 5 days to reach completion even with
a stronger acid solution. The benzyl substrate (21) converted
much more rapidly and cleanly. Although it was expected that
these strongly acidic conditions would lead to full equilibration
of isomers, the product ratios were very different in the two
series; this could, of course, be attributed to selective hydrolysis
of the equatorial isovalerate 23eq. In both cases, the axial–equa-
torial diastereomers were not separable therefore equilibrations
were conducted on the mixtures in CD3CN as before. The
product ratios fit the pattern established in the spiro-O,O-acetal
series with a higher axial preference found for the isovalerate
(ca. 2.5 : 1) than for the benzyl ether (ca. 1.5 : 1).
Scheme 8 Reagents and conditions: (i) 1 mol% aq. HI, CD3CN,
20 °C, 0.5–72 h (NMR). [isomer ratios to nearest 5%.]
the desired O-benzyl cyanohydrin to be obtained in good yield
on multigram scale.26 Completion of the route by reduction and
sulfonylation proceeded without complication. The two sub-
strates (17 and 19) were converted into methoxybutenolides 20
and 21, respectively, by 1O2 followed by dehydration of the
intermediate hydroperoxides with Ac2O (Scheme 7).27
Equilibration studies
In a separate project28 we found that attempts to effect 5-endo
cyclisation of epoxyalcohol 22 (Fig. 2)29 with an excess of I2 in
acetonitrile, en route to pyrenolide D isomers, led to scrambling
of the 4-spiro-centre. On this basis, we initially selected these
mild conditions to effect equilibration of the 6ax and 6eq diaster-
eomers. However, the results were not reproducible and, suspect-
ing adventitious HI to be the active catalyst,30 NMR-tube
reactions were set up in CD3CN with the addition of 1 mol% HI
(57% aq. solution). Under these conditions, interconversion
occurred generally rapidly, with the thermodynamic ratio being
fully attained within 2 h. For each substrate, both separated dia-
stereomers converged to the same equilibrium ratio (Scheme 8)
and the final NMR spectra were essentially identical. The NMR
spectra of the OH and OBn substrates indicated the formation of
by-products, including 5,5-spiroacetal isomers after prolonged
reaction times (days). Attempts to effect isomerisation with HI in
CDCl3 were unsuccessful, presumably due to poor solubility and
reduced dissociation of the acid in this solvent.
Discussion
Although one can only speculate on the physical origins of the
trends displayed by the equilibria in Schemes 8 and 9, it is clear
that the axial vs. equatorial preferences of 3-oxy substituents in
these spirocyclic systems do not follow from equilibrium free
energies (A-values) in the cyclohexyl or tetrahydropyranyl
parents. The preference could be a manifestation of the gauche
effect31 in which two additional (C–H)σ-(C–O)σ* interactions
may operate in the axial isomer (Fig. 3); this effect should be
more pronounced with the –OX substituents formally derived
from the acids (HOX) with the lower pKa.32
The interpretation of the gauche effect in terms of hyperconju-
gation implies lengthening of the interacting C–H and C–O
bonds accompanied by shortening of the intervening C–C bonds.
Comparison bond lengths taken from the crystal structures of
6ax and 6eq (Fig. 4) do indeed show that the two relevant
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butylcyclohexyl)34 with dynamic configurational interconversion
by acid catalysis. This study has found a synthetically useful
axial preference for 3-acyloxy substituents in these spirocycles,
which provides confidence that the total synthesis of AL-1 and
related molecules could be achieved from either enantiomer of 2-
(3,4-dihydroxybutyl)furan following the general route implied in
Scheme 2.
Fig. 4 Comparison key bond lengths (Å) in 6ax and 6eq from X-ray
data.
Experimental
In the NMR listings, protons are assigned by number according
to the compound systematic name, with assignments by sub-
structure included only where appropriate for clarity.
C–Hax bonds in 6ax are longer than those in 6eq (Δave
=
+0.0455 Å); furthermore, both relevant C–O bonds in 6ax are
longer than their counterparts in 6eq although the differences are
small (Δave = +0.007 Å); against this, there is no evidence of
C–C bond contraction in 6ax vs. 6eq (Δave = +0.002 Å) and the
C(OH)–H bond in 6ax is shorter than in 6eq (Δave = −0.013 Å).
All of this has to be considered in view of differential crystal
packing effects between the isomers and the solution-phase
study which indicates very little difference between the axial and
equatorial diastereomers in 6 (i.e. the gauche effect is the least
significant in this compound).
For derivatives 7–9, for which no crystal structure data were
available, we turned to computation to offer some insight into
our results. Thus, for each structure we performed a confor-
mational search (Monte Carlo, MMFF);33 for expediency, the
twist-boat conformers and those having an equatorial C–OCO
bond were discarded; the geometries of the remaining confor-
mers were then individually optimised (B3LYP/6-31G*) and the
relative Boltzmann-weighted energies obtained. These calcu-
lations, which neglect entropic contributions and solvation
effects, showed qualitative agreement with the NMR-derived
ratios, all derivatives (including 6) showing a small favourable
energy for the axial isomers [−(0.85–2.22 kJ mol−1)] corre-
sponding to equilibrium ratios of 1.41–2.45 : 1 in their favour.
By examination of the computed bond lengths, the only consist-
ent pattern is that the C–OR bond is longer in the axial isomers
than the equatorial isomers (Δave = +0.0068 Å).
4-(Furan-2-yl)butan-1,2-diol35
A mixture of alkene 313 (3.00 g, 24.6 mmol), NMO (3.17 g,
26.6 mmol), OsO4 (69 mg, 0.271 mmol), acetone (70 mL) and
water (10 mL) was stirred at RT for 16 h and then poured onto
hydrochloric acid (1.0 M, 100 mL). The mixture was extracted
with ethyl acetate (5 × 100 mL) and the combined organic layers
were washed with brine (100 mL), dried over MgSO4 and con-
centrated in vacuo. Column chromatography (petrol–ethyl
acetate, 1 : 1) afforded the title diol as a colourless oil (3.27 g,
85%). Rf 0.10 (petrol–ethyl acetate, 1 : 1); νmax/cm−1 (thin film)
3384s br, 2933s, 1597m, 1509s, 1146m; δH (CDCl3, 400 MHz)
1.75–1.82 (2 H, m, 2 × H-3), 1.97 (2 H, br s, 2 × OH),
2.71–2.88 (2 H, m, 2 × H-4), 3.48 (1 H, dd, J 11.0, 7.5 Hz) and
3.67 (1 H, dd, J 11.0, 3.0 Hz, 2 × H-1), 3.78 (1 H, dtd, J 7.5,
5.0, 3.0 Hz, H-2), 6.02 (1 H, dd, J 3.0, 1.0 Hz), 6.29 (1 H, dd,
J 3.0, 1.5 Hz) and 7.31 (1 H, dd, J 1.5, 1.0 Hz, Fu); δC (CDCl3,
100 MHz) 24.1 (CH2), 31.4 (CH2), 66.7 (CH2), 71.4 (CH),
105.2 (CH), 110.2 (CH), 141.1 (CH), 155.3 (C); HRMS (ESI+)
found 179.0685; C8H12NaO3 (MNa+) requires 179.0679.
1-(tert-Butyldimethylsilyloxy)-4-(furan-2-yl)butan-2-ol
Finally, any interpretation of configurational preferences based
on intrinsic factors within each molecule, has to be tempered by
a consideration of differential solvation effects. Acetonitrile (εr =
37.5) should favour the more polar forms of molecules where
these can interconvert (as in 6–9, 23 and 24) and the computed
dipole moments for the lowest energy conformer are certainly
larger for 8ax and 9ax than their equatorial isomers (4.86 D and
4.75 D, respectively vs. 2.50 D and 2.70 D, respectively).
The computed dipole moments for the hydroxy compounds are
2.90 D for 6ax and 3.17 D for 6eq, in line with a slight prefer-
ence for the equatorial isomer; the benzyl derivatives do not fit
the pattern (7ax, μD = 4.25 D; 7eq, μD = 5.10 D).
A solution of 4-(furan-2-yl)butan-1,2-diol (3.06 g, 19.6 mmol),
imidazole (1.72 g, 25.3 mmol) and tert-butyldimethylsilyl chlor-
ide (2.92 g, 19.4 mmol) in THF (50 mL) was stirred for 3 h at
0 °C. The mixture was diluted with ether (100 mL), poured onto
water (100 mL), and the separated aqueous layer was extracted
with ether (2 × 50 mL). The combined organic layers were
washed sequentially with NaHCO3 solution (sat. aq., 50 mL)
and brine (50 mL), then dried over MgSO4 and concentrated in
vacuo. Column chromatography (petrol–ether, 10 : 1) afforded
the title alcohol as a colourless oil (4.70 g, 89%). Rf 0.55
(petrol–ether, 1 : 1); νmax/cm−1 (thin film) 3444s br, 2930s,
1598m, 1508m, 1256s; δH (CDCl3, 400 MHz) 0.09 and 0.10 (2
× 3 H, 2 × s, Si(CH3)2), 0.92 (9 H, s, SiC(CH3)3), 1.72–1.77 (2
H, m, 2 × H-3), 2.45 (1 H, br s, OH), 2.68–2.76 (2 H, m, 2 ×
H-4), 3.43 (1 H, dd, J 10.0, 7.0 Hz) and 3.63 (1 H, dd, J 10.0,
3.5 Hz, 2 × H-1), 3.64–3.70 (1 H, m, H-2), 5.99 (1 H, d, J 3.0
Hz), 6.27 (1 H, dd, J 3.0, 2.0 Hz) and 7.31 (1 H, d, J 2.0 Hz,
Fu); δC (CDCl3, 100 MHz) −5.4 (CH3), −5.4 (CH3), 18.3 (C),
24.2 (CH2), 25.9 (CH3), 31.2 (CH2), 67.1 (CH2), 71.0 (CH),
104.9 (CH), 110.1 (CH), 140.9 (CH), 155.7 (C); HRMS (ESI+)
found 271.1732; C14H27O3Si (MH+) requires 271.1724.
In summary, it appears that the results can be understood, at
least qualitatively, on the basis of a stabilising gauche effect,
originating in (C–H)σ-(C–O)σ* hyperconjugation, combined
with favourable solvation of the more polar isomers.
Conclusion
Butenolide–tetrahydropyran and butenolide–N-sulfonylpiperi-
dine spiroacetals couple conformational biasing (cf. 4-tert-
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1-(tert-Butyldimethylsilyloxy)-4-(furan-2-yl)-2-
(triisopropylsilyloxy)butane
MCPBA (642 mg, 70% by weight, 3.72 mmol) was added to
complete the oxidation. After a further 1 h, Na2S2O3 solution
(1.0 M, 50 mL) was added and the mixture was stirred vigor-
ously for 5 min. The separated organic layer was washed with
NaHCO3 solution (sat. aq., 50 mL) and the combined aqueous
layers back-extracted with dichloromethane (2 × 30 mL). The
combined organic extracts were dried over MgSO4 and concen-
trated in vacuo. The crude residue was immediately taken up in
dichloromethane (95 mL), and NMO (2.40 g, 20.5 mmol) and
TPAP (230 mg, 0.654 mmol) were added. The mixture was
stirred for 14 h then further portions of NMO (2.40 g,
20.5 mmol) and TPAP (195 mg, 0.555 mmol) were added. After
4 h, the reaction showed no further progression (TLC) therefore
solid Na2SO4 (5.0 g, 35 mmol) was added, the mixture was
stirred for 1 h, then diluted with ether (200 mL), filtered through
a pad of Celite, and concentrated in vacuo. The residue was
purified by column chromatography (petrol–ether, 19 : 1 → 9 : 1)
to yield the title spirocycles 5ax (1.75 g, 29%) and 5eq (2.11 g,
35%) as colourless oils. Data for 5ax: Rf 0.58 (petrol–ether,
1 : 1); νmax/cm−1 (thin film) 2942s, 1774s, 1464m, 1093s; δH
(CDCl3, 400 MHz) 1.06–1.13 (21 H, m, Si(i-Pr)3), 1.57 (1 H,
ddd, J 13.5, 4.0, 2.5 Hz, H-10), 1.88–1.95 (1 H, m) and 2.14 (1
H, tdd, J 13.5, 4.5, 2.5 Hz, 2 × H-9), 2.41 (1 H, td, J 13.5, 4.5
Hz, H-10), 3.82 (1 H, dt, J 12.0, 2.0 Hz, H-7), 4.01 (1 H, app. br
s, H-8), 4.07 (1 H, dd, J 12.0, 1.5 Hz, H-7), 6.11 (1 H, d, J 5.5
Hz, H-3), 7.18 (1 H, d, J 5.5 Hz, H-4); δC (CDCl3, 100 MHz)
12.2 (CH), 18.1 (CH3), 26.4 (CH2), 26.8 (CH2), 63.7 (CH2),
69.7 (CH), 106.9 (C), 122.3 (CH), 154.3 (CH), 170.6 (C);
HRMS (ESI+) found 349.1806; C17H30NaO4Si (MNa+) requires
349.1806. Data for 5eq: Rf 0.41 (petrol–ether, 1 : 1); νmax/cm−1
(thin film) 2945s, 2867s, 1775s, 1463m, 1101m; δH (CDCl3,
400 MHz) 1.02–1.08 (21 H, m, Si(i-Pr)3), 1.87–2.10 (4 H, m, 2
× H-9 and 2 × H-10), 3.74 (1 H, t, J 10.0 Hz, H-7), 3.86 (1 H,
ddd, J 10.0, 5.0, 2.0 Hz, H-8), 3.91 (1 H, dd, J 10.0, 5.0 Hz,
H-7), 6.12 (1 H, d, J 5.5 Hz, H-3), 7.11 (1 H, d, J 5.5 Hz, H-4);
δC (CDCl3, 100 MHz) 12.2 (CH), 18.0 (CH3), 29.4 (CH2), 31.5
(CH2), 65.4 (CH2), 69.1 (CH), 105.5 (C), 123.4 (CH), 153.7
(CH), 170.2 (C); HRMS (ESI+) found 349.1807; C17H30NaO4Si
(MNa+) requires 349.1806.
To a stirred solution of 1-(tert-butyldimethylsilyloxy)-4-(furan-
2-yl)butan-2-ol (90 mg, 0.333 mmol) in dichloromethane
(1 mL) at 0 °C was added triisopropylsilyl trifluoromethanesulfo-
nate (0.15 mL, 0.56 mmol) and pyridine (0.30 mL, 3.72 mmol).
The mixture was stirred for 30 min then poured onto NH4Cl sol-
ution (sat. aq., 10 mL) and extracted with ether (3 × 10 mL).
The combined organic layers were washed sequentially with
NaHCO3 solution (sat. aq., 10 mL) and brine (10 mL), then
dried over MgSO4 and concentrated in vacuo. Column chromato-
graphy (petrol–dichloromethane, 50 : 1) afforded the title com-
pound as a colourless oil (140 mg, 99%). Rf 0.42 (petrol–
dichloromethane, 20 : 1); νmax/cm−1 (thin film) 2946s, 1597s,
1508m, 1012s; δH (CDCl3, 400 MHz) 0.09 (6 H, s, Si(CH3)2),
0.92 (9 H, s, SiC(CH3)3), 1.08 (21 H, app. s, Si(i-Pr)3),
1.83–2.04 (2 H, m, 2 × H-3), 2.71–2.78 (2 H, m, 2 × H-4), 3.48
(1 H, dd, J 10.0, 7.5 Hz) and 3.62 (1 H, dd, J 10.0, 5.0 Hz, 2 ×
H-1), 3.88–3.92 (1 H, m, H-2), 5.59 (1 H, dd, J 3.5, 1.0 Hz),
6.28 (1 H, dd, J 2.0, 1.0 Hz) and 7.30 (1 H, dd, J 3.5, 2.0 Hz,
Fu); δC (CDCl3, 100 MHz) −5.4 (two peaks, 2 × CH3), 12.6
(CH), 18.1 (CH3), 18.3 (C), 22.9 (CH2), 25.9 (CH3), 32.6 (CH2),
66.5 (CH2), 72.1 (CH), 104.4 (CH), 110.0 (CH), 140.7 (CH),
156.6 (C); HRMS (ESI+) found 427.3056; C23H47O3Si2 (MH+)
requires 427.3058.
4-(Furan-2-yl)-2-(triisopropylsilyloxy)butan-1-ol (4)
H2SiF6 (0.13 mL, 25% by weight solution in water, 0.23 mmol)
was added to a solution of 1-(tert-butyldimethylsilyloxy)-4-
(furan-2-yl)-2-(triisopropylsilyloxy)butane (500 mg, 1.17 mmol)
in acetonitrile (10 mL) at 0 °C. The mixture was stirred at 0 °C
for 30 min, diluted with ether (30 mL) and poured onto
NaHCO3 solution (sat. aq., 30 mL). The separated aqueous layer
was extracted with ether (2 × 30 mL) and the combined organic
layers were dried over MgSO4 and concentrated in vacuo.
Column chromatography (petrol–ether, 2 : 1) afforded alcohol 4
as a colourless oil (262 mg, 72%). [Further elution yielded the
diol, 4-(furan-2-yl)butan-1,2-diol, as a colourless oil (40 mg,
22%)]. Rf 0.16 (petrol–ether, 9 : 1); νmax/cm−1 (thin film) 2944s,
2867s, 1600m, 1510m, 1260m, 1113m; δH (CDCl3, 400 MHz)
1.02–1.10 (21 H, m, Si(i-Pr)3), 1.88–2.05 (2 H, m, 2 × H-3),
2.60–2.76 (2 H, m, 2 × H-4), 3.56 (1 H, dd, J 10.0, 3.5 Hz) and
3.67 (1 H, dd, J 10.0, 7.0 Hz, 2 × H-1), 3.86–4.01 (1 H, m,
H-2), 5.99 (1 H, dd, J 3.0, 1.0 Hz), 6.27 (1 H, dd, J 3.0, 2.0 Hz)
and 7.30 (1 H, dd, J 2.0, 1.0 Hz, Fu); δC (CDCl3, 100 MHz)
12.5 (CH), 18.1 (CH3), 23.7 (CH2), 32.1 (CH2), 65.4 (CH2),
72.0 (CH), 104.9 (CH), 110.1 (CH), 140.9 (CH), 155.4 (C);
HRMS (ESI+) found 335.2010; C17H32NaO3Si (MNa+) requires
335.2013.
(5R*,8S*)-8-Hydroxy-1,6-dioxaspiro[4.5]dec-3-en-2-one (6ax)
To a stirred solution of silyl ether 5ax (1.47 g, 4.50 mmol) in
THF (35 mL) at 0 °C was added dropwise TBAF (5.0 mL, 1.0
M in THF, 5.0 mmol). The solution was allowed to warm to RT,
stirred for 14 h, and then concentrated in vacuo. Purification by
column chromatography (petrol–ethyl acetate, 3 : 2) afforded
alcohol 6ax (519 mg, 68%) as a white solid. Rf 0.10 (petrol–
ethyl acetate, 1 : 1); m.p. 54 °C; νmax/cm−1 (thin film) 3444m br,
2939m, 1767s, 1247s, 1108s, 1000s, 917s, 818s, 701s; δH
(400 MHz, CDCl3) 1.56 (1 H, ddd, J 13.5, 4.5, 2.5 Hz, H-10),
1.89–1.95 (1 H, m) and 2.12 (1 H, tdd, J 13.5, 4.5, 2.5 Hz, 2 ×
H-9), 2.33 (1 H, td, J 13.5, 4.5 Hz, H-10), 2.69 (1 H, br s, OH),
3.85 (1 H, dt, J 12.5, 2.0 Hz, H-7), 3.94 (1 H, app. s, H-8), 4.09
(1 H, dd, J 12.5, 1.5 Hz, H-7), 6.09 (1 H, d, J 5.5 Hz, H-3), 7.20
(1 H, d, J 5.5 Hz, H-4); δC (100 MHz, CDCl3) 25.6 (CH2), 26.1
(CH2), 62.8 (CH), 69.0 (CH2), 106.7 (C), 123.0 (CH), 154.2
(CH), 170.6 (C); HRMS (ESI−) found 169.0505; C8H9O4 [(M –
H+)−] requires 169.0506.
(5R*,8S*)-8-Triisopropylsilyloxy-1,6-dioxaspiro[4.5]dec-3-en-2-
one (5ax) and (5S*,8S*)-8-triisopropylsilyloxy-1,6-dioxaspiro
[4.5]dec-3-en-2-one (5eq)
MCPBA (5.04 g, 70% by weight, 20.4 mmol) was added to a
stirred solution of alcohol 4 (5.81 g, 18.6 mmol) in dichloro-
methane (95 mL) at 0 °C. After 1 h, a further portion of
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 3506–3518 | 3511

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(5S*,8S*)-8-Hydroxy-1,6-dioxaspiro[4.5]dec-3-en-2-one (6eq)
alcohol 6ax (50 mg, 0.294 mmol) in dichloromethane (750 μL).
The reaction mixture was stirred for 1 h and then concentrated in
vacuo. Purification by column chromatography (petrol–ether,
3 : 2) afforded ester 8ax (47 mg, 75%) as a white solid. Rf 0.18
(petrol–ether, 3 : 2); m.p. 108 °C; νmax/cm−1 (thin film) 3098w,
2940m, 1769s, 1732s, 1442m, 1372s, 1232s, 911s, 822s, 696s;
δH (400 MHz, CDCl3) 1.59–1.67 (1 H, m, H-10), 1.99–2.05 (1
H, m, H-9), 2.11 (3 H, s, CH3), 2.16–2.27 (2 H, m, H-9 and
H-10), 3.95 (1 H, dt, J 13.0, 2.0 Hz) and 4.13 (1 H, dd, J 13.0,
1.5 Hz, 2 × H-7), 4.91–4.93 (1 H, m, H-8), 6.13 (1 H, d, J 5.5
Hz, H-3), 7.20 (1 H, d, J 5.5 Hz, H-4); δC (100 MHz, CDCl3)
21.2 (CH3), 23.1 (CH2), 26.7 (CH2), 65.6 (CH), 66.3 (CH2),
106.1 (C), 123.3 (CH), 153.7 (CH), 170.1 (C), 170.5 (C);
HRMS (EI) found 212.0676; C10H12O5 (M+) requires 212.0679.
To a stirred solution of silyl ether 5eq (2.11 g, 6.46 mmol) in
THF (50 mL) at 0 °C was added dropwise TBAF (7.1 mL, 1.0
M in THF, 7.1 mmol). The solution was allowed to warm to RT,
stirred for 14 h, and then concentrated in vacuo. Purification by
column chromatography (petrol–ethyl acetate, 3 : 2) afforded
alcohol 6eq (759 mg, 69%) as a pale yellow solid. Rf 0.15
(petrol–ethyl acetate, 1 : 1); m.p. 48 °C; νmax/cm−1 (thin film)
3418m br, 2951m, 1768s, 1233m, 1101m, 1021s, 918s, 815m,
714m; δH (400 MHz, CDCl3) 1.85–2.00 (3 H, m, H-9 and 2 ×
H-10), 2.00–2.08 (1 H, br s, OH), 2.13–2.19 (1 H, m, H-9), 3.70
(1 H, t, J 10.5 Hz, H-7), 3.82–3.90 (1 H, m, H-8), 3.93–3.97 (1
H, ddd, J 10.5, 5.0, 2.0 Hz, H-7), 6.14 (1 H, d, J 5.5 Hz, H-3),
7.15 (1 H, d, J 5.5 Hz, H-4); δC (100 MHz, CDCl3) 28.4 (CH2),
31.3 (CH2), 64.4 (CH), 68.6 (CH2), 105.8 (C), 123.2 (CH),
154.1 (CH), 170.7 (C); HRMS (ESI+) found 193.0472;
C8H10NaO4 (MNa+) requires 193.0471.
(5S*,8S*)-8-Acetoxy-1,6-dioxaspiro[4.5]dec-3-en-2-one (8eq)
Repetition of the procedure for acetate 8ax, starting instead with
alcohol 6eq, afforded ester 8eq as a white solid (50 mg, 80%).
Rf 0.21 (petrol–ether, 3 : 2); m.p. 68 °C; νmax/cm−1 (thin film)
3100w, 2962m, 1771s, 1738s, 1371s, 1233s, 1107s, 1035s,
1001s, 918s, 816m, 721m; δH (400 MHz, CDCl3) 1.86–2.05 (3
H, m, H-9 and 2 × H-10), 2.04 (3 H, s, CH3), 2.12–2.16 (1 H,
m, H-9), 3.77 (1 H, t, J 10.5 Hz) and 3.94 (1 H, ddd, J 10.5, 5.0,
2.0 Hz, 2 × H-7), 4.84–4.91 (1 H, m, H-8), 6.12 (1 H, d, J 5.5
Hz, H-3), 7.15 (1 H, d, J 5.5 Hz, H-4); δC (100 MHz, CDCl3)
21.0 (CH3), 25.0 (CH2), 31.0 (CH2), 65.2 (CH2), 66.3 (CH),
105.3 (C), 123.4 (CH), 153.4 (CH), 170.0 (C), 170.2 (C);
HRMS (ESI+) found 235.0579; C10H12NaO5 (MNa+) requires
235.0577.
(5R*,8S*)-8-Benzyloxy-1,6-dioxaspiro[4.5]dec-3-en-2-one (7ax)
Benzyl bromide (39 μL, 0.323 mmol) and Ag2O (204 mg,
0.880 mmol) were added to a stirred solution of alcohol 6ax
(50 mg, 0.294 mmol) in dichloromethane (500 μL). The reaction
mixture was stirred for 20 h and then concentrated in vacuo.
Purification by column chromatography (petrol–ether, 3 : 1)
afforded benzyl ether 7ax (45 mg, 59%) as a white solid. Rf 0.20
(petrol–ether, 7 : 3); νmax/cm−1 (thin film) 3090m, 3031m,
2936s, 1768s, 1454s, 1369s, 1246s, 909s, 815s, 697s; δH
(400 MHz, CDCl3) 1.59 (1 H, dt, J 13.5, 3.5 Hz, H-10),
2.08–2.14 (2 H, m, H-9 and H-10), 2.32–2.40 (1 H, m, H-9),
3.59 (1 H, m, H-8), 4.06 (2 H, app. s, 2 × H-7), 4.61 (2 H, s,
CH2Ph), 6.12 (1 H, d, J 5.5 Hz, H-3), 7.22 (1 H, d, J 5.5 Hz,
H-4), 7.28–7.40 (5 H, m, Ph); δC (100 MHz, CDCl3) 22.8
(CH2), 26.7 (CH2), 66.3 (CH2), 69.1 (CH), 70.3 (CH2), 106.7
(C), 123.1 (CH), 127.6 (CH), 127.8 (CH), 128.5 (CH), 138.1
(C), 154.2 (CH), 170.5 (C); HRMS (EI) found 260.1052;
C15H16O4 (M+) requires 260.1043.
(5R*,8S*)-8-Isovaleryloxy-1,6-dioxaspiro[4.5]dec-3-en-2-one (9ax)
Isovaleric acid (32 μL, 0.294 mmol), DCC (61 mg, 0.296 mmol)
and one crystal of DMAP were added to a stirred solution of
alcohol 6ax (50 mg, 0.294 mmol) in dichloromethane (750 μL).
The reaction mixture was stirred for 12 h and then concentrated
in vacuo. Purification by column chromatography (petrol–ether,
3 : 2) afforded ester 9ax (65 mg, 87%) as a colourless oil. Rf
0.47 (petrol–ether, 3 : 2); νmax/cm−1 (thin film) 3098w, 2960s,
2873m, 1771s, 1732s, 1371s, 911s, 822s, 698s; δH (400 MHz,
CDCl3) 0.95 (6 H, d, J 6.6 Hz, CH(CH3)2), 1.62–1.64 (1 H, m,
H-10), 1.98–2.03 (1 H, m, H-9), 2.05–2.17 (1 H, m, CH(CH3)2),
2.18–2.26 (2 H, m, H-9 and H-10), 2.24 (2 H, d, J 7.5 Hz,
CH2CO), 3.94 (1 H, dt, J 13.0, 2.0 Hz) and 4.13 (1 H, dd, J
13.0, 1.5 Hz, 2 × H-7), 4.94 (1 H, app. s, H-8), 6.12 (1 H, d, J
5.5 Hz, H-3), 7.18 (1 H, d, J 5.5 Hz, H-4); δC (100 MHz,
CDCl3) 22.3 (CH3), 23.1 (CH2), 25.8 (CH), 26.8 (CH2), 43.5
(CH2), 65.2 (CH), 66.3 (CH2), 106.1 (C), 123.3 (CH), 153.8
(CH), 170.1 (C), 172.5 (C); HRMS (ESI+) found 277.1041;
C13H18NaO5 (MNa+) requires 277.1046.
(5S*,8S*)-8-Benzyloxy-1,6-dioxaspiro[4.5]dec-3-en-2-one (7eq)
Repetition of the procedure for benzyl ether 7ax, starting instead
with alcohol 6eq, afforded benzyl ether 7eq as a white solid
(45 mg, 59%). Rf 0.14 (petrol–ether, 7 : 3); m.p. 42 °C; νmax
/
cm−1 (thin film) 2949s, 1768s, 1454m, 1372m, 1238s, 1097s,
915s, 814m, 699m; δH (400 MHz, CDCl3) 1.87–2.01 (3 H, m,
H-9 and 2 × H-10), 2.18–2.24 (1 H, m, H-9), 3.58–3.65 (1 H, m,
H-8), 3.80 (1 H, t, J 10.5 Hz) and 4.00 (1 H, ddd, J 10.5, 5.0,
2.0 Hz, 2 × H-7), 4.57 and 4.64 (2 × 1 H, 2 × d, J 12.0 Hz,
CH2Ph), 6.12 (1 H, d, J 5.5 Hz, H-3), 7.12 (1 H, d, J 5.5 Hz,
H-4), 7.27–7.39 (5 H, m, Ph); δC (100 MHz, CDCl3) 25.9
(CH2), 31.3 (CH2), 66.8 (CH2), 70.8 (CH2), 71.1 (CH), 105.7
(C), 123.4 (CH), 127.6 (CH), 127.8 (CH), 128.5 (CH), 138.2
(C), 153.7 (CH), 170.2 (C); HRMS (EI) found 260.1048;
C15H16O4 (M+) requires 260.1043.
(5S*,8S*)-8-Isovaleryloxy-1,6-dioxaspiro[4.5]dec-3-en-2-one (9eq)
Repetition of the procedure for isovalerate 9ax, starting instead
with alcohol 6eq, afforded ester 9eq as a colourless oil (69 mg,
92%). Rf 0.32 (petrol–ether, 3 : 2); νmax/cm−1 (thin film) 3099w,
2961s, 2874m, 1772s, 1733s, 1371m, 1240s, 1103s, 1022s,
(5R*,8S*)-8-Acetoxy-1,6-dioxaspiro[4.5]dec-3-en-2-one (8ax)
Acetic acid (17 μL, 0.294 mmol), DCC (61 mg, 0.296 mmol)
and one crystal of DMAP were added to a stirred solution of
3512 | Org. Biomol. Chem., 2012, 10, 3506–3518
This journal is © The Royal Society of Chemistry 2012

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2-[4-N-(4-Methylbenzenesulfonamido)butyl]furan (12)
919s, 815m, 720m; δH (400 MHz, CDCl3) 0.92 (6 H, d, J 6.6
Hz, CH(CH3)2), 1.86–1.90 (1 H, m, H-10), 1.98–2.18 (4 H, m,
2 × H-9, H-10 and CH(CH3)2), 2.16 (2 H, d, J 6.5 Hz, CH2CO),
3.78 (1 H, t, J 10.5 Hz) and 3.94 (1 H, ddd, J 10.5, 5.0, 2.0 Hz,
2 × H-7), 4.86–4.93 (1 H, m, H-8), 6.12 (1 H, d, J 5.5 Hz, H-3),
7.15 (1 H, d, J 5.5 Hz, H-4); δC (100 MHz, CDCl3) 22.3 (CH3),
25.1 (CH2), 25.8 (CH), 31.0 (CH2), 48.3 (CH2), 65.2 (CH2),
66.0 (CH), 105.3 (C), 123.4 (CH), 153.5 (CH), 170.0 (C), 172.3
(C); HRMS (ESI+) found 277.1060; C13H18NaO5 (MNa+)
requires 277.1046.
To a solution of Na2CO3 (1.78 g, 16.7 mmol) in water (10 mL)
was added 2-(4-aminobutyl)furan38 (0.78 g, 5.60 mmol) in THF
(10 mL). The reaction mixture was stirred until a homogeneous
solution was achieved then p-toluenesulfonyl chloride (3.19 g,
16.7 mmol) was added. The reaction mixture was stirred for
6.5 h and then diluted with water (100 mL) and ethyl acetate
(100 mL). The aqueous layer was extracted with ethyl acetate (3
× 75 mL) and the combined organic layers were dried over
MgSO4, filtered and concentrated in vacuo. Purification by
column chromatography (petrol–ether, 4 : 1 → 1 : 1) gave the
title compound (12) as a white solid (1.41 g, 86%). Rf 0.30
(petrol–ether, 1 : 1); m.p. 46–48 °C; νmax/cm−1 (thin film) 3284s
br, 2942m, 2867m, 1598m, 1428m, 1325s, 1159s, 1094s, 815m,
732m, 664s; δH (400 MHz, CDCl3) 1.45–1.55 (2 H, m, 2 ×
H-3), 1.56–1.66 (2 H, m, 2 × H-2), 2.43 (3 H, s, CH3), 2.56 (2
H, t, J 7.5 Hz, 2 × H-1), 2.94 (2 H, q, J 6.5 Hz, 2 × H-4), 4.78
(1 H, t, J 6.5 Hz, NH), 5.93 (1 H, d, J 3.0 Hz), 6.25 (1 H, dd, J
3.0, 2.0 Hz) and 7.27 (1 H, d, J 2.0 Hz, Fu), 7.30 and 7.75 (2 ×
2 H, 2 × d, J 8.0 Hz, Ar); δC (100 MHz, CDCl3) 21.5 (CH3),
25.0 (CH2), 27.1 (CH2), 29.0 (CH2), 42.9 (CH2), 105.0 (CH),
110.1 (CH), 127.1 (CH), 129.7 (CH), 136.9 (C), 141.0 (CH),
143.4 (C), 155.5 (C); HRMS (ESI+) found 316.0977;
C15H19NNaO3S (MNa+) requires 316.0978.
2-[3-N-(4-Methylbenzenesulfonamido)propyl]furan (10)36
To a solution of p-toluenesulfonamide (6.74 g, 39.4 mmol) in
dry DMSO (20 mL) was added KOH (1.25 g, 22.3 mmol). The
reaction mixture was stirred at 50 °C for 2 h, then 2-(3-iodopro-
pyl)furan37 (4.04 g, 17.1 mmol) added and stirring continued for
1.5 h at 50 °C. After cooling to RT, the mixture was diluted with
water (100 mL), extracted with dichloromethane (3 × 100 mL);
the combined organics were then washed with water (2 ×
150 mL), brine (50 mL), and dried over MgSO4 and concen-
trated in vacuo. Purification by column chromatography (petrol–
ethyl acetate, 3 : 1 → 1 : 1) gave the title compound (10) as a
white crystalline solid (3.74 g, 79%). Data as reported.36
6-(4-Methylbenzenesulfonyl)-1-oxa-6-azaspiro[4.4]non-3-en-2-
one (11)
6-(4-Methylbenzenesulfonyl)-1-oxa-6-azaspiro[4,5]dec-3-en-2-
one (13)
Method A. To a stirred solution of sulfonamide 10 (0.10 g,
0.36 mmol) in anhydrous dichloromethane (25 mL) at 0 °C was
added peracetic acid (0.23 mL, 32% by weight in acetic acid,
1.10 mmol). The reaction mixture was stirred for 16 h and then
concentrated in vacuo. Purification by column chromatography
(petrol–ethyl acetate, 2 : 1) gave the spirocycle (11) as an orange
oil (24 mg, 23%).
Method A. To a stirred solution of sulfonamide 12 (110 mg,
0.37 mmol) in anhydrous dichloromethane (25 mL) at 0 °C was
added peracetic acid (0.23 mL, 32% by weight in acetic acid,
1.10 mmol). The reaction mixture was stirred for 16 h and then
concentrated in vacuo. Purification by column chromatography
(petrol–ethyl acetate, 2 : 1) gave the spirocycle (13) as a colour-
less oil that solidified on standing (22 mg, 19%).
Method B. To a solution of sulfonamide 10 (400 mg,
1.43 mmol) in dichloromethane (30 mL) at 0 °C was added
MCPBA (950 mg, 65% by weight, 3.58 mmol). The solution
was allowed to warm to RT, stirred for 16 h then quenched with
Na2S2O3 solution (sat. aq., 100 mL). The aqueous layer was
extracted with ethyl acetate (3 × 100 mL), the combined extracts
concentrated in vacuo, then H2SO4 (30% aq., 5.0 mL) added.
The mixture was stirred at RT for 16 h, neutralised with
NaHCO3 solution (sat. aq., 100 mL) and extracted with ethyl
acetate (3 × 100 mL). The combined organic layers were dried
over MgSO4, concentrated in vacuo, and the residue purified by
column chromatography (petrol–ethyl acetate, 3 : 1 → 1 : 1) to
give the title compound (11) as a pale brown oil (302 mg, 72%).
Rf 0.20 (petrol–ethyl acetate, 2 : 1); νmax/cm−1 (thin film)
2960m, 1767s, 1598w, 1452w, 1353s, 1239m, 1163s, 912m,
665m; δH (400 MHz, CDCl3) 1.94–2.01 (1 H, m, H-9),
2.02–2.10 (2 H, m, 2 × H-8), 2.29–2.38 (1 H, m, H-9), 2.42 (3
H, s, CH3), 3.53 (1 H, td, J 8.5, 4.5 Hz) and 3.72 (1 H, app. q, J
8.5 Hz, 2 × H-7), 6.16 (1 H, d, J 5.5 Hz, H-3), 7.31 (2 H, d, J
8.5 Hz, Ar), 7.44 (1 H, d, J 5.5 Hz, H-4), 7.64 (2 H, d, J 8.5 Hz,
Ar); δC (100 MHz, CDCl3) 21.6 (CH2), 21.7 (CH3), 39.2 (CH2),
49.5 (CH2), 101.2 (C), 121.8 (CH), 127.6 (CH), 129.7 (CH),
135.3 (C), 144.3 (C), 154.8 (CH), 170.0 (C); HRMS (ESI+)
found 316.0611; C14H15NNaO4S (MNa+) requires 316.0614.
Method B. MCPBA (184 mg, 70% by weight, 0.745 mmol)
was added to a stirred solution of sulfonamide 12 (100 mg,
0.341 mmol) in dichloromethane (5 mL) at 0 °C. The reaction
mixture was allowed to warm to RT, stirred for 16 h then
quenched with Na2S2O3 solution (sat. aq., 20 mL). The separated
aqueous layer was extracted with ethyl acetate (3 × 20 mL), the
combined extracts concentrated in vacuo, then H2SO4 (30% aq.,
3.0 mL) was added. The mixture was stirred at RT for 16 h, then
neutralised with NaHCO3 solution (sat. aq., 20 mL) and
extracted with ethyl acetate (3 × 20 mL). The combined organic
layers were dried over MgSO4, concentrated in vacuo, and
purified by column chromatography (petrol : ethyl acetate, 3 : 1)
to afford the title compound (13) as a white solid (93 mg, 89%).
Rf 0.61 (petrol–ethyl acetate, 1 : 1); m.p. 118–120 °C; νmax/cm−1
(thin film) 2950m, 1770s, 1598m, 1446m, 1346s, 1248m, 1164s,
913m, 707m; δH (400 MHz, CDCl3) 1.52–1.58 (1 H, m, H-10),
1.74–1.84 (3 H, m, H-8 and 2 × H-9), 1.87–1.99 (1 H, m, H-8),
1.95–2.05 (1 H, m, H-10), 2.41 (3 H, s, CH3), 3.08 (1 H, td, J
11.5, 3.0 Hz) and 4.10 (1 H, ddd, J 11.5, 4.0, 3.0 Hz, 2 × H-7),
5.97 (1 H, d, J 5.5 Hz, H-3), 7.29 and 7.49 (2 × 2 H, 2 × d, J 8.0
Hz, Ar), 7.79 (1 H, d, J 5.5 Hz, H-4); δC (100 MHz, CDCl3)
20.1 (CH2), 21.6 (CH3), 24.5 (CH2), 37.6 (CH2), 45.7 (CH2),
95.5 (C), 118.2 (CH), 127.3 (CH), 129.9 (CH), 135.3 (C), 144.4
This journal is © The Royal Society of Chemistry 2012
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(C), 157.9 (CH), 169.9 (C); HRMS (ESI+) found 330.0767;
C15H17NNaO4S (MNa+) requires 330.0770.
purification (1.52 g, 90%). Rf 0.14 [chloroform–methanol–NH3
solution (conc. aq.), 10 : 1 : 0.1]; νmax/cm−1 (thin film) 3297s br,
3116m, 2926s, 2857m, 1655s, 1508s, 1145s, 1074s; δH
(400 MHz, CD3OD) 1.69 (1 H, dtd, J 14.0, 9.0, 5.5 Hz) and
1.75–1.86 (1 H, m, 2 × H-3), 2.56 (1 H, dd, J 13.0, 8.0 Hz, H-1)
and 2.64–2.75 (2 H, m, H-1 and H-4), 2.80 (1 H, ddd, J 15.0,
9.0, 5.5 Hz, H-4), 3.55 (1 H, tt, J 8.0, 4.5 Hz, H-2), 6.05 (1 H,
dd, J 3.0, 1.0 Hz), 6.29 (1 H, dd, J 3.0, 2.0 Hz) and 7.34 (1 H,
dd, J 2.0, 1.0 Hz, Fu); δC (100 MHz, CD3OD) 24.1 (CH2), 33.3
(CH2), 47.3 (CH2), 71.7 (CH), 104.9 (CH), 110.1 (CH), 141.1
(CH), 156.0 (C); HRMS (ESI+) found 178.0841; C8H13NNaO2
(MNa+) requires 178.0838.
3-(Furan-2-yl)propanal22 (15)
Zinc dust (1.00 g, 15.3 mmol) was added to a stirred solution
of bis(cyclopentadienyl)titanium(IV) dichloride (76 mg,
0.305 mmol) and triethylamine hydrochloride (4.23 g,
30.7 mmol) in degassed dichloromethane (120 mL) at RT. When
the reaction mixture changed from a dark red to yellow colour
(typically 2 min), 3-(2-furyl)acrolein (14, 750 mg, 6.14 mmol)
was added and stirring continued for 1 h. The reaction was then
quenched with NH4Cl solution (sat. aq., 100 mL), filtered
through a Celite pad, the aqueous layer extracted with dichloro-
methane (3 × 100 mL) and the combined organic layers dried
over MgSO4. After removal of the solvent in vacuo, the title
compound (15) was obtained as a colourless oil (732 mg, 96%)
that was sufficiently pure to use in the next reaction without
further purification. Rf 0.30 (petrol–ether, 8 : 1); δH (400 MHz,
CDCl3) 2.80 (2 H, t, J 7.5, 2 × H-2), 2.99 (2 H, t, J 7.5, 2 ×
H-3), 6.03 (1 H, d, J 2.5 Hz), 6.28 (1 H, dd, J 2.5, 1.5 Hz) and
7.31 (1 H, d, J 1.5 Hz, Fu), 9.83 (1 H, s, H-1); δC (100 MHz,
CDCl3) 20.7 (CH2), 41.9 (CH2), 105.5 (CH), 110.2 (CH), 141.3
(CH), 153.8 (C), 201.0 (CH).
N-[4-(Furan-2-yl)-2-hydroxybutyl]-4-methylbenzenesulfonamide
(16)
p-Toluenesulfonyl chloride (418 mg, 2.19 mmol) was added to a
stirred solution of 1-amino-4-(furan-2-yl)butan-2-ol (328 mg,
2.11 mmol), triethylamine (588 μL, 4.22 mmol) and DMAP
(13 mg, 0.106 mmol) in dichloromethane (13 mL) at 0 °C. After
stirring for 1 h at 0 °C, the reaction mixture was diluted with
water (50 mL) and dichloromethane (50 mL). The separated
aqueous layer was extracted with dichloromethane (2 × 50 mL),
the combined organic layers were washed successively with
hydrochloric acid (2.0 M, 100 mL), NaHCO3 solution (sat. aq.,
100 mL), brine (100 mL), then dried over MgSO4, and concen-
trated in vacuo. Purification by column chromatography (metha-
nol–dichloromethane, 0.5 → 4%) afforded the title compound
(16) as a beige solid (614 mg, 94%). Rf 0.13 (methanol–dichlor-
omethane, 2%); m.p. 70–72 °C; νmax/cm−1 (thin film) 3520s br,
3284s, 2925s, 1598s, 1508s, 1326s, 1160s, 1091m; δH
(400 MHz, CDCl3) 1.76 (2 H, m, 2 × H-3), 2.42 (3 H, s, CH3),
2.60–2.86 (4 H, m, H-1, 2 × H-4 and OH), 3.04 (1 H, ddd, J
13.0, 7.0, 3.0 Hz, H-1), 3.71 (1 H, br s, H-2), 5.44 (1 H, d, J
5.5, NH), 5.96 (1 H, d, J 2.0 Hz, Fu), 6.25 (1 H, dd, J 3.0, 2.0
Hz, Fu), 7.25–7.31 (3 H, m, Ar and Fu), 7.74 (2 H, d, J 8.5 Hz,
Ar); δC (100 MHz, CDCl3) 21.5 (CH3), 23.9 (CH2), 32.7 (CH2),
48.6 (CH2), 69.6 (CH), 105.2 (CH), 110.2 (CH), 127.1 (CH),
129.8 (CH), 136.6 (C), 141.0 (CH), 143.6 (C), 155.0 (C);
HRMS (ESI+) found 332.0926; C15H19NNaO4S (MNa+) requires
332.0927.
4-(Furan-2-yl)-2-hydroxybutanenitrile
K2CO3 (92 mg, 0.67 mmol) and trimethylsilyl cyanide
(2.33 mL, 18.5 mmol) were added to a solution of aldehyde 15
(1.65 g, 13.3 mmol) in dry DMF (37 mL) at 0 °C. The reaction
mixture was warmed to RT and stirred for 40 min then water
(150 mL) and ether (150 mL) were added. The separated organic
layer was washed with water (2 × 100 mL), the aqueous layers
back-extracted with ether (100 mL), and the combined organic
layers dried over MgSO4 and concentrated in vacuo. Purification
by flash chromatography (methanol–dichloromethane, 0 → 2%)
afforded the title compound as a colourless oil (1.65 g, 82%). Rf
0.15 (dichloromethane); νmax/cm−1 (thin film) 3441s br, 2959s,
2230w, 1718m, 1508m, 1255s, 1112s, 1009s; δH (400 MHz,
CDCl3) 2.19 (2 H, app. q, J 7.0 Hz, 2 × H-3), 2.84–2.91 (2 H,
m, 2 × H-4), 3.24 (1 H, br s, OH), 4.49 (1 H, td, J 7.0, 2.0 Hz,
H-2), 6.08 (1 H, d, J 3.0 Hz), 6.29–6.31 (1 H, m) and 7.73 (1 H,
s, Fu); δC (100 MHz, CDCl3) 23.1 (CH2), 33.5 (CH2), 60.2
(CH), 106.2 (CH), 110.3 (CH), 119.8 (C), 141.6 (CH), 153.2
(C); HRMS (FI) found 151.0629; C8H9NO2 (M+) requires
151.0628.
N-[4-(Furan-2-yl)-2-(isovaleryloxy)butyl]-4-
methylbenzenesulfonamide (17)
Trimethylsilyl trifluoromethanesulfonate (20 μL, 0.74 M in
dichloromethane, 14.8 μmol) was added to a solution of sulfona-
mide 16 (200 mg, 0.646 mmol) and isovaleric anhydride
(193 μL, 0.966 mmol) in dichloromethane (3 mL) at −10 °C.
After stirring at this temperature for 1 h, the reaction was
quenched with NaHCO3 solution (sat. aq., 10 mL) then the sep-
arated aqueous layer was extracted with dichloromethane (3 ×
10 mL), and the combined organic layers were dried over
MgSO4 and concentrated in vacuo. Purification by column
chromatography (petrol–ether, 2 : 1) afforded the title compound
(17) as a pale yellow oil (203 mg, 80%). Rf 0.10 (petrol–ether,
4 : 1); νmax/cm−1 (thin film) 3284s, 2960s, 2872m, 1735s,
1598m, 1449s, 1333s, 1253m, 1162s, 1094s; δH (400 MHz,
1-Amino-4-(furan-2-yl)butan-2-ol
LiAlH4 (638 mg, 97% by weight, 16.3 mmol) was added to a
solution of 4-(furan-2-yl)-2-hydroxybutanenitrile (1.65 g,
10.9 mmol) in ether (20 mL) at 0 °C and the reaction mixture
was stirred at RT for 30 min. The solution was re–cooled to
0 °C, then water (0.6 mL), NaOH solution (20% aq., 0.6 mL),
and a further portion of water (2 mL) were added in sequence.
The suspension was stirred at RT for 10 min, filtered through a
Celite plug, and the solvent removed in vacuo to afford the title
compound as a yellow oil that was used without further
3514 | Org. Biomol. Chem., 2012, 10, 3506–3518
This journal is © The Royal Society of Chemistry 2012

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CDCl3) 0.94 (6 H, d, J 6.5 Hz, CH(CH3)2), 1.84–1.98 (2 H, m,
2 × H-3), 2.01–2.10 (1 H, m, CH(CH3)2), 2.13 (2 H, d, J 7.0 Hz,
CH2CO), 2.42 (3 H, s, ArCH3), 2.62 (2 H, app. q, J 7.5 Hz, 2 ×
H-4), 3.08–3.13 (2 H, m, 2 × H-1), 4.83–4.90 (1 H, m, H-2),
4.92 (1 H, t, J 6.5 Hz, NH), 5.96 (1 H, d, J 3.0 Hz), 6.26 (1 H,
dd, J 3.0, 2.0 Hz) and 7.27–7.29 (1 H, m, Fu), 7.31 and 7.73 (2
× 2 H, 2 × d, J 8.0 Hz, Ar); δC (100 MHz, CDCl3) 21.5 (CH3),
22.3 (CH3), 23.7 (CH2), 25.6 (CH), 29.9 (CH2), 43.0 (CH2),
46.1 (CH2), 71.4 (CH), 105.4 (CH), 110.2 (CH), 127.0 (CH),
129.8 (CH), 136.8 (C), 141.1 (CH), 143.6 (C), 154.2 (C), 172.9
(C); HRMS (ESI+) found 416.1500; C20H27NNaO5S (MNa+)
requires 416.1502.
(CH), 135.8 (C), 141.5 (CH), 153.3 (C); HRMS (FI) found
241.1102; C15H15NO2 (M+) requires 241.1097.
2-Benzyloxy-4-(furan-2-yl)butan-1-amine
LiAlH4 (79 mg, 97% by weight, 2.02 mmol) was added to a sol-
ution of 2-benzyloxy-4-(furan-2-yl)butanenitrile (326 mg,
1.35 mmol) in ether (4.5 mL) at 0 °C and the reaction mixture
was stirred at RT for 10 min. The reaction was quenched at 0 °C
by sequential addition of water (0.1 mL), NaOH solution (20%
aq., 0.1 mL), and a further portion of water (0.6 mL). The sus-
pension was stirred at RT for 10 min then filtered through a pad
of Celite and concentrated in vacuo to afford the title compound
as a colourless oil (283 mg, 85%) that was sufficiently pure to
use in the next reaction without purification. Rf 0.32 [chloro-
2-[3,3-Bis(benzyloxy)propyl]furan (18)
form–methanol–NH3 solution (conc. aq.), 10 : 1 : 0.1]; νmax
/
Aldehyde 15 (200 mg, 1.61 mmol) was added to a solution of
N-chlorosuccinimide (11 mg, 0.082 mmol) and thiourea
(3.0 mg, 0.039 mmol) in anhydrous benzyl alcohol (2.0 mL) at
RT. After stirring for 4 h, the reaction mixture was poured onto a
short column of silica and eluted with petrol–ether (30 : 1).
Evaporation of the solvent in vacuo afforded the title compound
(18) as a colourless oil (400 mg, 77%). Rf 0.51 (petrol–ether,
7 : 1); νmax/cm−1 (thin film) 3031s, 2933s, 2872s, 1598m,
1497m, 1454s, 1354s, 1124s 1047s; δH (400 MHz, CDCl3)
2.11–2.17 (2 H, m, 2 × H-2), 2.78 (2 H, t, J 7.5 Hz, 2 × H-1),
4.60 and 4.71 (2 × 2 H, 2 × d, J 11.5 Hz, 2 × CH2Ph), 4.81
(1 H, t, J 6.0 Hz, H-3), 5.97 (1 H, dd, J 3.0, 1.0 Hz, Fu),
6.29 (1 H, dd, J 3.0, 2.0 Hz, Fu), 7.30–7.41 (11 H, m, Fu
and 2 × Ph); δC (100 MHz, CDCl3) 23.4 (CH2), 31.7 (CH2),
67.5 (CH2), 101.4 (CH), 105.0 (CH), 110.1 (CH), 127.7 (CH),
127.8 (CH), 128.5 (CH), 138.1 (C), 141.0 (CH), 155.2 (C);
HRMS (ESI+) found 345.1461; C21H22NaO3 (MNa+) requires
345.1461.
cm−1 (thin film) 3064w, 3031m, 2928s, 2864s, 1672s, 1596s,
1508s, 1497s, 1069s; δH (400 MHz, CDCl3) 1.32 (2 H, br s,
NH2), 1.82–1.92 and 1.92–2.03 (2 × 1 H, 2 × m, 2 × H-3), 2.76
(1 H, dd, J 13.5, 6.5 Hz, H-1), 2.71–2.77 (2 H, m, 2 × H-4),
2.88 (1 H, dd, J 13.5, 4.0 Hz, H-1), 3.44 (1 H, tt, J 6.5, 4.0 Hz,
H-2), 4.55 and 4.59 (2 × 1 H, 2 × d, J 11.5 Hz, CH2Ph), 5.98 (1
H, dd, J 3.0, 1.0 Hz, Fu), 6.29 (1 H, dd, J 3.0, 2.0 Hz, Fu),
7.28–7.40 (6 H, m, Fu and Ph); δC (100 MHz, CDCl3) 24.0
(CH2); 30.2 (CH2), 44.8 (CH2), 71.5 (CH2), 79.8 (CH), 104.9
(CH), 110.1 (CH), 127.7 (CH), 127.8 (CH), 128.4 (CH), 138.6
(C), 140.9 (CH), 155.7 (C); HRMS (ESI+) found 246.1484;
C15H20NO2 (MH+) requires 246.1489.
N-[2-Benzyloxy-4-(furan-2-yl)butyl]-4-
methylbenzenesulfonamide (19)
p-Toluenesulfonyl chloride (43 mg, 0.226 mmol) was added to a
stirred solution of 2-benzyloxy-4-(furan-2-yl)butan-1-amine
(50 mg, 0.204 mmol), triethylamine (56 μL, 41 mg,
0.405 mmol) and DMAP (1.0 mg, 0.008 mmol) in dichloro-
methane (1 mL) at 0 °C. After stirring for 1 h at RT, the reaction
mixture was diluted with water (10 mL) and dichloromethane
(10 mL). The separated aqueous layer was extracted with
dichloromethane (2 × 10 mL) and the combined organic layers
were washed sequentially with hydrochloric acid (2.0 M,
15 mL), NaHCO3 solution (sat. aq., 15 mL), and brine (10 mL),
then dried over MgSO4, and concentrated in vacuo. Purification
by column chromatography (petrol–ether, 4 : 1 → 1 : 1) afforded
the title compound (19) as a pale yellow oil (66 mg, 81%). Rf
0.52 (dichloromethane); νmax/cm−1 (thin film) 3288s, 3032s,
2926s, 1598m, 1496s, 1330s, 1162s, 1092s; δH (400 MHz,
CDCl3) 1.81 and 1.95 (2 × 1 H, 2 × dtd, J 14.0, 7.5, 6.0 Hz, 2 ×
H-3), 2.43 (3 H, s, CH3), 2.65 (2 H, t, J 7.5 Hz, 2 × H-4), 2.94
(1 H, dt, J 13.0, 6.0 Hz) and 3.15 (1 H, ddd, J 13.0, 6.0, 4.0 Hz,
2 × H-1), 3.51 (1 H, qd, J 6.0, 4.0 Hz, H-2), 4.36 and 4.48 (2 ×
1 H, 2 × d, J 11.5 Hz, CH2Ph), 4.73 (1 H, t, J 6.0 Hz, NH), 5.93
(1 H, dd, J 3.0, 1.0 Hz, Fu), 6.27 (1 H, dd, J 3.0, 2.0 Hz, Fu),
7.23–7.38 (8 H, m, Fu, Ph and Ar), 7.70 (2 H, d, J 8.0 Hz, Ar);
δC (100 MHz, CDCl3) 21.5 (CH3), 23.6 (CH2), 30.0 (CH2), 45.5
(CH2), 71.5 (CH2), 76.4 (CH), 105.2 (CH), 110.2 (CH), 127.1
(CH), 127.8 (CH), 128.0 (CH), 128.6 (CH), 129.7 (CH), 136.7
(C), 137.8 (C), 141.0 (CH), 143.4 (C), 154.9 (C); HRMS (ESI+)
found 422.1396; C22H25NNaO4S (MNa+) requires 422.1397.
2-Benzyloxy-4-(furan-2-yl)butanenitrile
Trimethylsilyl trifluoromethanesulfonate (673 μL, 3.72 mmol)
was added dropwise to a solution of tri(o-tolyl)phosphine
(1.27 g, 4.17 mmol) and acetal 18 (600 mg, 1.86 mmol) in
dichloromethane (15 mL) at −10 °C. The solution was allowed
to warm to RT, stirred until TLC analysis indicated complete
consumption of starting material (typically 1 h), then cooled to
0 °C and trimethylsilyl cyanide (699 μL, 5.58 mmol) added.
After stirring at RT for 6 h, the reaction was quenched with
NaHCO3 solution (sat. aq., 20 mL), the aqueous layer extracted
with dichloromethane (3 × 20 mL), and the combined organic
layers dried over MgSO4 and concentrated in vacuo. Purification
by column chromatography (petrol–ether, 100 : 1 → 40 : 1)
afforded the title compound as a colourless oil (328 mg, 73%).
Rf 0.24 (petrol–ether, 10 : 1); νmax/cm−1 (thin film) 3033m,
2932s, 2871s, 2239w, 1599m, 1508s, 1455s, 1336s, 1145s,
1099s; δH (400 MHz, CDCl3) 2.15–2.30 (2 H, m, 2 × H-3), 2.86
(2 H, t, J 7.5 Hz, 2 × H-4), 4.17 (1 H, dd, J 7.5, 6.0 Hz, H-2),
4.53 and 4.87 (2 × 1 H, 2 × d, J 11.5 Hz, CH2Ph), 5.98 (1 H,
dd, J 3.0, 0.5 Hz), 6.28 (1 H, dd, J 3.0, 2.0 Hz) and 7.31 (1 H,
dd, J 2.0, 0.5 Hz, Fu), 7.33–7.43 (5 H, m, Ph); δC (100 MHz,
CDCl3) 23.2 (CH2), 32.0 (CH2), 66.5 (CH), 72.4 (CH2), 106.0
(CH), 110.2 (CH), 118.0 (C), 128.3 (CH), 128.5 (CH), 128.7
This journal is © The Royal Society of Chemistry 2012
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N-[2-Isovaleryloxy-4-(2-methoxy-5-oxo-2,5-dihydrofuran-2-yl)
butyl]-4-methylbenzenesulfonamide (20)
J 5.5 Hz, CHvCHCO), 7.21–7.36 (7 H, m, Ph and Ar), 7.69 (2
H, d, J 8.0 Hz, Ar); δC (125 MHz, CDCl3) 21.5 (CH3), 25.3
(CH2), 32.4/32.5 (CH2), 45.3/45.4 (CH2), 51.2 (CH3), 71.4 (2
peaks, CH2), 76.6 (CH), 110.7 (2 peaks, C), 125.0 (2 peaks,
CH), 127.0 (CH), 127.8 (CH), 128.0 (CH), 128.5 (CH), 129.8
(CH), 136.6/136.7 (C), 137.7 (C), 143.5 (C), 153.4 (2 peaks,
CH), 169.7 (C); HRMS (ESI+) found 468.1451; C23H27NNaO6S
(MNa+) requires 468.1451.
Oxygen gas was bubbled through a stirred solution of sulfona-
mide 17 (150 mg, 0.381 mmol) and rose bengal (2.0 mg,
1.97 μmol) in methanol (10 mL) for 2 min. Maintaining a slow
stream of oxygen, the solution was cooled to 0 °C and irra-
diated39 for 10 min. The reaction mixture was concentrated in
vacuo, then the crude residue was taken up in pyridine (5 mL)
and acetic anhydride (36 μL, 0.382 mmol) added. After stirring
for 15 min at RT, the reaction mixture was diluted with water
(20 mL), the aqueous layer extracted with dichloromethane (2 ×
30 mL), the combined organic layers washed with CuSO4 sol-
ution (sat. aq., 2 × 30 mL), water (30 mL), and then dried over
MgSO4 and concentrated in vacuo. Purification by column
chromatography (methanol–dichloromethane, 1%) afforded the
title compound (20) as a viscous, colourless oil (166 mg, 99%)
and as a 1 : 1 mixture of diastereomers. Rf 0.32 (methanol–
dichloromethane, 1%); νmax/cm−1 (thin film) 3277br, 2960m,
2873m, 1768s, 1733s, 1495s, 1453s, 1159s; δH (400 MHz,
C6D6) 0.92 (2 peaks, 6 H, d, J 6.5 Hz, CH(CH3)2), 1.62–1.97 (4
H, m, 2 × H-3 and 2 × H-4), 2.04 (3 H, s, ArCH3), 2.06–2.16 (3
H, m, CHCH2CO), 2.87 (2 peaks, 3 H, s, OCH3), 2.99–3.06 (2
H, m, 2 × H-1), 4.92–5.00 (1 H, m, H-2), 5.41/5.43 (1 H, t, J 6.5
Hz, NH), 5.74/5.76 (1 H, d, J 5.5 Hz,vCHCO), 6.34/6.36 (1 H,
d, J 5.5 Hz, CHvCHCO), 6.97 and 7.92 (2 × 2 H, 2 × d, J 8.0
Hz, Ar); δC (100 MHz, C6D6) 21.1 (CH3), 22.3 (CH3), 25.7
(CH2 and CH), 33.2 (CH2), 43.2 (CH2), 46.0/46.1 (CH2), 50.6
(CH3), 71.6 (2 peaks, CH), 110.1 (C), 125.0 (CH), 127.4 (CH),
129.9 (CH), 138.1 (C), 143.2 (C), 152.8 (2 peaks, CH), 169.3 (2
peaks, C), 172.5 (2 peaks, C); HRMS (ESI+) found 462.1543;
C21H29NNaO7S (MNa+) requires 462.1557.
(5R*,8S*)-8-Isovaleryloxy-6-(4-methylbenzenesulfonyl)-1-oxa-6-
azaspiro[4.5]dec-3-en-2-one (23ax) and (5S*,8S*)-8-
isovaleryloxy-6-(4-methylbenzenesulfonyl)-1-oxa-6-azaspiro[4.5]
dec-3-en-2-one (23eq)
H2SO4 (40% aq., 1.0 mL) was added to neat sulfonamide 20
(167 mg, 0.380 mmol) and the suspension stirred at RT for 5
d. The reaction mixture was diluted with NaHCO3 solution (sat.
aq., 50 mL), the aqueous layer extracted with ethyl acetate (3 ×
50 mL), and the combined organics washed with brine (50 mL)
and dried over MgSO4 then concentrated in vacuo. Purification
by column chromatography (methanol–dichloromethane, 0 →
3%) afforded both diastereomers of the title compound (23ax/
23eq, dr = 65 : 35) as a pale yellow oil (42 mg, 27%). Rf 0.11
(dichloromethane); νmax/cm−1 (thin film) 2970s, 2922m, 1766s,
1728s, 1345s, 1164s; δH (400 MHz, CDCl3) [ax/eq refer to
23ax/23eq] 0.97 (6 H, d, J 6.5 Hz, CH(CH3)2, eq), 1.02 (6 H, d,
J 6.5 Hz, CH(CH3)2, ax), 1.47–1.52 (1 H, m, H-10, both),
1.61–2.40 (4 H, m, H-10, 2 × H-9 and CH(CH3)2, both), 2.29 (2
H, d, J 7.0 Hz, CH2CO, eq) overlapping 2.30 (2 H, d, J 7.0 Hz,
CH2CO, ax), 2.42 (3 H, s, ArCH3, ax), 2.43 (3 H, s, ArCH3, eq),
3.06 (1 H, t, J 11.5 Hz, H-7, eq), 3.27 (1 H, dd, J 13.0, 2.0 Hz,
H-7, ax), 4.22–4.27 (2 H, m, H-7, both), 5.01 (1 H, tdd, J 11.5,
5.5, 5.0 Hz, H-8, eq), 5.13–5.17 (1 H, m, H-8, ax), 6.01 (1 H, d,
J 5.5 Hz, H-3, eq), 6.02 (1 H, d, J 5.5 Hz, H-3, ax), 7.29 (2 H,
d, J 8.5 Hz, Ar, ax), 7.31 (2 H, d, J 8.5 Hz, Ar, eq), 7.48 (2 H, d,
J 8.5 Hz, Ar, ax), 7.49 (2 H, d, J 8.5 Hz, Ar, eq), 7.77 (1 H, d, J
5.5 Hz, H-4, eq), 7.85 (1 H, d, J 5.5 Hz, H-4, ax); δC (100 MHz,
CDCl3) 21.6 (CH3, ax), 21.7 (CH3, eq), 22.3 (CH3, eq), 22.4
(CH3, ax), 25.6 (CH2, eq), 25.7 (CH, both), 25.8 (CH2, ax), 31.9
(CH2, eq), 32.6 (CH2, ax), 43.3 (CH2, eq), 43.5 (CH2, ax), 47.6
(CH2, eq), 48.0 (CH2, ax), 64.7 (CH, ax), 67.3 (CH, eq), 94.2
(C, eq), 94.9 (C, ax), 118.7 (CH, ax), 119.0 (CH, eq), 127.2
(CH, ax), 127.3 (CH, eq), 129.9 (CH, ax), 130.0 (CH, eq), 135.0
(C, eq), 135.3 (C, ax), 144.6 (C, ax), 144.8 (C, eq), 156.6 (CH,
eq), 157.1 (CH, ax), 169.3 (C, eq), 169.5 (C, ax), 171.9 (C, eq),
172.5 (C, ax); HRMS (ESI+) found 430.1295; C20H25NNaO6S
(MNa+) requires 430.1295.
N-[2-Benzyloxy-4-(2-methoxy-5-oxo-2,5-dihydrofuran-2-yl)
butyl]-4-methylbenzenesulfonamide (21)
Oxygen gas was bubbled through a stirred solution of sulfona-
mide 19 (20 mg, 0.05 mmol) and rose bengal (1.0 mg,
0.98 μmol) in methanol (1 mL) for 2 min. Maintaining a slow
stream of oxygen, the solution was cooled to 0 °C and irra-
diated39 for 10 min. The reaction mixture was concentrated in
vacuo, then the crude residue was taken up in pyridine (0.6 mL)
and acetic anhydride (5.0 μL, 0.049 mmol) added. After stirring
for 15 min at RT, the reaction mixture was diluted with water
(5 mL), the aqueous layer extracted with dichloromethane (2 ×
5 mL), the combined organic layers washed with CuSO4 solution
(sat. aq., 2 × 10 mL), water (5 mL), and then dried over MgSO4
and concentrated in vacuo. Purification by column chromato-
graphy (methanol–dichloromethane, 1%) afforded the title com-
pound (21) as a colourless oil (17 mg, 76%) and as a
1 : 1 mixture of diastereomers. Rf 0.17 (methanol–dichloro-
methane, 0.5%); νmax/cm−1 (thin film) 3288s br, 3061m, 2928s,
1770s, 1599w, 1455m, 1333s, 1267s, 1163s, 1092s; δH
(500 MHz, CDCl3) 1.58–1.74 (2 H, m, 2 × H-3), 1.78–1.98 (2
H, m, 2 × H-4), 2.42 (3 H, s, ArCH3), 2.90/2.94 (1 H, dd,
J 13.0, 6.0 Hz) and 3.04–3.10 (1 H, m, 2 × H-1), 3.17 (3 H, s,
OCH3), 3.51/3.52 (1 H, app. quin, J 5.5 Hz, H-2), 4.37/4.38 and
4.43/4.45 (2 × 1 H, 2 × d, J 11.5 Hz, CH2Ph), 4.93 (1 H, t, J 6.0
Hz, NH), 6.20 (1 H, d, J 5.5 Hz,vCHCO), 7.07/7.08 (1 H, d,
(5R*,8S*)-8-Benzyloxy-6-(4-methylbenzenesulfonyl)-1-oxa-6-
azaspiro[4.5]dec-3-en-2-one (24ax) and (5S*,8S*)-8-Benzyloxy-6-
(4-methylbenzenesulfonyl)-1-oxa-6-azaspiro[4.5]dec-3-en-2-one
(24eq)
H2SO4 (40% aq., 1.0 mL) was added to neat sulfonamide 21
(177 mg, 0.397 mmol) and the suspension stirred at RT for 2
d. The reaction mixture was diluted with NaHCO3 solution (sat.
aq., 20 mL), the aqueous layer extracted with ethyl acetate (3 ×
20 mL), and the combined organics washed with brine (20 mL)
3516 | Org. Biomol. Chem., 2012, 10, 3506–3518
This journal is © The Royal Society of Chemistry 2012

View Article Online
6 (a) Y. Nakamura, Y. Ohto, A. Murakami, S. Jiwajinda and H. Ohigashi, J.
Agric. Food Chem., 1998, 46, 5031; (b) Y. Nakamura, N. Kawamoto,
Y. Ohto, K. Torikai, A. Murakami and H. Ohigashi, Cancer Lett., 1999,
140, 37.
7 The authors in Ref. 6a state that their AL-1 is identical to that isolated by
Bohlmann et al. from Artemisia douglasiana although in Bohlmann’s
paper the enol ether stereochemistry is represented as Z- rather than E-.
F. Bohlmann, N. Ates, J. Jakupovic, R. M. King and H. Robinson, Phyto-
chemistry, 1982, 21, 2691.
8 E. L. Eliel, K. D. Hargrave, K. M. Pietrusiewicz and M. Manoharan, J.
Am. Chem. Soc., 1982, 104, 3635.
9 For example: L. Ma, F. Ge, C.-P. Tang, C.-Q. Ke, X.-Q. Li,
A. Althammer and Y. Ye, Tetrahedron, 2011, 67, 3533.
10 B. Wallnofer, O. Hofer and H. Greger, Phytochemistry, 1989, 28, 2687.
11 (a) The situation arises commonly in the total synthesis of natural pro-
ducts containing the 1,7-dioxaspiro[5.5]undecane core as articulated, for
example, in: K. Mori, H. Watanabe, K. Yanagi and M. Minobe, Tetrahe-
dron, 1985, 41, 3663; (b) For more general discussion see: F. Perron and
K. F. Albizati, Chem. Rev., 1989, 89, 1617.
12 M. G. Nonato, M. J. Garson, R. J. W. Truscott and J. A. Carver, Phyto-
chemistry, 1993, 34, 1159.
13 S. J. Hobson and R. Marquez, Org. Biomol. Chem., 2006, 4, 3808.
14 V. VanRheenan, R. C. Kelly and D. Y. Cha, Tetrahedron Lett., 1976, 17,
1973.
and dried over MgSO4 then concentrated in vacuo. Purification
by column chromatography (methanol–dichloromethane, 0 →
1%) afforded both diastereomers of the title compound (24ax/
24eq, dr = 15 : 85) as a pale yellow solid (130 mg, 79%). Rf
0.47 (methanol–dichloromethane, 0.5%); m.p. 164–166 °C;
νmax/cm−1 (thin film) 3030s, 2922s, 1770s, 1580m, 1341s,
1161s, 1101s; NMR data for 24ax: δH (400 MHz, CDCl3) 1.40
(1 H, ddd, J 13.5, 4.5, 2.5 Hz, H-10), 1.92 (1 H, tdd, J 13.5, 4.5,
3.0 Hz) and 1.97–2.03 (1 H, m, 2 × H-9), 2.42 (3 H, s, CH3),
2.50 (1 H, td, J 13.5, 4.5 Hz, H-10), 3.14 (1 H, dd, J 13.0, 1.5
Hz, H-7), 3.73–3.82 (1 H, m, H-8), 4.39 (1 H, ddd, J 13.0, 3.0,
2.0 Hz, H-7), 4.55 and 4.78 (2 × 1 H, 2 × d, J 12.0 Hz, CH2Ph),
5.99 (1 H, d, J 5.5 Hz, H-3), 7.29 (2 H, d, J 8.5 Hz, Ar),
7.30–7.44 (5 H, m, Ph), 7.52 (2 H, d, J 8.5 Hz, Ar), 7.80 (1 H,
d, J 5.5 Hz, H-4); δC (100 MHz, CDCl3) 21.6 (CH3), 25.2
(CH2), 32.4 (CH2), 46.6 (CH2), 68.7 (CH), 69.9 (CH2), 95.4 (C),
118.6 (CH), 127.2 (CH), 127.7 (CH), 127.8 (CH), 128.5 (CH),
129.9 (CH), 135.7 (C), 137.9 (C), 144.4 (C), 157.5 (CH), 169.9
(C); NMR data for 24eq: δH (400 MHz, CDCl3) 1.63 (1 H, ddd,
J 13.5, 4.0, 3.0 Hz, H-10), 1.79 (1 H, tdd, J 13.5, 11.0, 4.0 Hz,
H-9), 2.04 (1 H, td, J 13.5, 4.5 Hz, H-10), 2.11–2.17 (1 H, m,
H-9), 2.42 (3 H, s, CH3), 2.94 (1 H, t, J 11.0 Hz, H-7), 3.72
(1 H, tt, J 11.0, 4.5 Hz, H-8), 4.29 (1 H, ddd, J 11.0, 4.5, 1.5
Hz, H-7), 4.65 (2 H, s, CH2Ph), 5.99 (1 H, d, J 5.5 Hz, H-3),
7.29 (2 H, d, J 8.5 Hz, Ar), 7.31–7.41 (5 H, m, Ph), 7.46 (2 H,
d, J 8.5 Hz, Ar), 7.74 (1 H, d, J 5.5 Hz, H-4); δC (100 MHz,
CDCl3) 21.6 (CH3), 26.9 (CH2), 36.1 (CH2), 48.7 (CH2), 71.0
(CH2), 72.8 (CH), 94.4 (C), 118.8 (CH), 127.3 (CH), 127.6
(CH), 127.9 (CH), 128.5 (CH), 129.9 (CH), 135.0 (C), 138.0
(C), 144.7 (C), 156.9 (CH), 169.5 (C); HRMS (ESI+) found
436.1175; C22H23NNaO5S (MNa+) requires 436.1189.
15 A. S. Pilcher and P. DeShong, J. Org. Chem., 1993, 58, 5130.
16 Crystal data for compound 6ax: (colourless plate, 0.16 × 0.20 ×
0.24 mm): C8H10O4 Mr = 170.16; orthorhombic, space group Pbca; a =
7.0008(2) Å, b = 9.0561(2) Å, c = 24.0388(5) Å, β = 90°, V = 1524.06
(6) Å3; Z = 8; μ = 0.120 mm−1; Dcalc = 1.483 g cm−3; Reflections col-
lected = 3461; independent reflections = 1723 (Rint = 0.024); R values
[I > 2σ(I), 1276 reflections]: R1 = 0.0363, wR2 = 0.0972; ρmin/max
=
−0.34/0.32 e Å−3; CCDC 842957. Crystal data for compound 6eq: (col-
ourless block, 0.10 × 0.10 × 0.10 mm): C8H10O4 Mr = 170.16; monocli-
nic, space group P21/n; a = 7.5000(3) Å, b = 6.0089(2) Å, c = 17.9334
(7) Å, β = 94.8761(15)°, V = 805.28(5) Å3; Z = 4; μ = 0.113 mm−1; Dcalc
= 1.403 g cm−3; Reflections collected = 3347; independent reflections =
1822 (Rint = 0.023); R values [I > 2σ(I), 1492 reflections]: R1 = 0.0484,
wR2 = 0.1581; ρmin/max = −0.27/0.34 e Å−3; CCDC 842958.
17 (a) M. A. Ciufolini and C. Y. Wood, Tetrahedron Lett., 1986, 27, 5085;
(b) M. A. Ciufolini, C. Y. W. Hermann, Q. Dong, T. Shimizu,
S. Swaminathan and N. Xi, Synlett, 1998, 105.
18 W.-S. Zhou, Z.-H. Lu and Z.-M. Wang, Tetrahedron, 1993, 49, 2641.
19 B. S. Nash, Chemistry Part II thesis, University of Oxford, 2007.
20 S. Macnaughton, D.Phil. thesis, University of Oxford, 2011.
21 A. D. Kosal and B. L. Ashfeld, Org. Lett., 2010, 12, 44.
22 Cf. C.-C. Li, S. Liang, X.-H. Zhang, Z.-X. Xie, J.-H. Chen, Y.-D. Wu
and Z. Yang, Org. Lett., 2005, 7, 3709 in which hydrogenation of alde-
hyde 14 in the presence of Lindlar catalyst led to competitive reduction
of the aldehyde, necessitating re-oxidation of the so-formed 2-(3-hydro-
xypropyl)furan.
23 K. Iwanami and T. Oriyama, Chem. Lett., 2004, 33, 1324.
24 Y. Mei, P. A. Bentley and J. Du, Tetrahedron Lett., 2009, 50, 4199.
25 T. Miura and Y. Masaki, J. Chem. Soc., Perkin Trans. 1, 1995, 2155.
26 H. Fujioka, A. Goto, K. Otake, O. Kubo, K. Yahata, Y. Sawama and
T. Maegawa, Chem. Commun., 2010, 46, 3976.
27 (a) C. S. Foote, M. T. Wuesthoff, S. Wexler, I. G. Burstain, R. Denny, G.
O. Schenck and K.-H. Schulte-Elte, Tetrahedron, 1967, 23, 2583;
(b) Ac2O work-up details: Y. Fall, B. Vidal, D. Alonso and G. Gómez,
Tetrahedron Lett., 2003, 44, 4467.
28 D. Woollaston, D.Phil. thesis, University of Oxford, 2007.
29 Cf. E. Pavlakos, T. Georgiou, M. Tofi, T. Montagnon and
G. Vassilikogiannakis, Org. Lett., 2009, 11, 4556.
Equilibration experiments
Single butenolide spiroacetals (6–9) or spiro-N,O-acetals
(23, 24) (5–20 mg) were dissolved in CD3CN (0.6 mL) in
a standard NMR tube. Hydriodic acid (aq., 57% by weight,
1 mol%) was then added and equilibration monitored by
NMR spectroscopy. Equilibrium was usually reached within
30 min–24 h.
Notes and references
1 (a) A. A. Ponomarev and I. A. Markushina, Dokl. Akad. Nauk SSSR,
1959, 126, 99; (b) V. Dedek, P. Trska and R. Hofeditz, Collect. Czech.
Chem. Commun., 1968, 33, 3565; (c) H. Fukuda, M. Takeda, Y. Sato and
O. Mitsunobu, Synthesis, 1979, 368; (d) B. L. Feringa and R.
J. Butselaar, Tetrahedron Lett., 1982, 23, 1941; (e) P. DeShong, R.
E. Waltermire and H. L. Ammon, J. Am. Chem. Soc., 1988, 110, 1901;
(f) F. Perron and K. F. Albizati, J. Org. Chem., 1989, 54, 2044; (g) P.
J. Kocienski, Y. Fall and R. Whitby, J. Chem. Soc., Perkin Trans. 1,
1989, 841; (h) R. C. D. Brown and P. J. Kocienski, Synlett, 1994, 417;
(i) P. J. Kocienski, R. C. D. Brown, A. Pommier, M. Procter and
B. Schmidt, J. Chem. Soc., Perkin Trans. 1, 1998, 9; ( j) S. Bartlett,
R. Hodgson, J. M. Holland, M. Jones, C. Kilner, A. Nelson and
S. Warriner, Org. Biomol. Chem., 2003, 1, 2393.
2 Y. Lefebvre, Tetrahedron Lett., 1972, 13, 133.
3 J. Robertson, P. Meo, J. W. P. Dallimore, B. M. Doyle and C. Hoarau,
Org. Lett., 2004, 6, 3861.
4 J. Robertson, K. Stevens and S. Naud, Synlett, 2008, 2083.
5 J. Robertson, P. T. Chovatia, T. G. Fowler, J. M. Withey and D.
J. Woollaston, Org. Biomol. Chem., 2010, 8, 226.
30 Using I2 in the presence of an excess of triethylamine (in CD3CN) led to
no isomerisation.
31 (a) S. Wolfe, Acc. Chem. Res., 1972, 5, 102; (b) K. B. Wiberg, M.
A. Murcko, K. E. Laidig and P. J. MacDougall, J. Phys. Chem., 1990, 94,
6956; (c) A. J. Kirby and N. H. Williams, in The Anomeric Effect and
Associated Stereoelectronic Effects, ed. G. R. J. Thatcher, American
Chemical Society, ACS Symposium Series, Washington, DC, 1993, pp.
55–69.
32 C. Thibaudeau, J. Plavec, N. Garg, A. Papchikhin and J. Chattopadhyaya,
J. Am. Chem. Soc., 1994, 116, 4038.
33 Spartan ‘10, Wavefunction, Inc., Irvine, CA; Y. Shao, L. F. Molnar,
Y. Jung, J. Kussmann, C. Ochsenfeld, S. T. Brown, A. T. B. Gilbert, L.
V. Slipchenko, S. V. Levchenko, D. P. O’Neill, R. A. DiStasio Jr., R.
This journal is © The Royal Society of Chemistry 2012
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View Article Online
C. Lochan, T. Wang, G. J. O. Beran, N. A. Besley, J. M. Herbert, C.
Y. Lin, T. Van Voorhis, S. H. Chien, A. Sodt, R. P. Steele, V. A. Rassolov,
P. E. Maslen, P. P. Korambath, R. D. Adamson, B. Austin, J. Baker,
E. F. C. Byrd, H. Dachsel, R. J. Doerksen, A. Dreuw, B. D. Dunietz, A.
D. Dutoi, T. R. Furlani, S. R. Gwaltney, A. Heyden, S. Hirata, C.-P. Hsu,
G. Kedziora, R. Z. Khalliulin, P. Klunzinger, A. M. Lee, M. S. Lee, W.
Z. Liang, I. Lotan, N. Nair, B. Peters, E. I. Proynov, P. A. Pieniazek, Y.
M. Rhee, J. Ritchie, E. Rosta, C. D. Sherrill, A. C. Simmonett, J.
E. Subotnik, H. L. Woodcock III, W. Zhang, A. T. Bell, A.
K. Chakraborty, D. M. Chipman, F. J. Keil, A. Warshel, W. J. Hehre, H.
F. Schaefer, J. Kong, A. I. Krylov, P. M. W. Gill and M. Head-Gordon,
Phys. Chem. Chem. Phys., 2006, 8, 3172.
34 E. L. Eliel and S. H. Wilen, Stereochemistry of Organic Compounds,
Wiley, 1994.
35 I. García, M. Pérez, P. Besada, G. Gómez and Y. Fall, Tetrahedron Lett.,
2008, 49, 1344.
36 A. Okano, K. Tsukamoto, S. Kosaka, H. Maeda, S. Oishi, T. Tanaka,
N. Fujii and H. Ohno, Chem.–Eur. J., 2010, 16, 8410.
37 C. Rogers and B. A. Keay, Can. J. Chem., 1992, 70, 2929.
38 (a) V. C. Arsenijevic and D. D. Stefanovic, C. R. Chim., 1956, 243, 964;
(b) J. S. Ng, J. R. Behling, A. L. Campbell, D. Nguyen and B. Lipshutz,
Tetrahedron Lett., 1988, 29, 3045.
39 Light source: 160 W daylight ‘Solar Glo Sun Simulating’ lamp (www.
exo-terra.com).
3518 | Org. Biomol. Chem., 2012, 10, 3506–3518
This journal is © The Royal Society of Chemistry 2012