The one-pot, multi-component construction of highly substituted tetrahydropyran-4-ones using the Maitland-Japp reaction

Article abstract of DOI:10.1039/b508252h

A one-pot, multi-component reaction for the synthesis of highly substituted tetrahydropyran-4-ones, based on the long forgotten Maitland-Japp reaction has been realised. Two different aldehydes and a derivative of a β-ketoester can be condensed regioselectively in the presence of a Lewis acid to form tetrahydropyran-4-ones in excellent yields. The diastereoselectively of the reaction was found to be dependant upon the nature of the Lewis acid and the temperature at which the reaction was carried out. This procedure was also extended to the formation of tetrahydropyran-4-ones in greater than 95% enantiomeric excess. The Royal Society of Chemistry 2005.

Full text of DOI:10.1039/b508252h

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A R T I C L E
The one-pot, multi-component construction of highly substituted
tetrahydropyran-4-ones using the Maitland–Japp reaction†‡
Paul A. Clarke,* William H. C. Martin, Jason M. Hargreaves, Claire Wilson§ and
Alexander J. Blake§
School of Chemistry, University of Nottingham, University Park, Nottingham, Notts, UK NG7
2RD. E-mail: paul.clarke@nottingham.ac.uk; Fax: +44 115 9513564; Tel: +44 115 9513566
Received 13th June 2005, Accepted 13th July 2005
First published as an Advance Article on the web 26th August 2005
A one-pot, multi-component reaction for the synthesis of highly substituted tetrahydropyran-4-ones, based on the
long forgotten Maitland–Japp reaction has been realised. Two different aldehydes and a derivative of a b-ketoester
can be condensed regioselectively in the presence of a Lewis acid to form tetrahydropyran-4-ones in excellent yields.
The diastereoselectively of the reaction was found to be dependant upon the nature of the Lewis acid and the
temperature at which the reaction was carried out. This procedure was also extended to the formation of
tetrahydropyran-4-ones in greater than 95% enantiomeric excess.
into a synthetically useful procedure for the synthesis of highly
substituted tetrahydropyran-4-ones.
Introduction
Tetrahydropyran (THP) rings are ubiquitous in the natural
product arena, and over the years many methods have been
Results and discussion
developed for their construction. Some of the most widely
used methods are intramolecular epoxide opening, manipula-
tion of carbohydrates,1 hetero Diels–Alder cyclisations,2,3 Prins
reactions4,5 and intramolecular Michael reactions.6 Our interest
in the formation of THP rings arose from the reports of Maitland
and Japp, who showed that 3-butanone and 2 molecules of
benzaldehyde could be condensed in a low yielding process to
generate a substituted THP ring.7 In the 1930s, Cornubert and
Robinet investigated the analogous acid mediated condensation
of acetonedicarboxylic acid with benzaldehyde. In this case
cyclisation proceeded with concomitant decarboxylation to give
two stereoisomers of the pyranone product in a 250 : 1 ratio
(Scheme 1).8
We proposed to improve on the Maitland–Japp procedure by
developing a reaction utilising a b-ketoester, instead of a ketone,
as the building block for the THP ring. Taking advantage of
the marked difference in reactivity of the a and c positions of
a b-ketoester would allow for the synthesis of unsymmetrical
pyran products. The three reactions that would then constitute
the new variant of the Maitland–Japp reaction would be: a
regioselective aldol reaction at the c position of a b-ketoester
to give 1, followed by a Knoevenagel condensation of a second
aldehyde at the a position of the b-ketoester to furnish 2, and
then an intramolecular oxy-Michael reaction to give the pyran
ring 3. It was hoped that the new reaction would be under
thermodynamic control, and, as in the Maitland–Japp reaction,
give the all-equatorial product 3 (Scheme 2).
Scheme 1 The Maitland–Japp and Cornubert–Robinet reactions.
It was not until 1968, that the stereochemistry of the pyranone
products obtained in the Maitland–Japp and the Cornubert–
Robinet reactions were determined. In one of the first uses of
high field 1H NMR for stereochemical determination, Whiting
and Baxter were able to determine that the major compounds
formed in both the Maitland–Japp and the Cornubert–Robinet
reactions were the all-equatorial pyranones.9,10 We were attracted
to the multi-component, one-pot nature of the Maitland–Japp
reaction and desired to see if, with the application of modern
synthetic methods, the Maitland–Japp reaction could be turned
Scheme 2 Updating the Maitland–Japp reaction.
The two-pot reaction
Studies commenced by the use of Weiler dianion chemistry
of methyl acetoacetate,11 which furnished the d-hydroxy b-
ketoesters 1 in quantitative yields. These aldol products were
used in crude form for subsequent reactions, as in most
cases purification by column chromatography led to significant
degradation of the product to give the enone 4 (Scheme 3).
Attention now turned to developing the Knoevenagel and
intramolecular oxy-Michael steps of the reaction pathway. We
were hopeful that both steps could be combined in a tandem
reaction as literature precedent indicated that both processes
could be Lewis acid mediated. Precedent for the Lewis acid
catalysis of Knoevenagel reactions was seen in the work of
† Taken in part from the PhD thesis of William H. C. Martin, University
of Nottingham, 2005.
‡ Electronic supplementary information (ESI) available: chiral shift
NMR experiments. See http://dx.doi.org/10.1039/b508252h
§ Corresponding authors for information concerning crystallographic
data.
T h i s j o u r n a l i s
T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 5
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 5 5 1 – 3 5 6 3
3 5 5 1
©

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Fig. 1 1H NMR data.
Scheme 3 Reagents and conditions: (i) NaH, THF, 0 ◦C then nBuLi,
RCHO, −78 ◦C to RT.
Table 1 The two-pot Maitland–Japp reaction
Compound
R
R1
Yield (%)a
Ratiob 5 : 6
a
b
c
d
e
f
Ph
2-Furyl
Ph
66
68
55
55
80
80
2.6 : 1
6.8 : 1
1 : 1
1 : 1.4
6.4 : 1
12.3 : 1
Ph
iPr
nPr
iPr
Hexyl
Ph
Heptyl
Hexyl
nPr
a Isolated yield after flash column chromatography, calculated over
two steps from methyl acetoacetate. b Determined from the 1H NMR
(400 MHz) of the crude reaction mixture.
Lehnert,12 and an example of using a Lewis acid to promote
the intramolecular oxy-Michael reaction was provided by the
work of Paterson and Osbourne.13
Initial studies focused on using boron trifluoride etherate as
the Lewis acid promoter.14 The d-hydroxy b-ketoester 1a was
treated with 2-furfural and an equivalent of boron trifluoride
etherate in methylene chloride at room temperature. Reaction
was found to be rapid (∼1 minute) and, upon 1H NMR
analysis of the crude reaction mixture, was found to have
given the pyran products 5a and 6a in a 2.6 : 1.0 ratio in
favour of the 2,6 cis isomer 5a (Scheme 4 and Table 1).
The combined Knoevenagel and intramolecular oxy-Michael
reaction conditions were applied to a range of d-hydroxy b-
ketoesters and aldehydes, and in all cases the reaction was
complete within one hour and gave the pyran products as a
mixture of cis and trans isomers that were separable by column
chromatography to give the pyran products 5 and 6 in moderate
to good yield (Scheme 4 and Table 1).
Fig. 2 X-Ray crystal structures for 5b and 6b.
The 2,6 trans structure 6 was initially incorrectly assigned
as the enol form of the 2,6 cis isomer.14 It was not possible
to determine the stereochemistry of the 2,6 trans isomer 6 by
1H NMR techniques as the two sides of the ring existed in
completely separate spin systems and this led to the initial
misassignment of the structure of 6. A gradient NOE experiment
indicated that protons H6 and H2 were not close enough in space
to give a positive NOE, eluding to the 2,6 trans arrangement of
the pyran ring. The first positive evidence that the 2,6 trans
stereochemical assignment of 6 was correct was seen when a
crude mixture of the pyrans 5b and 6b was decarboxylated by
treatment with hydrogen peroxide and lithium hydroxide to give
the two products of the Cornubert–Robinet reaction 7 and 8,
the 1H NMRs of which were readily distinguishable (Scheme 5).
The ratio of the cis isomer 7 to the trans isomer 8 was the same
as the ratio of the cis isomer 5b to the trans isomer 6b in the
starting material (Scheme 5).
Scheme 4 Reagents and conditions: (i) R1CHO, BF3·OEt2, CH2Cl2, RT.
Stereochemical assignment of the pyran-4-one products
Evidence to support the stereochemical assignment of the 2,6 cis
isomer 5 was provided by 1H NMR analysis (Fig. 1). In addition,
the X-ray crystal structure was solved for 5b, which confirmed
the stereochemical assignment of the pyran keto-forms (Fig. 2).¶
Scheme 5 Reagents and conditions: (i) H2O2, LiOH, THF–H2O, 80 ◦C,
¶ Diffraction data were acquired on a Bruker SMART1000 (5b) or a
Bruker SMART APEX (6b) CCD area detector diffractometer equipped
with an Oxford Cryosystems open-flow cryostat operating at 150 K. The
structures were solved by direct methods and refined by full-matrix least-
squares on F2. Crystal data for 5b. C19H18O4, M = 310.33, monoclinic,
82%.
Unambiguous proof for the 2,6 trans structure was provided
by the single crystal X-ray structure of 6b (Fig. 2).¶ Comparison
a = 13.0132(10), b = 8.6004(7), c = 14.1620(11), b = 91.558(2)◦, V =
1584.4(2) A , T = 150(2) K, Z = 4, Dx = 1.301 g cm−3. Final R1 [2746 F >
Z = 2, Dx = 1.328 g cm−3. Final R1 [2913 F > 4r(F)] = 0.0401, wR2
[all 3507 F2] = 0.111. CCDC reference numbers 250776 and 250777. See
http://dx.doi.org/10.1039/b508252h for crystallographic data in CIF
or other electronic format.
3
˚
4r(F)] = 0.0375, wR2 [all 3656 F2] = 0.105. Crystal data for 6b. C19H18O4,
M = 310.33, triclinic, a = 5.5429(5), b = 9.5351(8), c = 15.1955(13), a =
82.937(2), b = 85.273(2), c = 77.190(2)◦, V = 775.9(2)3, T = 150(2) K,
3 5 5 2
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 5 5 1 – 3 5 6 3

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between the crystal structures of 5b and 6b also shed light on
why the 2,6 cis isomer of the pyran rings favoured the keto form,
whilst the 2,6 trans isomer existed exclusively in the enol form.
In the trans enol tautomer, a hydrogen bond was seen between
10 with iso-butyraldehyde proceeded smoothly at −78 ◦C but
the Knoevenagel reaction with butanal proved problematic. No
reaction occurred at −78 ◦C and it was only as the reaction
approached room temperature that consumption of the aldol
1
1
the enol proton and the ester carbonyl, as indicated by the H
product was observed. Analysis of the H NMR of the crude
NMR of the trans compounds in which the enol proton was at
12 ppm. The pyran ring was markedly flattened thus minimising
the penalty for having the C2 substituent on the ring in a pseudo
axial position. The 2,6 cis isomer was seen to be in a chair
conformation with all the substituents equatorial. Furthermore,
it was clear to see from the crystal structure that tautomerisation
to give the enol form of the 2,6 cis isomer would have resulted
in a destabilising steric clash between the substituent on C2 and
the ester group on C3.
reaction mixture showed that small amounts of the pyran
product 5c had been formed but that dehydration products 4
constituted the majority of the product mixture. It was found,
however, that no additional Lewis acid was required to promote
the Knoevenagel/oxy-Michael steps and when only one equiv-
alent of titanium tetrachloride was used in the reaction, cleaner
formation of the pyran products 5c–6c as a 1 : 1 mixture of
isomers was observed. However, the desired pyran products were
still heavily contaminated with enone products 4. Indeed, when
the Mukaiyama aldol reaction was conducted and then allowed
to warm to room temperature, without addition of the second
aldehyde, a complex, non separable, mixture of compounds was
observed by 1H NMR. In contrast, the d-hydroxy b-ketoester 1c
derived from Chan’s diene 10 and iso-butyraldehyde was stable
to a variety of Lewis acidic conditions at room temperature,
which we reasoned was due to the elimination of silanol being a
more facile process than the elimination of water.
Evidently in order to develop a viable one-pot pyran forming
reaction the aldol product would need to be in the non-
silylated form before addition of the second aldehyde. Indication
as to how this might be achieved came from the work of
Soriente et al.,17 therefore, trifluoroacetic acid in THF was
added to the aldol product 11a and this gave the d-hydroxy
b-ketoester 1a in quantitative yield. This enabled the subsequent
Knoevenagel/oxy-Michael reactions to proceed without prob-
lem. Using this approach, a viable protocol for the one-pot pyran
forming reaction was quickly developed (Scheme 7 and Table 2).
In cases where the substituent on C2 was aromatic, some
1
of the cis enol form was seen in the H NMR of the crude
reaction mixture. This was most marked for 2,6 diphenyl pyran
(Table 1, entry b) where the cis enol form 9b constituted 25%
1
of the product in the crude H NMR, but upon standing in
chloroform, tautomerisation to give entirely the cis keto form
5b was observed. Interestingly, the cis enol tautomer 9b showed
a long-range coupling between H2 and H5a and H5b of 2.0 Hz
1
and a H–1H NMR correlation experiment confirmed that a
5-bond coupling was present. The enol form of 9b was never
isolated but a gradient NOE experiment performed on a mixture
of the cis enol and cis keto forms showed a positive NOE of 6%
between H2 and H6, proving the 2,6 cis relationship between
these two protons (Fig. 3). In Table 1, entry a, the cis enol
tautomer constituted 7.5% of the total product and for entry
e, the amount of cis enol compound observed was 15% of the
product. In both these cases rapid tautomerisation to give the
cis keto form was observed upon exposure to chloroform.
Fig. 3 NOE data.
Scheme 7 Reagents and conditions: (i) TiCl4 or Yb(OTf)3, RCHO,
−78 ◦C then TFA, R2CHO, −78 ◦C–RT.
The one-pot reaction
The reaction proved general to a range of aldehydes and, in all
cases, gave completely chemoselective addition of the coupling
partners (Scheme 7, Table 2). It was decided to investigate the
effect that using a different Lewis acid would have on the
reaction so ytterbium triflate was used in place of titanium
tetrachloride. The pyran forming reaction was performed in
exactly the same way as in the titanium tetrachloride case and
gave comparable yields of the pyran products. The distribution
of products varied markedly from the titanium tetrachloride
case, however, favouring the 2,6 cis isomer 5 (Scheme 7, Table 3).
The reasons for this remarkable change in selectivity will be
discussed later.
Although many of the problems inherent in the original
Maitland–Japp reaction had been surmounted, one of the major
advantages had been lost as two separate reactions were now
required to generate the pyranone product. It was decided to
investigate developing a Lewis acid mediated aldol reaction
using Chan’s diene15 10 as the nucleophile which could be
incorporated into the tandem Lewis acid mediated Knoevenagel
condensation with a second aldehyde and intramolecular oxy-
Michael ring closure (Scheme 6).
Table 2 The TiCl4 promoted one-pot Maitland–Japp reaction
Compound
R
R1
Yield (%)a
Ratiob 5 : 6
b
c
g
h
i
Ph
Ph
nPr
Ph
98
98
82
88
88
74
93
80
1 : 3
1 : 1
1 : 3
1 : 4
1 : 1
1 : 2
1 : 3
1 : 0
iPr
iPr
iPr
(CH2)2C CH2
CH2OBn
Ph
=
nPr
Cyhex
Pr
j
Scheme 6 The revised one-pot Maitland–Japp reaction.
k
l
p-MeOC6H4
Ph
iPr
Titanium tetrachloride has been reported to catalyse both
the Mukiayama aldol reaction16 and also the Knoevenagel
condensation,12 so it was decided to investigate its use in
developing the one-pot reaction. Mukaiyama aldol reaction of
a Isolated yield after flash column chromatography. b Determined from
the 1H NMR (400 MHz) of the crude reaction mixture.
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 5 5 1 – 3 5 6 3
3 5 5 3

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Table 3 The Yb(OTf)3 promoted one-pot Maitland–Japp reaction
disfavoured, as a steric clash would arise between the C2 and C3
substituents. We suggest that in the absence of Lewis acid that
the 2,6 cis isomer 5 would be favoured over the 2,6 trans isomer
6, and that it is due to the low solubility of ytterbium triflate
in methylene chloride, precluding complexation to all the pyran
molecules in solution, that led to the increased amount of the
2,6 cis isomer 5 seen with ytterbium triflate.
Further evidence that the Lewis acid mediated cyclisation
reaction was reversible was seen when enone 13, obtained by
Knoevenagel condensation of benzaldehyde with the d-hydroxy
b-ketoester 12,14,18 was exposed to the pyran forming conditions,
and gave the furan 15 as a 1 : 1 mixture of geometrical
isomers (Scheme 8). Quenching of the reaction after 30 seconds
resulted in the exclusive formation of the pyran 14, which, when
resubmitted to the reaction conditions, gave the furan 15. The
conclusion drawn was that the pyran forming reaction was
reversible, and with time the thermodynamically more stable
furan product was formed by 5-exo-trig cyclisation of the alcohol
onto the pendant double bond.
Compound
R
R1
Yield (%)a
Ratiob 5 : 6
b
c
g
h
i
Ph
Ph
nPr
Ph
98
91
80
93
81
86
91
75
2.5 : 1
10 : 1
2.5 : 1
2 : 1
6 : 1
11 : 1
2 : 1
iPr
iPr
iPr
(CH2)2C CH2
CH2OBn
Ph
=
nPr
Cyhex
Pr
j
k
l
p-MeOC6H4
Ph
iPr
1 : 0
a Isolated yield after flash column chromatography. b Determined from
the 1H NMR (400 MHz) of the crude reaction mixture.
Investigation of the reaction mechanism
One of the major benefits of the original Maitland–Japp reaction
was that it delivered single isomers of the tetrahydropyran
product. However, our updated version of the Maitland–
Japp reaction furnished mixtures of diastereomers. In order to
understand the diastereoselectivity of the reaction, we needed
to establish whether the pyran forming step was reversible and
under thermodynamic control. To this end, the 2,6 cis 5b and
the 2,6 trans 6b isomers were separated and resubmitted to the
pyran forming reaction conditions for 18 hours. For each Lewis
acid the same isomeric distribution of products was established,
irrespective of the starting isomer, proving that the reaction was
under thermodynamic control (Table 4).
As can be seen for entries 1 and 2 in Table 4, the equilibrium
for the reaction mediated by titanium tetrachloride was found to
be markedly temperature dependent, favouring the 2,6 cis isomer
5b at −78 ◦C and the 2,6 trans isomer 6b at 0 ◦C. However, this
temperature dependence was not found to be general for all the
reactions studied. In the case of the formation of the pyrans 5g
and 6g the equilibrium was found to be 1.3 : 1.0 in favour of
the 2,6 trans isomer 6g at room temperature, but, contrary◦to
the previous example, when the product was stirred at −84 C
for 24 hours under the reaction conditions the equilibrium was
found to have moved even further in favour of the 2,6 trans
isomer 6g.
From the evidence above we concluded that the reaction was
under thermodynamic control. It must, therefore, hold that the
two Lewis acids, titanium tetrachloride and ytterbium triflate,
interact with the two diastereomers of the product differently.
It had already been established that the 2,6 trans isomer 6
favours the enol tautomer whilst the 2,6 cis isomer 5 exists
predominantly in the keto form. It can therefore be postulated
that the diastereoselectivity of the pyran forming reaction is
dependent on how well a particular Lewis acid can coordinate
to the enol framework, thereby stabilising the 2,6 trans isomer 6.
We propose that titanium tetrachloride could form a chelate with
the 2,6 trans isomer 6 that would stabilise it with respect to the 2,6
cis isomer 5. It can be hypothesised that the energy penalty for
having a pseudo axial substituent in the 2,6 trans isomer 6 is not
particularly large as it can be seen in the crystal structure (Fig. 2)
that the pyran ring is markedly flattened, reducing any 1,3 diaxial
interactions. The 2,6 cis isomer 5 has all its substituents in
equatorial positions and tautomerisation to the enol form is
Scheme 8 Reagents and conditions: (i) PhCHO, CH2Cl2, EDDA, 56%;
(ii) BF3·OEt2, CH2Cl2, <1 min, 0 ◦C, 92%; (iii) BF3·OEt2, CH2Cl2,
20 min, 0 ◦C, 80%.
Reaction kinetics
Having established that the reaction was under thermodynamic
control, experiments were performed in order to determine how
fast the equilibrium distribution of cis and trans isomers was
arrived at. This was achieved by conducting the addition of
the second aldehyde at a number of different temperatures and
monitoring the reaction at set intervals. The first system studied
was the formation of the bisphenyl pyrans 5b and 6b. Although
◦
the Knoevenagel reaction did not take place at −78 C, it did
occur slowly at −65 ◦C, with only a 38% conversion after 5 hours
1
reaction time. However, the only product observed in the H
NMR was the 2,6 cis isomer 5b, indicating that the 2,6 cis isomer
5b is the kinetic product at −65 ◦C. The reaction was much more
rapid at −40 ◦C giving appreciable amounts of the pyran product
(13%) after 1 hour. The only product formed at this time was the
2,6 cis isomer 5b, indicating that at −40 ◦C this was the kinetic
product. However, after 5 hours some of the 2,6 trans isomer 6b
was observed.
When the study was carried out at room temperature a
further complication arose as a new compound was seen in
1
the H NMR of the aliquot removed after 1 minute. This new
compound was not seen in the 1H NMR of the aliquot removed
after 48 hours, suggesting that its formation was reversible.
Table 4 Equilibration studies on 5b and 6b
Entry
Equilibration conditions
Temp
5b : 6b ratio when 5b was resubmitteda
5b : 6b ratio when 6b was resubmitteda
1
2
3
4
TiCl4–TFA
TiCl4–TFA
BF3·OEt2
0 ◦
−78 ◦
RT
C
C
29 : 71
75 : 25
44 : 56
71 : 29
29 : 71
75 : 25
44 : 56
71 : 29
Yb(OTf)3–TFA
RT
a Determined from the 1H NMR (400 MHz) of the crude reaction mixture.
3 5 5 4
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 5 5 1 – 3 5 6 3

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Table 5 Time dependence of the pyran ratio (5b : 6b) in the TiCl4
promoted Maitland–Japp reaction at 20 ◦
C
Entry Time/min Dimer (%)a Conversion (%)b Ratio 5b : 6b
1
2
3
4
5
0.5
1
10
60
2880
0
50
41
41
0
0
26
59
50
100
—
85 : 15
41 : 59
36 : 64
25 : 75
a % of starting material present as dimer. b % of starting material
converted to pyran.
It is suggested that this compound is the dimer 16 resulting
from Lewis acid mediated formation of a benzylic carbocation
followed by formation of an ether linkage (Scheme 9, Table 5).
Indeed, when the aldol reaction was run as normal and quenched
with TFA and then heated at 30 ◦C, without addition of a
second equivalent of benzaldehyde, clean conversion to this new
compound was observed. If the formation of the dimer 16 is
discounted it can be seen that at room temperature the 2,6 cis
isomer 5b is still the kinetic product, with the 2,6 trans isomer
6b predominating after 10 min.
Fig. 4 Modes of cyclisation.
The study was repeated for the reaction catalysed by ytterbium
triflate, and at room temperature it was found that the 2,6 cis
isomer 5b was the kinetic product with none of the 2,6 trans 6b
isomer seen until 5 minutes had elapsed. None of the dimer 16
was observed at any point in the reaction.
In order to establish whether all four modes of cyclisation were
accessible it was necessary to investigate whether scrambling of
the enone double bond geometry was possible under the reaction
conditions. The (Z)-17 and (E)-18 isomers of the Knoevenagel
product of methyl acetoacetate and benzaldehyde were separated
by column chromatography and were then submitted to the
Lewis acid reaction conditions (Scheme 10). Rapid double
bond scrambling was observed by analysis with TLC and after
12 hours 1H NMR analysis showed that the same ratio of E and
Z isomers was present in each reaction. It had therefore been
shown that all 4 modes of cyclisation in Fig. 4 were valid.
Scheme 9 Reagents and conditions: (i) PhCHO, TiCl4, CH2Cl2, −78 ◦C
then TFA 30 ◦C, 2 hr, 73%.
In order to establish whether the formation of the 2,6 cis
isomer 5 as the kinetic product was a general feature of the pyran
forming reaction it was decided to expand the study to include
different substrates. The one-pot titanium tetrachloride and
ytterbium triflate mediated formation of the pyrans 5g and 6g
was studied at room temperature. In both cases the first product
formed (1 min) was the 2,6 cis isomer 5g and with time (60 min
for TiCl4 and 20 min for Yb(OTf)3) the equilibrium distribution
was established. In the case of the TiCl4 reaction, complete
consumption of starting material took 20 min although in the
case of the Yb(OTf)3 mediated reaction complete consumption
of starting material took only 5 min. It was important to note,
however, that the rate of the reaction was much slower than that
observed for the formation of the bisphenyl pyran, with amounts
of the 2,6 trans isomer 6g being formed before the reaction had
gone to completion.
Scheme 10 Reagents and conditions: (i) PhCHO, PhH, AcOH, piperi-
dine, reflux, 64%; (ii) TiCl4, TFA, CH2Cl2, 36 h; (iii) BF3·OEt2, CH2Cl2,
36 h.
Use of tert-butyl esters
There are 4 possible modes of cyclisation available once
the Knoevenagel condensation has occurred (Fig. 4). In the
transition state depicted as A, the oxygen attacks the bottom
face of the (Z)-enone to give the 2,6 cis pyran and both the
R substituents are in favourable pseudo equatorial positions.
If the alcohol attacks the top face of the (Z)-enone C to give
the 2,6 trans isomer then R1 is in an unfavourable pseudo axial
position. Addition to the bottom face of the (E)-enone B gives
the 2,6 cis product but in this case both R substituents are in
unfavourable pseudo axial positions. Finally, addition of the
oxygen nucleophile to the bottom face of the (E)-enone to
give the 2,6 trans isomer leads to the transition state D where
R2 is in a pseudo axial position. Using this analysis it can be
hypothesised that the mode of cyclisation depicted as A will
have the lowest energy barrier of the four modes to achieve the
correct confirmation for cyclisation and will therefore lead to
the kinetic product 5.
Now that we understood that the reaction was under thermo-
dynamic control and that the 2,6 cis and 2,6 trans isomers
were rapidly interconverting under the reaction conditions, we
initiated attempts to develop a reaction that would give us only
one diastereomer of the pyran product. Given that the 2,6 cis
isomer 5 favoured the keto form whilst the 2,6 trans isomer 6
existed exclusively as the enol tautomer, this led us to consider
using decarboxylation as a way in which to favour the formation
of the 2,6 cis isomer. It was postulated, that if conditions could
be found to effect an in situ decarboxylation of the pyranone
product, that the 2,6 cis isomer 5 might be decarboxylated faster
than the 2,6 trans isomer 6, thereby funnelling the reaction
towards the 2,6 cis isomer. To enable an in situ decarboxylation
to be developed it was decided to investigate the use of the
diene 19 (Scheme 11) as it was envisaged that the tert-butyl ester
would be removed upon prolonged exposure to trifluoroacetic
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 5 5 1 – 3 5 6 3
3 5 5 5

View Article Online
Asymmetric synthesis of tetrahydropyran-4-ones
The development of the Maitland–Japp reaction had furnished
a one-pot, chemo- and diastereoselective process that was appli-
cable to a wide range of aldehydes to give the tetrahydropyran-
4-one products in good yields. To be a truly useful process to
the synthetic chemist it was deemed necessary to develop an
asymmetric version of the reaction. We rationalised that if the
sense of chirality of the initially formed hydroxyl stereocentre
could be controlled, then it may prove possible to use this stere-
ocentre to control the sense of the other stereocentres formed in
the cyclisation reaction. However, under the reaction conditions
there is the clear potential for the hydroxyl stereocentre to
racemise either via a retro-aldol reaction or via formation of
a stabilised cation. This would obviously thwart any attempt to
develop an asymmetric version of the Maitland–Japp reaction.
In order to assess the feasibility of an asymmetric Maitland–
Japp reaction it was decided to study the cyclisation of d-hydroxy
b-ketoesters synthesised from starting materials available from
the chiral pool. The compounds 24 and 25 were commercially
available in enantiomerically pure form, and the Claisen con-
densation of 24 with the anion of tert-butyl acetate proceeded
smoothly to give the d-hydroxy b-ketoester 26 in respectable
yield.20 However, when these conditions were applied to 25 the
d-hydroxy b-ketoester 28 was formed in only 50% conversion,
by analysis of the 1H NMR of the crude reaction mixture, and
was found to be inseparable from the starting material. In an
attempt to drive the reaction to completion the temperature of
the reaction was raised but this resulted in the formation of the
lactone 27. It eventually proved possible to deliver the desired
product 28 in 82% yield by extending the reaction time at −20 ◦C
to 12 hours (Scheme 13).
Scheme 11 Reagents and conditions: (i) TiCl4, RCHO, −78 ◦C then
TFA, py, R1CHO, −78 ◦C–RT.
Table 6 The Maitland–Japp reaction of diene 19
Compound
R
R1
Yield (%)a
Ratiob 20 : 21
a
b
c
iPr
Ph
Ph
Ph
nPr
Ph
92
98
91
44
14 : 1
4 : 1
2 : 1
Cyhex
d
iPr
10 : 1
a Isolated yield after flash column chromatography. b Determined from
the 1H NMR (400 MHz) of the crude reaction mixture.
acid. The diene 19 was synthesised in the same way as Chan’s
diene,19 in an 80% yield from tert-butyl acetoacetate.
The conditions developed for the pyran forming reaction
based on Chan’s diene were applied to the diene 19, however,
to avoid decomposition of the initial aldol product during the
reaction, pyridine was added to the reaction after the initial
aldol reaction had gone to completion and prior to addition
of the second aldehyde. Using these new conditions the pyran
products 20 and 21 were formed in good yield, although no
in situ decarboxylation was observed (Scheme 11, Table 6). It
was a surprise, however, to discover that in all cases the 2,6
diastereoselectivity was completely reversed, with respect to the
titanium tetrachloride promoted pyran forming reaction using
Chan’s diene, giving predominantly the 2,6 cis isomer 20.
With the use of forcing conditions it did prove possible to
effect an in situ decarboxylation of the pyran products. After
the pyran reaction was complete, trifluoroacetic acid was added
to the reaction mixture. Stirring of the reaction for 12 hours
at room temperature gave a more polar compound, although
subsequent heating gave the pyran-4-one products 22 and 23
in moderate yield (Scheme 12, Table 7). It was interesting to
note that in the reaction to give the bisphenyl product, entry
1 Table 10, the ratio of the 2,6 cis to the 2,6 trans isomer was
exactly the same as that seen when the reaction was stopped
to give the ester compound. This suggests that the conditions
employed for the decarboxylation did not alter the equilibrium
between the 2,6 cis and the 2,6 trans compounds and implies that
the trans isomer undergoes decarboxylation by tautomerising to
the keto form of the 2,6 trans isomer.
Scheme 13 Reagents and conditions: (i) CH3CO2 Bu, LDA, −78 ◦C,
t
◦
t
t
72%; (ii) CH3CO2 Bu, LDA, −78 C–RT, 55%; (iii) CH3CO2 Bu, LDA,
−20 ◦C, 82%.
With the enantiomerically pure precursors to cyclisation in
hand, the previously developed cyclisation conditions were
employed. Treatment of 26 with benzaldehyde and titanium
tetrachloride/pyridine gave the pyran product 29 in a 10.0 :
1.0 ratio in favour of the 2,6 cis isomer with no erosion of
1
enantiomeric excess by chiral shift H NMR spectroscopy. In
Scheme 12 Reagents and conditions: (i) TiCl4, RCHO, −78 ◦C then
TFA, py, R1CHO, −78 ◦C to RT, then TFA, 12 h then py, 80 ◦C, 6 h.
the case of 28 the decarboxylative variant of the reaction was
used to give the 2,6 cis substituted pyranone 22d, in a 10 : 1.0 ratio
to the 2,6 trans isomer, again with no loss of enantiomeric excess
by chiral shift 1H NMR spectroscopy (Scheme 14). For details
of chiral shift NMR experiments see supporting information.‡
Table 7 The decarboxylative Maitland–Japp reaction
Compound
R
R1
Yield (%)a
Ratiob 22 : 23
Conclusions
A number of cyclisation strategies inspired by the Maitland–
Japp reaction have been developed. The two-pot approach
utilised an anionic aldol reaction followed by a Lewis acid medi-
ated Knoevenagel condensation and concomitant oxy-Michael
ring closure to give the pyran products in reasonable yield. By
using a Lewis acid mediated aldol reaction it was possible to
b
d
e
Ph
Ph
C8H17
Ph
iPr
Ph
92
64
33
4 : 1
10 : 1
5 : 1
a Isolated yield after flash column chromatography. b Determined from
the 1H NMR (400 MHz) of the crude reaction mixture.
3 5 5 6
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 5 5 1 – 3 5 6 3

View Article Online
CDCl3) d 3.84 (1H, ddd, J = 9.1, 5.8, 2.9 Hz, H-5), 3.74 (3H, s,
OMe), 3.51 (2H, s, H-2), 2.71 (1H, dd, J = 17.3, 2.9 Hz, H-4),
2.61 (1H, dd, J = 17.3, 9.1 Hz, H-4), 1.70 (dseptets, J = 6.7,
5.8 Hz, H-6), 0.93 (3H, d, J = 6.7 Hz, H-7 or 8), 0.91 (3H, d,
J = 6.7 Hz, H-7 or 8) ppm; 13C NMR (100 MHz; CDCl3) d
203.9, 167.5, 72.2, 52.4, 49.8, 46.8, 33.1, 18.5, 17.6 ppm; m/z
(ES+) 252 (20%, M+ + Na + CH3CN), 211 (100%, M+ + Na),
171 (40%, M+ − OH); HRMS: found (M+ + Na), 211.0962.
C9H16O4 requires (M+ + Na), 211.0946.
5-Hydroxy-3-oxo-undecanoic acid methyl ester 1c. Colour-
=
less oil. mmax (film) 3453 (OH), 2927, 2856, 1747 (C O), 1714
=
Scheme 14 Reagents and conditions: (i) TiCl4, py, PhCHO, 55%;
−1
1
(C O), 1437, 1323, 1240 cm ; H NMR (400 MHz; CDCl3) d
4.08 (1H, dddd, J = 8.8, 7.7, 4.4, 2.9 Hz, H-5), 3.73 (3H, s, OMe),
3.48 (2H, s, H-2), 2.71 (1H, dd, J = 17.2, 2.9 Hz, H-4), 2.63 (1H,
dd, J = 17.2, 8.8 Hz, H-4), 1.52–1.22 (11H, m, H-6–10 + OH),
0.86 (3H, t, J = 7.0 Hz, H-11) ppm; 13C NMR (100 MHz; CDCl3)
d 203.6, 167.3, 67.5, 52.4, 49.6, 36.4, 31.7, 29.6, 29.1, 25.3, 22.5,
14.0 ppm; m/z (EI+) 294 (30%, M+ + CH3CN + Na), 253
(100%, M+ + Na), 213 (40%, M+ − Me); HRMS: found (M+ +
CH3CN + Na), 294.1696. C12H22O4 requires (M+ + CH3CN +
Na), 294.1681; Anal. Calcd. for C12H22O4: C, 62.58; H, 9.63.
Found C, 62.80; H 9.83%.
(ii) TiCl4, (CH3)2CHCHO, TFA, py, reflux, 70%.
develop a one-pot reaction that gave the pyran products in
excellent yield. The reaction mechanism was elucidated and it
proved possible to alter the diastereoselectivity of the reaction by
changing the Lewis acid and the nature of the diene used in the
reaction. The transfer of chiral information in the pyran forming
reaction has been demonstrated and this led to the formation
of enantiomerically pure pyran products in good yield. Work
is ongoing to develop an asymmetric aldol reaction which can
be combined with the Knoevenagel/oxy-Michael reactions and
thus develop a one-pot procedure for the asymmetric synthesis
of highly functionalised tetrahydropyran-4-ones.
5-Hydroxy-3-oxo-tridecanoic acid methyl ester 1d. Colour-
=
less oil. mmax (film) 3418 (OH), 2924, 2855, 1746 (C O), 1714
−1
1
=
(C O), 1438, 1323, 1260 cm ; H NMR (400 MHz; CDCl3) d
4.05 (1H, dddd, J = 8.8, 7.7, 4.4, 2.9 Hz, H-5), 3.73 (3H, s, OMe),
3.49 (2H, s, H-2), 2.71 (1H, dd, J = 17.6, 2.9 Hz, H-4), 2.64 (1H,
dd, J = 17.6, 8.8 Hz, H-4), 1.52–1.21 (15H, m, H-6–12 + OH),
0.86 (3H, t, J = 7.0 Hz, H-13) ppm; 13C NMR (100 MHz;
CDCl3) d 203.8, 167.5, 67.6, 52.5, 49.7, 36.5, 33.7, 31.9, 29.6,
29.3, 25.6, 25.5, 22.7, 14.2 ppm; m/z (ES+) 281 (100%, M+ +
Na), 241 (30%, M+ − Me); HRMS: found (M+ + Na), 281.1732.
C14H26O4 requires (M+ + Na), 281.1728
Experimental
General
All NMR spectra were recorded as chloroform solutions. Thin
layer chromatography (TLC) was performed on pre-coated
plates (0.25 mm) silica UV254. The plates were developed using
ultraviolet light, basic potassium permanganate or ethanolic
anisaldehyde. Liquid chromatography was performed using
forced flow (flash column) with the solvent systems indicated.
The stationary phase was silica gel 60 (220–240 mesh) sup-
plied by Fluka. Dichloromethane was distilled from calcium
hydride; tetrahydrofuran and diethyl ether were distilled from
sodium/benzophenoneketyl. Benzene, DMSO and MeCN were
all distilled from calcium hydride prior to use. Hexane was
distilled prior to use. All other solvents and reagents were used
as received from commercial suppliers.
General procedure for the pyran forming reaction
To a stirred mixture of the d-hydroxy b-ketoester (0.25 mmol) in
CH2Cl2 (2 ml) at room temperature was added the aldehyde
(0.30 mmol) followed by boron trifluoride etherate (32 lL,
0.25 mmol). The yellow solution was stirred at room temperature
for 3 h and was then taken up in EtOAc (20 ml) and washed with
5% sodium metabisulfite (3 × 30 mL) and brine (2 × 30 mL),
dried (MgSO4), and concentrated in vacuo. Purification by flash
column chromatography (1 : 19 EtOAc–petroleum ether) gave
the pyran products 5 and 6.
General method for synthesis of aldol products
To a slurry of sodium hydride (414 mg, 10.34 mmol) in THF
(20 mL) at 0 ◦C was added methyl acetoacetate (100 mg,
8.62 mmol) slowly over 5 min during which time gas evolution
was observed. The colourless solution was stirred for 10 min
at 0 ◦C and then n-butyllithium (3.79 mL, 9.48 mmol, 2.5 M
in hexanes) was added. The light yellow solution was stirred at
room temperature for 20 min and was then cooled in an acetone–
dry ice bath. Once the internal temperature had reached −78 ◦C
the aldehyde (9.48 mmol) was added over a 5 min period. The
solution was kept at −78 ◦C for 5 min and was then warmed
to room temperature over 30 min. The light yellow solution
was stirred for 30 min and then H2O (10 ml) was added. The
mixture was extracted with EtOAc (50 mL) and washed with 5%
NaHCO3 (3 × 30 mL) and brine (2 × 30 mL), dried (MgSO4),
and concentrated in vacuo to give the aldol products 1 which
were used without further purification.
(2R*, 3R*, 6R*)-2-Furyl-6-phenyl-4-oxo-tetrahydro-pyran-3-
carboxylic acid methyl ester 5a. White solid. Mp: 88–90 ◦C;
=
=
mmax (film) 2950, 2920, 2845, 1745 (C O), 1716 (C O), 1657,
1440, 1345, 1264, 1217 cm−1; H NMR (400 MHz; CDCl3) d
1
7.44 (1H, dd, J = 1.8, 0.6 Hz, H-16), 7.43–7.30 (5H, m, Ph),
6.44 (1H, d, J = 3.2 Hz, H-14), 6.37 (1H, dd, J = 3.2, 1.8 Hz,
H-15), 5.20 (1H, d, J = 11.1 Hz, H-2), 4.89 (1H, dd, J = 10.8,
3.4 Hz, H-6), 4.03 (1H, dd, J = 11.1, 0.9 Hz, H-3), 3.73 (3H, s,
OMe), 2.83 (1H, dd, J = 14.6, 3.4 Hz, H-5eq), 2.77 (1H, ddd,
J = 14.6, 10.8, 0.9 Hz, H-5ax) ppm; 13C NMR (67.8 MHz;
CDCl3) d 200.7, 183.2, 150.7, 143.3, 128.7, 128.6, 126.1, 125.9,
110.4, 109.1, 78.6, 73.8, 60.6, 52.4, 48.7 ppm; m/z (CI+) 318
(62%, M+ + NH4), 301 (22%, M+ + H), 283 (28%, M+ − OH)
222 (58%), 205 (52%, M+ + H-furfural); HRMS: found (M+ +
NH4), 318.1342. C17H16O5 requires (M+ + NH4), 318.1341.
5-Hydroxy-3-oxo-5-phenyl-pentanoic acid methyl ester 1a21.
(2R*, 6S*)-2-Furyl-4-hydroxy-6-phenyl-2,3-dihydro-2H -
pyran-3-carboxylic acid methyl ester 6a. White solid. Mp: 81–
1
Colourless oil. H NMR (400 MHz; CDCl3) d 7.40–7.27 (5H,
m, Ph), 5.20 (1H, dd, J = 9.3, 3.4 Hz, H-5), 3.74 (3H, s, OMe),
3.51 (2H, s, H-2), 3.02 (1H, dd, J = 17.2, 9.3 Hz, H-4), 2.91 (1H,
dd, J = 17.2, 3.4 Hz, H-4) ppm.
83 ◦C; mmax (film) 2958, 2930, 1729 (C O), 1466, 1275, 1124,
=
1073 cm−1; H NMR (400 MHz; CDCl3) d 12.16 (1H, s, OH),
1
7.42 (1H, dd, J = 1.8, 0.9 Hz, H-16), 7.37–7.28 (5H, m, Ph),
6.35 (1H, dd, J = 3.2, 1.8 Hz, H-15), 6.26 (1H, ddd, J = 3.2,
0.9, 0.6 Hz, H-14), 5.77 (1H, brs, H-2), 4.74 (1H, dd, J = 10.8,
4.1 Hz, H-6), 3.71 (3H, s, OMe), 2.69 (1H, ddd, J = 18.1, 10.8,
5-Hydroxy-6-methyl-3-oxo-heptanoic acid methyl ester 1b.
=
Colourless oil. mmax (film) 3424 (OH), 2961, 2876, 1743 (C O),
−1
1
=
1713 (C O), 1439, 1327, 1272, 1042 cm ; H NMR (400 MHz;
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 5 5 1 – 3 5 6 3
3 5 5 7

View Article Online
0.9 Hz, H-5), 2.58 (1H, dd, J = 18.1, 4.1 Hz, H-5) ppm; 13C
NMR (67.8 MHz; CDCl3) d 171.0 (s), 170.7 (s), 153.3 (s), 142.8
(d), 140.6 (s), 128.5 (d), 127.9 (d), 125.9 (d), 110.0 (d), 109.8 (d),
97.1 (s), 69.2 (d), 67.0 (d), 51.7 (q), 35.5 (t), ppm; m/z (EI+)
300 (23%, M+), 268 (100%), 250 (43%); HRMS: found (M+),
300.0994. C17H16O5 requires (M+), 300.0998.
H); HRMS: found (M+ + NH4), 260.1863. C13H22O4 requires
(M+ + NH4), 260.1862.
(2R*, 6R*)-4-Hydroxy-6-(2-methyl-ethyl)-2-hexyl-2,3-dihydro-
2H-pyran-3-carboxylic acid methyl ester 6d. Colourless oil. mmax
−1
1
=
(film) 2951, 2861, 1663 (C O), 1624, 1443, 1270, 1221 cm ; H
NMR (400 MHz; CDCl3) d 12.04 (1H, s, OH), 4.44 (1H, d, J =
9.6, 2.7 Hz, H-2), 3.76 (3H, s, OMe), 3.47 (1H, ddd, J = 9.3, 7.3,
4.4 Hz, H-6), 2.25 (1H, dd, J = 17.6, 9.3 Hz, H-5), 2.18 (1H, dd,
J = 17.6, 4.4 Hz, H-5), 1.67 (1H, dseptets, J = 7.3, 6.9 Hz, H-7),
1.65–1.20 (10H, m, H-10–14), 0.99 (3H, d, J = 6.9 Hz, H-8 or
9), 0.92 (3H, d, J = 6.9 Hz, H-8 or 9), 0.89 (3H, t, J = 7.4 Hz,
H-15); 13C NMR (67.8 MHz; CDCl3) d 171.1 (s), 169.9 (s), 101.5
(s), 71.1 (d), 70.8 (d), 51.4 (q), 33.2 (t), 33.0 (t), 32.7 (d), 32.2 (t),
28.9 (t), 26.0 (t), 22.6 (t), 18.7 (q), 18.2 (q), 14.1 (q); m/z (CI+)
285 (39%, M+ + H), 267 (37%, M+ − OH), 199 (100%, M+ −
C6H13); HRMS: found (M+ + H), 285.2055. C16H28O4, requires
285.2066.
(2R*, 3R*, 6S*)-2,6-Bisphenyl-4-oxo-tetrahydro-pyran-3-
carboxylic acid methyl ester 5b. White solid. Mp: 133–135 ◦C;
=
=
mmax (film) 2953, 2921, 1747 (C O), 1717, (C O), 1496, 1455,
1274, 1067, 757, 699 cm−1; 1H NMR (400 MHz; CDCl3) d 7.50–
7.30 (10H, m, Ph), 5.13 (1H, d, J = 10.6 Hz, H-2), 4.95 (1H, dd,
J = 11.3, 3.0 Hz, H-6), 3.77 (1H, dd, J = 10.6, 0.8 Hz, H-3), 3.70
(3H, s, OMe), 2.86 (1H, dd, J = 14.3, 3.0 Hz, H-5eq), 2.79 (1H,
ddd, J = 14.3, 11.2, 0.8 Hz, H-5ax) ppm; 13C NMR (67.8 MHz;
CDCl3) d 201.1 (s), 167.8 (s), 139.9 (s), 138.6 (s), 128.8 (d), 128.8
(d), 128.6 (d), 128.1 (d), 126.8 (d), 125.6 (d), 81.0 (d), 78.9 (d),
64.6 (d), 52.1 (q), 48.9 (t) ppm; m/z (CI+) 310 (62%, M+), 293
(100%, M+ − OH); HRMS: found (M+), 310.1195. C19H18O4
requires (M+) 310.1205. Anal. Calcd. for C19H18O4: C, 73.53; H,
5.85. Found C, 73.22; H 5.95% and the minor enol tautomer of
the 2,6 cis isomer:
(2S*, 3R*, 6R*)-6-(2-Methyl-ethyl)-2-hexyl-4-oxo-tetrahydro-
pyran-3-carboxylic acid methyl ester 5d. Colourless oil. mmax
=
=
(film) 2957, 2929, 1749 (C O), 1718 (C O), 1463, 1362, 1262,
1
1121 cm−1; H NMR (400 MHz; CDCl3) d 3.83 (1H, m, H-2),
1
9b H NMR (400 MHz; CDCl3) d 7.50–7.30 (10H, m, Ph),
3.77 (3H, s, OMe), 3.34 (1H, ddd, J = 11.7, 6.8, 2.4 Hz, H-
6), 3.23 (1H, dd, J = 10.5, 0.8 Hz, H-3), 2.52 (1H, dd, J =
14.2, 2.4 Hz, H-5eq), 2.26 (1H, ddd, J = 14.2, 11.7, 0.8 Hz,
H-5ax), 1.79 (1H, m, H-7), 1.56 (4H, m, H-10,11), 1.29 (6H,
m, H-12,13,14), 0.95 (9H, m, H-8,9,15); 13C NMR (67.8 MHz;
CDCl3) d 203.3 (s), 168.9 (s), 81.9 (d), 78.5 (d), 63.5 (d), 52.2 (q),
44.7 (t), 35.2 (t), 33.5 (d), 31.8 (t), 29.0 (t), 25.4 (t), 22.7 (t), 18.3
(q), 18.2 (q), 14.1 (q) ppm; m/z (CI+) 285 (62%, M+ + H), 214
(100%, M+ − C5H11), 199 (20%, M+ − C6H13); HRMS: found
(M+ + H), 285.2059. C16H28O4 requires (M+ + H) 285.2066.
5.55 (1H, dd, J = 2.3, 1.9 Hz, H-2), 4.78 (1H, dd, J = 10.7,
2.7 Hz, H-6), 3.50 (3H, s, OMe), 2.79 (1H, ddd, J = 17.2, 10.7,
2.3 Hz, H-5), 2.61 (1H, ddd, J = 17.2, 2.7, 1.9 Hz, H-5) ppm.
(2R*, 6R*)-4-Hydroxy-2,6-diphenyl-2,3-dihydro-2H-pyran-3-
carboxylic acid methyl ester 6b. White solid. Mp: 118–120 ◦C;
=
mmax (film) 2955, 2918, 2849, 1745 (C O), 1662, 1443, 1269, 1219,
1063, 698 cm−1; 1H NMR (400 MHz; CDCl3) d 12.38 (1H, s, OH),
7.57–7.28 (10H, m, Ph), 5.80 (1H, d, J = 1.0 Hz, H2), 4.59 (1H,
dd, J = 10.8, 3.9 Hz, H-6), 3.67 (3H, s, OMe), 2.73 (1H, ddd,
J = 18.1, 10.8, 1.0 Hz, H-5), 2.60 (1H, dd, J = 18.1, 3.9 Hz, H-5)
ppm; 13C NMR (67.8 MHz; CDCl3) d 171.2, 165.8, 141.0, 140.8,
128.8, 128.4, 128.0, 127.9, 126.9, 126.0, 98.7, 73.7, 68.3, 52.2,
35.6 ppm; m/z (CI+) 310 (50%, M+), 279 (10%, M+ − OMe),
233 (77%, M+ − Ph); HRMS: found (M+), 310.1205. C19H18O4
requires (M+), 310.1205. Anal. Calcd. for C19H18O4: C, 73.53; H,
5.85. Found C, 73.32; H 5.75%.
(2S*, 3R*, 6R*)-6-Octyl-2-phenyl-4-oxo-tetrahydro-pyran-3-
carboxylic acid methyl ester 5e. Colourless oil. mmax (CHCl3)
=
=
2928, 2856, 1744 (C O), 1715 (C O), 1657, 1456, 1346, 1124,
1065, 992 cm−1; 1H NMR (400 MHz; CDCl3) d 7.40–7.22 (5H,
m, Ph), 4.90 (1H, d, J = 10.4 Hz, H-2), 3.85 (1H, dddd, J =
11.6, 7.3, 6.1, 2.4 Hz, H-6), 3.61 (3H, s, OMe), 3.59 (1H, 1H,
d, J = 10.4 Hz, H-3), 2.57 (1H, dd, J = 14.6, 2.4 Hz, H-5eq),
2.42 (1H, dd, J = 14.6, 11.6 Hz, H-5ax), 1.74 (1H, m, H-7),
1.60 (1H, m, H-7), 1.43–1.20 (12 H, m, H-8–13), 0.87 (3H, t,
J = 7.3 Hz, H-14) ppm; 13C NMR (65 MHz; CDCl3) d 202.0,
168.0, 138.9, 128.6, 127.9, 126.7, 80.7, 76.3, 64.5, 52.0, 47.0,
36.2, 31.8, 29.7, 29.4, 29.2, 25.2, 22.6, 14.1 ppm; m/z (CI+) 346
(55%, M+), 315 (23%, M+ − OMe), 287 (100%, M+ − CO2Me),
269 (81%, M+ − Ph); HRMS: found (M+) 346.2145. C21H30O4
requires (M+) 346.2144.
(2R*, 6R*)-4-Hydroxy-6-(2-methyl-ethyl)-2-propyl-2,3-
dihydro-2H-pyran-3-carboxylic acid methyl ester 6c. Colour-
=
less oil. mmax (film) 2954, 2873, 1723 (C O), 1663, 1624, 1271,
1
1220, 1065 cm−1; H NMR (400 MHz; CDCl3) d 12.05 (1H, s,
OH), 4.46 (1H, d, J = 10.3 Hz, H-2), 3.76 (3H, s, OMe), 3.47
(1H, ddd, J = 9.3, 7.3, 4.9 Hz, H-6), 2.25 (1H, dd, J = 17.6,
9.3 Hz, H-5), 2.19 (1H, dd, J = 17.6, 4.9 Hz, H-5), 1.68 (1H, dq,
J = 7.3, 6.8 Hz, H-7), 1.6–1.3 (4H, m, H-10 + H-11), 0.99 (3H,
d, J = 6.8 Hz, H-8 or 9), 0.93 (3H, t, J = 7.3 Hz, H-12), 0.92
(3H, d, J = 6.8 Hz, H-8 or 9); 13C NMR (67.8 MHz; CDCl3) d
203.2, 168.8, 81.8, 78.1, 63.3, 52.1, 44.6, 37.2, 33.4, 18.7, 18.2,
18.0, 13.8 ppm; m/z (ES+) 306 (100%, M+ + Na + CH3CN),
(2S*, 3R*, 6R*)-6-Heptyl-2-propyl-4-oxo-tetrahydro-pyran-3-
carboxylic acid methyl ester 5f. mmax (film) 2956, 2932, 1747
−1
=
=
(C O), 1718 (C O), 1458, 1436, 1339, 1260, 1128, 1032 cm ;
1H NMR (400 MHz; CDCl3) d 3.86 (1H, ddd, J = 10.5, 8.5,
2.6 Hz, H-2), 3.77 (3H, s, OMe), 3.62 (1H, dddd, J = 11.4, 8.2,
4.1, 2.3 Hz, H-6), 3.22 (1H, dd, J = 10.5, 0.8 Hz, H-3), 2.46
(1H, dd, J = 14.3, 2.3 Hz, H-5eq), 2.25 (1H, ddd, J = 14.3, 11.4,
0.8 Hz, H-5ax), 1.70–1.21 (14H, m, H-7 to H-11–13 + H-14)
0.92 (6H, m, H-12 + H-15) ppm; 13C NMR (67.8 MHz; CDCl3)
d 203.6, 169.7, 79.1, 64.2, 53.0, 48.2, 38.1, 37.1, 32.6, 29.9, 26.1,
23.5, 19.6, 14.9, 14.7 ppm; m/z (CI+) 302 (100%, M+ + NH4),
285 (33%, M+ + H); HRMS: found (M+ + NH4), 285.2063.
C16H28O4 requires (M+ + NH4), 285.2066.
265 (38%, M+ + Na), 243 (37%, M+ + H), 171 (63%, M+
+
H–C3H7CHO); HRMS: found (M+ + Na + CH3CN), 306.1673.
C13H22O4 requires (M+ + Na + CH3CN), 306.1681.
(2S*, 3R*, 6R*)-6-(2-Methyl-ethyl)-4-oxo-2-propyl-tetrahydro-
pyran-3-carboxylic acid methyl ester 5c. Colourless oil. mmax
=
=
(film) 2961, 2933, 2873, 1748 (C O), 1717(C O), 1260,
1
1123 cm−1; H NMR (400 MHz; CDCl3) d 3.48 (1H, ddd, J =
10.5, 8.7, 2.6 Hz, H-2), 3.77 (3H, s, OMe), 3.34 (1H, ddd, J =
11.6, 6.7, 2.4 Hz, H-6), 3.23 (1H, dd, J = 10.5, 0.8 Hz, H-2), 2.51
(1H, dd, J = 14.2, 2.4 Hz, H-5), 2.25 (1H, ddd, J = 14.2, 11.6,
0.8 Hz), 1.80 (1H, dseptets, J = 6.7, 6.7 Hz, H-7), 1.55 (4H, m,
H-10,11), 1.00 (3H, d, J = 6.7 Hz, H-8 or 9), 0.92 (3H, d, J =
6.8 Hz, H-8 or 9), 0.91 (3H, t, J = 7.2 Hz, H-12); 13C NMR
(67.8 MHz; CDCl3) d 203.2 (s), 168.8 (s), 81.8 (d), 78.1 (d), 63.3
(d), 52.1 (q), 44.6 (t), 37.2 (t), 33.4 (d), 18.7 (t), 18.2 (q), 18.0 (q),
13.8 (q); m/z (ES+) 260 (100%, M+ + NH4), 243 (22%, M+ +
2,6 Bisphenyl pyran-4-one 7 and 8. To a solution of
2,6-bisphenyl-4-oxo-tetrahydro-pyran-3-carboxylic acid methyl
ester 5b and 4-hydroxy-2,6-diphenyl-2,3-dihydro-2H-pyran-3-
carboxylic acid methyl ester 5b (310 mg, 1.00 mmol) in THF–
H2O (10 mL, 4 : 1) was added hydrogen peroxide (450 lL,
4.00 mmol) followed by lithium hydroxide (38 mg, 1.60 mmol).
The reaction vessel was fitted with a reflux condenser and heated
at 80 ◦C for 4 days. The colourless solution was diluted with
3 5 5 8
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 5 5 1 – 3 5 6 3

View Article Online
EtOAc (30 mL) and washed with sodium metabisulfite (3 ×
30 mL) and brine (2 × 30 mL), dried (MgSO4), and concentrated
in vacuo. Purification by flash column chromatography (1 : 10
EtOAc–petroleum ether) gave pyran products 7 and 8 as an
inseparable mixture (204 mg, 82%) the data of which matched
that previously reported.
9), 0.97 (3H, d, J = 6.7 Hz, H-8 or 9) ppm; 13C NMR (100 MHz;
CDCl3) d 202.6 (s), 168.1 (s), 139.2 (s), 128.6 (d), 128.6 (d), 126.7
(d), 81.9 (d), 80.6 (d), 52.1 (q), 43.9 (t), 33.1 (d), 18.8 (q), 17.8
(q) ppm; m/z (CI+) 276 (72%, M+), 199 (100%, M+ − Ph), 167
(75%); HRMS: found (M+), 276.1359. C16H20O4 requires (M+),
276.1362.
1
7 H NMR (400 MHz; CDCl3) d 7.48–7.31 (10H, m, Ph),
Minor enol tautomer 9g, constituting 20% of the purified
1
4.86 (2H, dd, J = 10.3, 3.4 Hz, H-2 + H-6), 2.68 (2H, dd, J =
13.7, 3.4 Hz, H-3eq + H-5eq), 2.68 (2H, dd, J = 13.7, 10.3 Hz,
H-3ax + H-5ax) ppm.
sample by H NMR (500 MHz; CDCl3) d 7.40–7.28 (5H, m,
Ph), 5.30 (1H, dd, J = 2.6, 1.8 Hz, H-2), 3.46 (3H, s, OMe), 3.38
(1H, ddd, J = 10.6, 6.7, 2.9 Hz, H-6), 2.46 (1H, ddd, J = 17.2,
10.6, 2.6 Hz, H-5), 2.31 (1H, ddd, J = 17.2, 2.9, 1.8 Hz, H-5),
1.77 (1H, octet, J = 6.7 Hz, H-7), 0.96 (3H, d, J = 6.7 Hz, H-8
or 9), 0.79 (3H, d, J = 6.7 Hz, H-8 or 9) ppm. Upon standing in
chloroform this gave the cis keto isomer above.
8 1H NMR (400 MHz; CDCl3) d 7.48–7.31 (10H, m, Ph), 5.14
(2H, dd, J = 6.4, 5.4 Hz, H-2 + H-6), 2.93 (2H, ddd, J = 14.7,
6.4, 1.0 Hz, H-3 + H-5), 2.85 (2H, ddd, J = 14.7, 5.4, 1.0 Hz,
H-3 + H-5) ppm.
(2S*, 3R*, 6R*)-6-(2-Methyl-ethyl)-4-oxo-2-(pent-5-ene)-
tetrahydro-pyran-3-carboxylic acid methyl ester 5h. Colourless
General procedure for the one-pot Maitland–Japp reaction. The
titanium tetrachloride promoted reaction
=
=
oil. mmax (film) 2961, 2876, 1747 (C O), 1660 (C O), 1344, 1268,
1222, 1130, 1038, 913 cm−1; 1H NMR (400 MHz; CDCl3) d 5.75
(1H, dddd, J = 17.1, 10.3, 7.3, 6.4 Hz, H-12), 4.98 (1H, ddt,
J = 17.1, 3.4, 2.0 Hz, H-13trans), 4.93 (1H, ddt, J = 10.3, 3.4,
1.5 Hz, H-13cis), 3.80 (1H, ddd, J = 10.8, 9.3, 2.9 Hz, H-2),
3.70 (3H, s, OMe), 3.28 (1H, ddd, J = 11.7, 6.8, 2.0 Hz, H-6),
3.19 (1H, dd, J = 10.8, 1.0 Hz, H-3), 2.45 (1H, dd, J = 14.2,
2.0 Hz, H-5eq), 2.23 (1H, ddd, J = 14.2, 11.7, 1.0 Hz, H-5ax),
2.22 (2H, m, H-10), 1.76 (1H, octet, J = 6.8 Hz, H-7), 1.62 (2H,
m, H-11), 0.99 (3H, d, J = 6.8 Hz, H-8 or 9), 0.90 (3H, d, J =
6.8 Hz, H-8 or 9) ppm; 13C NMR (100 MHz; CDCl3) d 202.7,
168.6, 137.6, 115.1, 81.7, 77.4, 63.1, 52.0, 44.6, 34.1, 33.4, 29.5,
18.2, 18.1 ppm; m/z (ES+) 318 (68%, M+ + Na + CH3CN), 277
To a solution of aldehyde (1.00 mmol) in CH2Cl2 (10 mL) at
−78 ◦C was added titanium tetrachloride (111 lL, 1.00 mmol).
The black solution was stirred for 2 min and then Chan’s
diene (570 lL, 2.00 mmol) was added over a 1 min period.
The black solution was stirred at −78 ◦C for 1 h and then
trifluoroacetic acid (308 lL 4 mmol) was added. After 2 min
the second aldehyde (1.20 mmol) was added and the solution
was allowed to warm to room temperature over a 5 min period.
The black solution was stirred at room temperature for 2 h
and was then diluted with EtOAc (40 mL) and washed with 5%
NaHCO3 (3 × 30 mL), 5% sodium metabisulfite (3 × 30 mL) and
brine (2 × 30 mL), dried (MgSO4), and concentrated in vacuo.
Purification by flash column chromatography (1 : 19 EtOAc–
petroleum ether) gave the pyran products 5 and 6.
+
+
=
(100%, M + Na), 171 (98%, M + H–CH2 CH(CH2)2CHO);
HRMS: found (M+ + Na), 277.1425. C14H22O4 requires (M+ +
Na) 277.1416.
General procedure for the one-pot Maitland–Japp reaction. The
ytterbium triflate promoted reaction
(2R*, 6R*)-4-Hydroxy-6-(2-methyl-ethyl)-4-oxo-2-(pent-5-
ene)-2,3-dihydro-2H-pyran-3-carboxylic acid methyl ester 6h.
=
To a suspension of ytterbium(III) triflate (620 mg, 1.00 mmol)
in CH2Cl2 (10 mL) at −78 ◦C was added aldehyde (1 mmol)
followed by Chan’s diene (570 lL, 2.00 mmol). The white
mixture was stirred at −78 ◦C for 40 min and then triflu-
oroacetic acid (308 lL, 4 mmol) was added followed by the
second aldehyde (1.2 mmol). The mixture was warmed to room
temperature over 5 min and then stirred at room temperature
for 2 h. The mixture was then diluted with EtOAc (40 mL) and
washed with 5% NaHCO3 (3 × 30 mL) and brine (2 × 30 mL),
dried (MgSO4), and concentrated in vacuo. Purification by flash
column chromatography (1 : 19 EtOAc–petroleum ether) gave
pyran products 5 and 6, which were spectroscopically identical
to those made via the titanium tetrachloride method.
Colourless oil. mmax (film) 2956, 1748, 1662 (C O), 1623, 1443,
1
1365, 1270, 1221, 1067 cm−1; H NMR (400 MHz; CDCl3) d
12.04 (1H, s, OH), 5.85 (1H, ddt, J = 17.2, 10.3, 6.8 Hz, H-
12), 5.07 (1H, ddt, J = 17.2, 1.5, 1.5 Hz, H-13cis), 4.97 (1H,
ddt, J = 10.3, 1.5, 1.5 Hz, H-13trans), 4.46 (1H, d, J = 6.8 Hz,
H-2), 3.75 (3H, s, OMe), 3.46 (1H, ddd, J = 12.7, 7.3, 5.4 Hz,
H-6), 2.22 (4H, m, H-5 + H-10), 1.69 (3H, m, H-7 + H-11),
1.00 (3H, d, J = 6.8 Hz, H-8 or 9), 0.92 (3H, d, J = 6.8 Hz,
H-8 or 9) ppm; 13C NMR (67.8 MHz; CDCl3) d (67.8 MHz;
CDCl3) 171.0 (s), 170.1 (s), 138.3 (d), 114.5 (t), 101.1 (s), 70.9
(d), 70.5 (d), 51.4 (q), 33.1 (d), 32.1 (t), 31.8 (t), 30.2 (t), 18.7
(q), 18.2 (q) ppm; m/z (ES+) 318 (48%, M+ + Na + CH3CN),
277 (100%, M+ + Na), 255 (12%, M+ + H), 171 (98%, M+ + H–
+
=
CH2 CH(CH2)2CHO); HRMS: found (M + Na + CH3CN),
(2R*, 6R*)-4-Hydroxy-6-(2-methyl-ethyl)-2-phenyl-2,3-dihydro-
2H-pyran-3-carboxylic acid methyl ester 6g. White solid. Mp:
57–58 ◦C; mmax (film) 2957, 1661, 1624, 1442, 1269, 1223 cm−1; 1H
NMR (400 MHz; CDCl3) d 12.32 (1H, s, OH), 7.38–7.30 (5H, m,
Ph), 5.65 (1H, s, H-2), 3.65 (3H, s, OMe), 3.14 (1H, ddd, J = 10.8,
6.8, 3.9 Hz, H-6), 2.38 (1H, dd, J = 18.1, 10.8 Hz, H-5ax), 2.25
(1H, dd, J = 18.1, 3.9 Hz, H-5eq), 1.63 (1H, oct, J = 6.8 Hz, H-
7), 0.83 (3H, d, J = 6.8 Hz, H-8 or 9), 0.80 (3H, d, J = 6.8 Hz,
H-8 or 9) ppm; 13C NMR (100 MHz; CDCl3) d 171.8, 171.0,
140.9, 128.4, 127.9, 127.6, 98.5, 72.5, 71.4, 51.5, 32.6, 32.2, 18.3,
17.7 ppm; m/z (CI+) 276 (65%, M+), 199 (100%, M+ − Ph), 167
(82%); HRMS: found (M+), 276.1360. C16H20O4 requires (M+),
276.1362.
318.1681. C14H22O4 requires (M+ + Na + CH3CN) 318.1674.
(2R*, 6S*)-4-Hydroxy-2-(2-benzyloxy)-methyl-6-propyl-2,3-
dihydro-2H-pyran-3-carboxylic acid methyl ester 6i. Colourless
=
oil. mmax (film) 2957, 2872, 1661 (C O), 1622, 1443, 1290, 1217,
1
1074 cm−1; H NMR (400 MHz; CDCl3) d 12.15 (1H, s, OH),
7.35–7.26 (5H, m, Ph), 4.73 (1H, dd, J = 7.8, 2.0 Hz, H-2), 4.62
(1H, d, J = 12.2 Hz, H-11), 4.55 (1H, 12.2 Hz, H-11), 3.91 (1H,
m, H-6), 3.70 (3H, s, OMe), 3.64 (1H, dd, J = 10.8, 7.8 Hz,
H-10), 3.54 (1H, dd, J = 10.8, 2.0 Hz, H-10), 2.20 (2H, m, H-5),
1.60 (2H, m, H-7), 1.44 (2H, m, H-8), 0.94 (3H, t, J = 7.3, Hz,
H-9) ppm; 13C NMR (100 MHz; CDCl3) d 171.5, 170.7, 138.4,
128.3, 127.7, 127.5, 96.8, 72.9, 71.0, 69.7, 66.7, 51.4, 37.8, 34.2,
18.5, 14.0 ppm; m/z (ES+) 343 (100% M+ + Na), 335 (38%);
HRMS: found, (M+ + Na) 343.1529. C18H24O5 requires (M+ +
Na) 343.1521.
(2R*, 3R*, 6S*)-6-(2-Methyl-ethyl)-4-oxo-2-phenyl-tetrahydro-
pyran-3-carboxylic acid methyl ester 5g. White solid. Mp: 59–
61 ◦C; mmax (film) 3031, 2964, 1746, 1717, 1250 cm−1; H NMR
1
(500 MHz; CDCl3) d 7.40–7.29 (5H, m, Ph), 4.90 (1H, d, J =
10.4 Hz, H-2), 3.62 (1H, ddd, J = 11.6, 6.7, 2.4 Hz, H-6), 3.61
(3H, s, OMe), 3.57 (1H, d, J = 10.4 Hz, H-3), 2.57 (1H, dd, J =
14.0, 11.6 Hz, H-5ax), 2.45 (1H, dd, J = 14.0, 2.4 Hz, H-5eq),
1.91 (1H, octet, J = 6.7 Hz, H-7), 0.99 (3H, d, J = 6.7 Hz, H-8 or
(2R*, 3R*, 6R*)-2-(2-Benzyloxy)-methyl-6-propyl-4-oxo-
tetrahydro-pyran-3-carboxylic acid methyl ester 5i. mmax (film)
=
=
2957, 2872, 1746 (C O), 1716 (C O), 1622, 1438, 1348, 1264,
1
1128 cm−1; H NMR (400 MHz; CDCl3) d 7.35–7.28 (5H, m,
Ph), 4.64 (1H, d, J = 12.3 Hz, H-11), 4.50 (1H, d, J = 12.3 Hz,
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 5 5 1 – 3 5 6 3
3 5 5 9

View Article Online
H-11), 4.11 (1H, ddd, J = 10.5, 4.1, 3.2 Hz, H-2), 3.68 (1H, m,
H-6), 3.66 (1H, dd, J = 10.5, 0.9 Hz, H-3), 3.66 (3H, s, OMe),
3.62 (1H, dd, J = 10.8, 3.2 Hz, H-10), 3.58 (1H, dd, J = 10.8,
4.1 Hz, H-10), 2.47 (1H, dd, J = 14.3, 2.4 Hz, H-5eq), 2.30 (1H,
dd, J = 14.3, 11.4 Hz, H-5ax), 1.70 (1H, m, H-7), 1.45 (3H,
m, H-7 + H-8), 0.93 (3H, t, J = 7.3 Hz, H-9) ppm; 13C NMR
(67.8 MHz; CDCl3) d 202.5 (s), 168.3 (s), 137.7 (s), 128.3 (d),
127.7 (d), 127.7 (d), 77.7 (d), 77.0 (d), 73.5 (t), 70.6 (t), 59.1 (d),
52.0 (q), 47.0 (t), 38.1 (t), 18.4 (t), 13.8 (q) ppm; m/z (ES+)
343 (100% M+ + Na), 335 (38%); HRMS: found, (M+ + Na)
343.1552. C18H24O5 requires (M+ + Na) 343.1521.
H-8), 0.92 (3H, t, J = 7.3 Hz, H-9) ppm; 13C NMR (67.8 MHz;
CDCl3) d 202.1 (s), 168.0 (s), 159.6 (s), 131.0 (s), 128.0 (d), 113.9
(d), 80.4 (d), 77.0 (d), 64.5 (d), 55.2 (q), 51.9 (q), 46.9 (t), 38.2
(t), 18.2 (t), 13.8 (q) ppm; m/z (ES+) 370 (90%, M+ + Na +
CH3CN), 329 (100%, M+ + Na); HRMS: found (M+ + Na),
329.1355. C17H22O5 requires (M+ + Na) 329.1365.
(2S*, 3R*, 6R*)-2-(2-Methyl-ethyl)-6-phenyl-4-oxo-tetrahydro-
pyran-3-carboxylic acid methyl ester 5l. White solid. Mp: 99–
101 ◦C; mmax (film) 2966, 2934, 1746 (C O), 1715 (C O), 1454,
1361, 1132, 1073 cm−1; 1H NMR (400 MHz; CDCl3) d 7.43–7.32
(5H, m, Ph), 4.73 (1H, dd, J = 11.7, 2.5 Hz, H-6), 4.00 (1H, dd,
J = 10.8, 2.9 Hz, H-2), 3.79 (3H, s, OMe), 3.53 (1H, dd, J =
10.8, 1.0 Hz, H-3), 2.75 (1H, dd, J = 14.2, 2.5 Hz, H-5eq), 2.52
(1H, ddd, J = 14.2, 11.7, 1.0 Hz, H-5ax), 1.84 (1H, dseptets, J =
6.8, 2.9 Hz, H-11), 1.10 (3H, d, J = 6.8 Hz, H-12 or 13), 1.05
(3H, d, J = 6.8 Hz, H-12 or 13) ppm; 13C NMR (67.8 MHz;
CDCl3) d 202.4, 168.6, 140.8, 128.5, 127.9, 125.2, 82.3, 77.9,
60.5, 52.1, 48.8, 31.5, 19.7, 15.3 ppm; m/z (CI+) 276 (5%, M+),
233 (100%, M+ − (CH3)2CH); HRMS: found (M+) 276.1360.
C16H20O4 requires (M+) 276.1362.
=
=
(2R*, 6R*)-4-Hydroxy-6-cyclohexyl-4-oxo-2-phenyl-2,3-
dihydro-2H-pyran-3-carboxylic acid methyl ester 6j. White
solid. Mp: 89–91 ◦C; mmax (film) 2924, 2852, 1661 (C O), 1624,
=
1443, 1361, 1277, 1242, 1218, 1051 cm−1; 1H NMR (400 MHz;
CDCl3) d 12.28 (1H, s, OH), 7.35–7.28 (5H, m, Ph), 5.60 (1H, s,
H-2), 3.63 (3H, s, OMe), 3.14 (1H, ddd, J = 10.8, 7.3, 3.9 Hz,
H-6), 2.36 (1H, dd, J = 17.6, 10.8 Hz, H-5), 2.23 (1H, dd, J =
17.6, 3.9 Hz, H-5), 1.86 (1H, m, H-7), 1.70–1.47 (4H, m, H-8 +
9), 1.36–1.01 (4H, m, H-8 + 9), 0.85 (1H, ddd, J = 24.5, 12.7,
3.9 Hz, H-10), 0.66 (1H, ddd, J = 24.5, 12.7, 3.9 Hz, H-10) ppm;
13C NMR (67.8 MHz; CDCl3) d 171.9 (s), 140.9 (s), 128.5 (d),
127.9 (d), 127.6 (d), 98.5 (s), 72.5 (d), 70.6 (d), 51.5 (q), 42.3 (d),
32.3 (t), 28.6 (t), 26.3 (t), 25.9 (t), 25.6 (t) ppm; m/z (CI+) 334
(100%, M+ + NH4), 317 (55%, M+ + H); HRMS: found (M+ +
NH4), 334.2013. C19H24O4 requires (M+ + NH4) 334.2013. Anal.
Calcd. for C19H24O4: C, 72.13; H, 7.65. Found C, 71.93; H 7.72%.
5-Hydroxy-8-methyl-2-methylmethanoate-3-oxo-1-phenyl-non-
1,2-ene-8-ene 13. To a solution of 5-hydroxy-3-oxo-8-ene-
nonanoic acid methyl ester 12 (200 mg, 0.93 mmol) in CH2Cl2
(5 ml) at room temperature was added ethylene diamine
diacetate (10 mg, 0.06 mmol) and benzaldehyde (101 mg,
1.10 mmol). The reaction mixture was stirred at room
temperature for 20 h at which point TLC analysis still showed
the presence of starting material. More ethylene diamine
diacetate (10 mg, 0.06 mmol) and benzaldehyde (101 mg,
1.10 mmol) was added to the reaction. After a further 48 h
the reaction mixture was taken up in EtOAc (25 ml), washed
with 5% sodium metabisulfite (5 × 20 ml), water (2 × 20 ml)
and brine (2 × 20 ml), dried (MgSO4), and concentrated in
vacuo. Purification by flash column chromatography (1 : 19
EtOAc–petroleum ether) gave the title compound 13 as a
mixture of geometrical isomers and as a colourless oil. Isomer
1: oil. (150 mg, 56%) mmax (film) 3438, 2956, 2957, 1727, 1620,
1449, 1379, 1269, 1124, 1073, 1039 cm−1; 1H NMR isomer
1 (400 MHz; CDCl3) d 7.75 (1H, s, H-1), 7.40 (5H, m, Ph),
4.70 (1H, s, H-9), 4.65 (1H, s, H-9), 4.12 (1H, m, H-5), 3.85
(3H, s, OMe), 2.97, (1H, s, OH), 2.77 (1H, dd, J = 18.1, 3.0 Hz,
H-4), 2.69 (1H, dd, J = 18.1, 8.5 Hz, H-4), 2.10 (2H, m, H-6),
(2S*, 3R*, 6R*)-6-Cyclohexyl-4-oxo-6-propyl-tetrahydro-
pyr◦an-3-carboxylic acid methyl ester 5j. White solid. Mp: 92–
=
=
94 C; mmax (film) 2927, 2854, 1748 (C O), 1716 (C O), 1453,
1
1338, 1136, 1066, 1030, 760, 699 cm−1; H NMR (400 MHz;
CDCl3) d 7.40–7.30 (5H, m, Ph), 4.89 (1H, d, J = 10.5 Hz, H-2),
3.63 (1H, ddd, J = 11.4, 6.1, 2.6 Hz, H-6), 3.61 (3H, s, OMe),
3.57 (1H, dd, J = 10.5, 0.6 Hz, H-3), 2.58 (1H, dd, J = 14.0,
2.6 Hz, H-5eq), 2.46 (1H, ddd, J = 14.0, 11.4, 0.6 Hz, H-5ax),
1.91 (1H, m, H-7), 1.80–1.55 (5H, m, H-7–11), 1.27 (5H, m,
H-7–11) ppm; 13C NMR (67.8 MHz; CDCl3) d 202.7 (s), 168.1
(s), 139.2 (s), 128.7 (d), 128.6 (d), 126.8 (d), 81.5 (d), 80.7 (d),
64.9 (d), 52.1 (q), 44.4 (t), 43.0 (d), 28.6 (t), 28.2 (t), 26.4 (t),
26.0 (t) ppm; m/z (ES+) 380 (100%, M+ + Na + CH3CN),
339 (77%, M+ + Na), 211 (46%); HRMS: found (M+ + Na +
CH3CN), 380.1866. C19H24O4 requires (M+ + Na + CH3CN)
380.1838. Anal. Calcd. for C19H24O4: C, 72.13; H, 7.65. Found
C, 72.12; H 7.72%.
1
1.62 (2H, m, H-7), 1.71 (3H, s, H-10) ppm; H NMR Isomer
2 (400 MHz; CDCl3) d 7.65 (1H, s, H-1), 7.43 (5H, m, Ph),
4.78 (1H, s, H-9), 4.73 (1H, s, H-9), 4.12 (1H, m, H-5), 3.86
(3H, s, OMe), 3.03 (1H, s, OH), 2.94 (1H, dd, J = 17.5, 3.0 Hz,
H-4), 2.85 (1H, dd, J = 17.5, 8.6 Hz, H-4), 2.16 (2H, m, H-6),
1.76 (2H, m, H-7), 1.67 (3H, s, H-10) ppm; 13C NMR isomer 1
(100 MHz; CDCl3) d 206.5, 165.2, 145.5, 141.9, 133.2, 132.9,
131.0, 130.0, 129.3, 110.4, 67.6, 52.9, 50.4, 34.3, 33.8, 22.7 ppm;
13C NMR isomer 2 (100 MHz; CDCl3) d 207.1, 168.3, 145.5,
142.3, 141.9, 131.0, 130.0, 129.8, 129.2, 110.5, 67.6, 52.9, 45.6,
34.5, 33.9, 22.7 ppm; m/z (CI+) 303 (100%, M+ + H), 302
(50%, M+), 199; HRMS: found (M+ + H), 303.1599. C18H22O4
requires (M+ + H) 303.1596.
(2R*, 6R*)-4-Hydroxy-2-(4-methoxyphenyl)-6-propyl-2,3-
dihydro-2H-pyran-3-carboxylic acid methyl ester 6k. Colour-
=
less oil. mmax (film) 3417, 2932, 1661 (C O), 1623, 1510, 1443,
1
1247, 1218, 823 cm−1; H NMR (400 MHz; CDCl3) d 12.28
(1H, s, OH), 7.24 (2H, d, J = 8.8 Hz, Ph), 6.87 (2H, d, J =
8.8 Hz, Ph), 5.58 (1H, d, J = 1,0 Hz, H-2), 3.83 (3H, s, OMe),
3.64 (3H, s, OMe), 3.48 (1H, m, H-6), 2.32 (1H, ddd, J = 18.1,
10.3, 1.0 Hz, H-5), 2.24 (1H, dd, J = 18.1, 4.4 Hz, H-5), 1.52–
1.13 (4H, m, H-7 + H-8), 0.76 (3H, t, J = 6.9 Hz, H-9) ppm; 13
C
NMR (67.8 MHz; CDCl3) d 171.4, 171.1, 159.0, 133.2, 129.5,
113.2, 98.8, 72.1, 65.8, 55.1, 51.5, 37.6, 34.7, 18.2, 13.7 ppm; m/z
(CI+) 306 (84%, M+), 275 (50%, M+ − OMe), 247 (80%, M+ −
CO2Me); HRMS: found (M+), 306.1454. C17H22O5 requires (M+)
306.1467.
(2R*, 6R*)-6-(4-Ene-butyl)-4-hydroxy-2-phenyl-2,3-dihydro-
2H-pyran-3-carboxylic acid methyl ester 14. To a solu-
tion of 5-hydroxy-8-methyl-2-methylmethanoate-3-oxo-1-
phenyl-non-1,2-ene-8-ene 13 (50 mg, 0.17 mmol) in CH2Cl2
(10 ml) at 0 ◦C was added boron trifluoride etherate (37 mg,
0.26 mmol). After 1 min the reaction was quenched with water
(2 ml). The reaction mixture was taken up in EtOAc (15 ml) and
washed with brine (2 × 10 ml), dried (MgSO4), and concentrated
in vacuo. Purification by flash column chromatography (1 :
19 EtOAc–petroleum ether) gave 14 as a coloured solid. Mp:
(2S*, 3R*, 6R*)-2-(4-Methoxyphenyl)-4-oxo-6-propyl-
tetrahydro-pyran-3-carboxylic acid methyl ester 5k. Colourless
=
=
oil. mmax (film) 2958, 2872, 1747 (C O), 1715 (C O), 1614, 1515,
1
1251, 1034 cm−1; H NMR (400 MHz; CDCl3) d 7.31 (2H, d,
J = 8.8 Hz, Ph), 6.87 (2H, d, J = 8.8 Hz, Ph), 4.84 (1H, d, J =
10.6 Hz, H-2), 3.84 (1H, dddd, J = 11.7, 9.5, 5.1, 2.2 Hz, H-6),
3.79 (3H, s, OMe), 3.59 (1H, dd, J = 10.6, 0.7 Hz, H-3), 2.55
(1H, dd, J = 14.3, 2.2 Hz, H-5eq), 2.41 (1H, ddd, J = 14.3, 11.7,
0.7 Hz, H-5ax), 1.71 (1H, dddd, J = 15.7, 9.9, 7.0, 5.1 Hz, H-7),
1.56 (1H, dddd, J = 15.7, 9.9, 9.5, 5.9 Hz, H-7), 1.43 (2H, m,
58–60 ◦C; (46 mg 92%) mmax (film) 2915, 2869, 1658 (C O),
=
1628, 1442, 1355, 1286, 1271, 1219 cm−1; 1H NMR (400 MHz;
CDCl3) d 7.35–7.30 (5H, m, Ph), 5.62 (1H, s, H-2), 4.56 (1H,
3 5 6 0
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 5 5 1 – 3 5 6 3

View Article Online
d, J = 0.7 Hz, H-10), 4.40 (1H, d, J = 0.7 Hz, H-10) 3.63
(3H, s, OMe), 3.47 (1H, dddd, J = 10.4, 8.3, 4.2, 4.2 Hz, H-6),
2.35 (1H, dd, J = 18.0, 10.4 Hz, H-5), 2.26 (1H, dd, J = 18.0,
4.2 Hz, H-5), 2.04 (1H, m, H-7), 1.78 (1H, m, H-7), 1.57 (2H,
m, H-8), 1.56 (3H, s, H-11) ppm; 13C NMR (67.8 MHz; CDCl3)
d 171.8, 171.5, 144.8, 140.8, 128.4, 128.0, 127.7, 110.1, 98.2,
72.7, 66.0, 51.5, 34.7, 33.5, 33.0, 22.3 ppm; m/z (CI+) 320
(80%, M+ + NH4), 303 (90%, M+ + H), 231 (43%), 224 (52%),
205 (100%), 177 (85%); HRMS: found (M+ + H), 303.1595.
C18H22O4 requires (M+ + H) 303.1596.
and 18. Isomer 1 (190 mg, 19%) 1H NMR (400 MHz; CDCl3) d
7.69 (1H, s, H-1), 7.42–7.40 (5H, m, Ph), 3.84 (3H, s, OMe), 2.34
(3H, s, H-4) ppm. Isomer 2 (450 mg, 45%) 1H NMR (400 MHz;
CDCl3) d 7.58 (1H, s, H-1), 7.45–7.39 (5H, m, Ph), 3.84 (3H, s,
OMe), 2.43 (3H, s, H-4) ppm.
General method for the tert-butyl one-pot pyran
To a solution of aldehyde (1.00 mmol) in CH2Cl2 (10 mL) at
−78 ◦C was added titanium tetrachloride (111 lL, 1.00 mmol).
The black solution was stirred for 2 min and then the diene
19 (454 mg, 1.50 mmol) was added over a 1 min period. The
black solution was stirred at −78 ◦C for 40 min and then
trifluoroacetic acid (231 lL, 3.0 mmol) was added followed by
pyridine (160 lL, 2 mmol). After 2 min the second aldehyde
(1.20 mmol) was added and the solution was allowed to warm
to room temperature over a 5 min period. The black solution
was stirred at room temperature for 90 min and was then diluted
with Et2O (40 mL) and washed with 5% NaHCO3 (3 × 30 mL),
5% CuSO4 (3 × 30 mL), 5% sodium metabisulfite (3 × 30 mL),
brine (2 × 30 mL), dried (MgSO4), and concentrated in vacuo.
Purification by flash column chromatography (1 : 10 EtOAc–
petroleum ether) gave the pyran products 20 and 21.
2-(2-Methylester-3-oxo-1-phenyl-but-3,4-ene)-5,5-dimethyl-
furan 15. To a solution of 5-hydroxy-2-methylester-3-oxo-1-
phenyl-non-1,2-ene-8-ene 13 (20 mg, 0.07 mmol) in CH2Cl2
(4 ml) at 0 ◦C was added boron trifluoride etherate (15 mg,
0.11 mmol). After 20 min the reaction mixture was warmed
to room temperature. The reaction mixture was stirred for a
further 24 h at room temperature and was then quenched with
water (2 ml). The reaction mixture was taken up in ethyl acetate
(20 ml) and washed with water (3 × 10 ml) and brine (2 ×
10 ml), dried (MgSO4), and concentrated in vacuo. Purification
by flash column chromatography (1 : 19 EtOAc–petroleum
ether) gave 15 as an oil as two geometric isomers: (16 mg 80%)
mmax (film) 2968, 1724, 1704, 1666, 1622, 1576, 1495, 1455,
1392, 1367, 1317, 1266, 1134, 1096, 1048, 1001, 870, 838 cm−1;
1H NMR isomer 2 (400 MHz; CDCl3) d 7.64 (1H, s, H-11),
7.52–7.36 (5H, m, Ph), 4.43 (1H, m, H-2), 3.85 (3H, s, OMe),
3.18 (1H, dd, J = 16.3, 5.2 Hz, H-8), 2.72 (1H, dd, J = 16.3,
7.6 Hz, H-8), 2.25 (1H, m, H-3), 1.79 (2H, m, H-4), 1.67 (1H,
m, H-3), 1.27 (3H, s, H-6 or 7), 1.25 (3H, s, H-6 or 7) ppm;
13C NMR isomer 1 (100 MHz; CDCl3) d 206.5, 165.2, 145.5,
141.9, 133.0, 131.0, 130.0, 129.3, 110.4, 67.6, 52.9, 50.4, 34.3,
33.8, 22.7 ppm; 13C NMR isomer 2 (100 MHz; CDCl3) d 207.1,
168.3, 145.5, 142.3, 131.0, 130.0, 129.8, 129.2, 110.5, 67.6, 52.9,
45.6, 34.5, 33.9, 22.7 ppm; m/z (ES+) 303 (75%, M+ + H), 302
(2S*, 3R*, 6R*)-6-(2-Methyl-ethyl)-2-propyl-4-oxo-tetrahydro-
pyran-3-carboxylic acid tert-butyl ester 20a. Colourless oil. mmax
=
=
(film) 2962, 2875, 1738 (C O), 1716 (C O), 1368, 1344, 1256,
1165, 1121 cm−1; 1H NMR (500 MHz; CDCl3) d 3.76 (1H, ddd,
J = 10.6, 8.4, 2.6 Hz, H-2), 3.30 (1H, ddd, J = 11.7, 7.0, 2.6 Hz,
H-6), 3.06 (1H, dd, J = 10.6, 0.7 Hz, H-3), 2.46 (1H, dd, J =
14.3, 2.6 Hz, H-5eq), 2.21 (1H, ddd, J 14.3, 11.7, 0.7 Hz, H-5ax),
1.76 (1H, octet, J = 6.6 Hz, H-7), 1.65–1.55 (2H, m, H-10), 1.47
(11H, m, H-15 + H-11), 0.99 (3H, d, J = 6.6 Hz, H-8 or H-9),
0.92 (3H, t, J = 7.3 Hz, H-12), 0.90 (3H, d, J = 6.6 Hz, H-8 or H-
9) ppm; 13C NMR (125 MHz; CDCl3) d 203.7, 167.6, 81.8, 78.2,
78.2, 64.2, 44.8, 37.1, 33.5, 28.1, 18.7, 18.3, 18.2, 13.9 ppm; m/z
(ES+) 348 (60%, M+ + Na + CH3CN), 307 (100%, M+ + Na),
251 (30%), 157 (50%); HRMS: found (M+ + Na + CH3CN),
348.2154. C16H28O4 requires (M+ + Na + CH3CN), 348.2151.
(85%, M+), 243 (65%, M+ − CO2Me); HRMS: found (M+
H), 303.1596. C18H22O4 requires (M+ + H) 303.1599.
+
Bis (5-hydroxy-3-oxo-5-phenyl-pentanoic acid methyl ester) 16.
To a solution of◦benzaldehyde (102 lL, 1.00 mmol) in CH2Cl2
(10 mL) at −78 C was added titanium tetrachloride (111 lL,
1.00 mmol). The black solution was stirred for 2 min and then
Chan’s diene (570 lL, 2.00 mmol) was added over a 1 min
period. The black solution was stirred at −78 ◦C for 1 h and
then trifluoroacetic acid (308 lL 4 mmol) was added. After
15 min, the solution was raised to 40 ◦C and stirred at this
temperature for 75 min and was then diluted with Et2O (40 mL)
and washed with 5% NaHCO3 (3 × 30 mL) and brine (2 ×
30 mL), dried (MgSO4), and concentrated in vacuo. Purification
by flash column chromatography (1 : 10 EtOAc–petroleum
ether) gave the dimer 16 as a yellow oil (81 mg, 73%) mmax (film)
3032, 2953, 1747, 1719, 1654, 1494, 1437, 1330, 1265, 1200,
(2S*, 3R*, 6R*)-2,6-Bisphenyl-4-oxo-tetrahydro-pyran-3-
carboxylic acid tert-butyl ester 20b. White solid. Mp: 131–
133 ◦C; mmax (film) 3034, 2979, 1732 (C O), 1715 (C O), 1456,
1348, 1159 cm−1; 1H NMR (400 MHz; CDCl3) d 7.51–7.30 (10H,
m, Ph), 5.05 (1H, d, J = 11.0 Hz, H-2), 4.93 (1H, dd, J = 11.6,
3.0 Hz, H-6), 3.63 (1H, d, J = 11.0 Hz, H-3), 2.82 (1H, dd,
J = 14.6, 3.0 Hz, H-5eq), 2.74 (1H, dd, J = 14.6, 11.6 Hz,
H-5ax), 1.34 (9H, s, H-21) ppm; 13C NMR (100 MHz; CDCl3)
d 201.7, 166.5, 140.2, 138.7, 128.7, 128.7, 128.6, 128.3, 127.2,
125.7, 82.1, 81.3, 79.0, 65.3, 49.1, 27.9 ppm; m/z (EI+) 352
=
=
(7%, M+), 296 (59%, M+ − OtBu), 251 (15%, M+ − CO2 Bu),
t
t
219 (42%, M+ − Bu–Ph) 205 (30%), 201, 104.1 (77%) 77 (31%,
Ph), 71 (49%); HRMS: found (M+), 352.1666. C22H24O4 requires
(M+) 352.1675. Anal. Calcd. for C22H24O4: C, 74.98; H, 6.86.
Found C, 74.83; H, 6.81%.
1
695 cm−1; H NMR (400 MHz; CDCl3) d 7.42–7.29 (10 H, m,
Ph), 5.38 (2H, dd, J = 8.3, 5.4 Hz, H-5), 3.72 (6H, s, OMe), 3.48
(2H, dd, J = 17.2, 8.3, Hz, H-4), 3.48 (4H, s, H-2), 3.23 (2H, dd,
J = 17.2, 5.4 Hz, H-4) ppm; 13C NMR (67.8 MHz; CDCl3) d
198.4 (s), 166.9 (s), 140.3 (s), 128.8 (d), 128.7 (d), 126.9 (d), 56.7
(d), 52.4 (q), 52.1 (t), 49.5 (t) ppm; m/z (EI+) 449 (85%, M+ +
Na), 431 (100%); HRMS: found (M+ + Na), 449.1584. C24H26O7
requires (M+ + Na) 449.1576.
(E) and (Z) 2-acetyl-1-phenyl-prop-1,2-enoic acid methyl ester
17 and 18. To a stirred solution of the methyl acetoacetate
(540 lL. 5.00 mmol) in benzene (25 mL), was added ben-
zaldehyde (508 lL, 5.00 mmol), glacial acetic acid (50 lL,
0.89 mmol), and piperidine (50 lL, 0.51 mmol). The solution
was heated at reflux for 4 h and then allowed to cool to room
temperature, then diluted with EtOAc (40 mL) and washed with
1M HCl (30 mL), 5% NaHCO3 (30 mL), and brine (30 mL),
dried (MgSO4), and concentrated in vacuo. Purification by flash
column chromatography (10% EtOAc–petroleum ether) gave 17
(2R*, 6R*)-4-Hydroxy-2,6-diphenyl-2,3-dihydro-2H-pyran-3-
carboxylic acid tert-butyl ester 21b. White solid. Mp: 120–
◦
=
122 C; mmax (film) 2977, 2923, 1659 (C O), 1621, 1454, 1394,
1281, 1153 cm−1; H NMR (400 MHz; CDCl3) d 12.49 (1H, s,
1
OH), 7.41–7.26 (10H, m, Ph), 5.67 (1H, s, H-2), 4.63 (1H, dd, J =
10.4, 3.7 Hz, H-6), 2.71 (1H, ddd, J = 17.7, 10.4, 1.2 Hz, H-5),
2.57 (1H, dd, J = 17.7, 3.7 Hz, H-5), 1.27 (9H, s, H-21) ppm; 13
C
NMR (100 MHz; CDCl3) d 170.4 (s), 170.0 (s), 141.1 (s), 141.1
(s), 128.6 (d), 128.5 (d), 128.0 (d), 127.8 (d), 126.0 (d), 126.0 (d),
99.9 (s), 81.8 (s), 73.8 (d), 68.4 (d), 35.6 (t), 28.0 (q) ppm; m/z
(ES+) 416 (40%, M+ + Na + CH3CN), 375 (100%, M+ + Na);
HRMS: found (M+ + Na), 375.1562. C22H24O4 requires (M+ +
Na) 375.1572.
(2S*, 3R*, 6R*)-2-Cyclohexyl-6-bisphenyl-4-oxo-tetrahydro-
pyran-3-carboxylic acid tert-butyl ester 20c. White solid.
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 5 5 1 – 3 5 6 3
3 5 6 1

View Article Online
◦
=
Mp: 91–93 C; mmax (film) 2977, 2930, 2855, 1738 (C O), 1715
=
(1H, ddd, J = 8.5, 6.8, 4.7 Hz, H-2), 2.91 (1H, ddd, J = 14.9,
5.1, 1.3 Hz, H-5), 2.83 (1H, ddd, J = 14.9, 6.0, 0.9 Hz, H-5),
2.48 (1H, ddd, J = 14.5, 4.7, 1.3 Hz, H-3), 2.43 (1H, ddd, J =
14.5, 8.5, 0.9 Hz, H-3), 1.80 (1H, octet, J = 6.8 Hz, H-13), 0.96
(3H, d, J = 6.8 Hz, H-14 or 15), 0.87 (3H, d, J = 6.8 Hz, H-14
or 15) ppm; 13C NMR (100 MHz; CDCl3) d 208.0 (s), 140.0 (s),
128.7 (d), 128.0 (d), 127.1 (d), 76.6 (d), 73.9 (d), 45.3 (t), 44.9 (t),
32.1 (d), 18.4 (q), 18.4 (q) ppm; m/z (CI+) 218 (59%, M+ + H),
175 (16%, M+ − C3H7), 131 (100%), 104.1 (77%) 77 (31%, Ph),
71 (49%); HRMS: found (M+ + H), 218.1307. C14H17O2 requires
(M+ + H) 218.1307.
−1
1
(C O), 1452, 1368, 1351, 1252, 1157, 1126, 988 cm ; H NMR
(400 MHz; CDCl3) d 7.41–7.29 (5H, m, Ph), 4.68 (1H, dd, J =
11.7, 2.6 Hz, H-6), 3.91 (1H, dd, J = 10.8, 2.6 Hz, H-2), 3.43
(1H, dd, J = 10.8, 0.9 Hz, H-3), 2.70 (1H, dd, J = 14.3, 2.6 Hz,
H-5eq), 2.48 (1H, ddd, J = 14.3, 11.7, 0.9 Hz, H-5ax), 1.94–1.64
(5H, m, Cy), 1.60 (9H, s, tBu), 1.17–1.41 (5H, m, Cy) ppm; 13
C
NMR (100 MHz; CDCl3) d 203.3, 167.6, 140.9, 128.6, 128.0,
125.4, 82.6, 82.0, 78.1, 61.0, 49.1, 41.7, 30.3, 28.1, 26.6, 26.5,
26.4, 26.2 ppm; m/z (ES+) 422 (75%, M+ + Na + CH3CN),
381 (100%, M+ + Na), 287 (81%, M+ − OtBu); HRMS: found
(M+ + Na), 381.2025. C22H30O4 requires (M+ + Na) 381.2041.
(2S*, 6R*)-6-Octyl-2-phenyl-4-oxo-tetrahydro-pyran 22e.
=
(2S*, 3R*, 6R*)-2-(2-Methyl-ethyl)-6-phenyl-4-oxo-tetrahydro-
pyran-3-carboxylic acid tert-butyl ester 20d. White solid. Mp:
Colourless oil. mmax (film) 2928, 2856, 1603 (C O), 1497, 1410,
1348, 1312, 1286, 1207, 1145, 1059, 814; H NMR (400 MHz;
1
84–86 ◦C; mmax (film) 2970, 1727 (C O), 1708 (C O), 1368,
1344, 1132 cm−1; 1H NMR (500 MHz; CDCl3) d 7.40–7.30 (5H,
m, Ph), 4.71 (1H, dd, J = 11.5, 2.6 Hz, H-6), 3.94 (1H, dd, J =
10.7, 2.6 Hz, H-2), 3.38 (1H, d, J = 10.7 Hz, H-3), 2.72 (1H,
dd, J = 14.5, 2.6 Hz, H-5eq), 2.49 (1H, dd, J = 14.5, 11.5 Hz,
H-5ax), 1.87 (1H, dseptet, J = 6.8, 2.6 Hz, H-13), 1.51 (9H, s,
H-18), 1.10 (3H, d, J = 6.8 Hz, H-14 or 15), 1.07 (3H, d, J =
6.8 Hz, H-14 or 15) ppm; 13C NMR (125 MHz; CDCl3) d 203.1
(s), 167.5 (s), 140.8 (s), 128.5 (d), 127.9 (d), 125.3 (d), 82.4 (d),
81.9 (s), 77.8 (d), 61.4 (d), 49.0 (t), 31.5 (d), 28.0 (q), 19.9 (q),
15.5 (q) ppm; m/z (EI+) 318 (2%, M+), 275 (10%, M+ − C3H7),
261 (69%, M+ − OtBu), 219 (80%) 173 (40%); HRMS: found
(M+), 318.1831. C19H26O4 requires (M+), 318.1831. Anal. Calcd.
for C19H26O4: C, 71.67; H, 8.23. Found C, 71.55; H, 8.12%.
CDCl3) d 7.28–7.40 (5H, m, Ph), 4.64 (1H, dd, J = 3.0, 11.6 Hz,
H-2), 3.76 (1H, dddd, J = 11.6, 7.3, 4.9, 2.4 Hz, H-6), 2.64 (1H,
ddd, J = 14.6, 3.0, 1.8 Hz, H-3eq), 2.54 (1H, d, J = 14.6, 11.6,
Hz, H-3ax), 2.47 (1H, ddd, J = 14.6, 2.4, 1.8 Hz, H-5eq), 2.37
(1H, dd, J = 14.6, 11.6 Hz, H-5ax), 1.77 (1H, m, H-7), 1.61
(1H, m, H-7), 1.49 (1H, m, H-8), 1.40 (1H, m, H-8), 1.35–1.18
(10H, m, H-9–13), 0.89 (3H, t, J = 6.7 Hz, H-14); 13C NMR
(100 MHz; CDCl3) d 207.2, 141.0, 128.6, 127.9, 125.6, 78.5,
77.4, 49.6, 47.8, 36.4, 31.8, 29.5, 29.4, 25.2, 25.2, 22.6 ppm; m/z
288 (88%, M+), 211 (6%, M+ − Ph), 175 (10%, M+ − C8H17),
147 (100%, M+ + H–C9H18O); HRMS: found (M+), 288.2102.
C10H14O3 requires (M+) 288.2089.
=
=
Starting with enantio-pure b-hydroxy ketoesters
(R)-5-Hydroxy-3-oxo-hexanoic acid tert-butyl ester 2620. To
a solution of diisopropylamine (4.15 mL, 29.6 mmol) in
THF (45 mL) at −78 ◦C was added nBuLi (11.86 mL,
29.65 mmol, 2.5 M hexanes) followed by tert-butylacetate
(3.44 mL, 25.4 mmol). After 1 min, (S)-3-hydroxy-butanoate
(1.00 g, 8.47 mmol) was added dropwise over a 5 min period.
The solution was stirred at −50 ◦C for 90 min and was
then left to stand at −15 ◦C for 15 min. The reaction was
quenched by pouring on to ice water (30 mL) and was then
extracted with Et2O (40 mL) and washed with brine (30 mL),
dried (MgSO4), and concentrated in vacuo. Purification by
flash column chromatography (20% EtOAc–pet. ether) gave 26
(950 mg, 72%), the data for which was in agreement with the
published literature values. 1H NMR (400 MHz; CDCl3) d 4.23
(1H, m, H-5), 3.38 (1H, d, J = 15.8 Hz, H-2), 3.34 (1H, d, J =
15.8 Hz, H-2), 2.98 (1H, d, J = 3.0 Hz, OH), 2.71 (1H, dd, J =
17.5, 3.0 Hz, H-4), 2.61 (1H, dd, J = 17.5, 8.5 Hz, H-4), 1.44
General method for the decarboxylative reaction
To a solution of aldehyde (1.00 mmol) in CH2Cl2 (10 mL) at
−78 ◦C was added titanium tetrachloride (111 lL, 1.00 mmol).
The black solution was stirred for 2 min and then the diene
19 (454 mg, 1.50 mmol) was added over a 1 min period. The
black solution was stirred at −78 ◦C for 40 min and then
trifluoroacetic acid (231 lL, 3.0 mmol) was added followed by
pyridine (160 lL, 2 mmol). After 2 min the second aldehyde
(1.20 mmol) was added and the solution was allowed to warm
to room temperature over a 5 min period. The black solution was
stirred at room temperature for 90 min and then trifluoroacetic
acid (770 lL 10 mmol) was added. The solution was stirred at
room temperature for a further 12 h and then pyridine (800 lL,
10 mmol) was added and the solution was heated at a vigorous
reflux for 2 h. The solution was cooled to room temperature and
diluted with Et2O (40 mL) and washed with 5% NaHCO3 (3 ×
30 mL), 5% CuSO4 (3 × 30 mL), 5% sodium metabisulfite (3 ×
30 mL) and brine (2 × 30 mL), dried (MgSO4), and concentrated
in vacuo. Purification by flash column chromatography (1 : 10
EtOAc–petroleum ether) gave pyran products 22 and 23.
t
(9H, s, Bu), 1.17 (3H, d, J = 6.4,Hz, H-6) ppm; [a]D (CHCl3,
c = 1), −28.7.
(R)-3-Hydroxy-butanoic acid methyl ester 2722. To a solution
of diisopropylamine (1.34 mL, 9.55 mmol) in THF (15 mL)
at −78 ◦C was added nBuLi (3.82 mL, 9.55 mmol, 2.5 M
hexanes) followed by tert-butylacetate (1.12 mL, 8.32 mmol).
After 10 min, methyl (R)-3-hydroxy-3-phenylpropanoate (0.50 g,
2.77 mmol) was added dropwise over a 5 min period. The
solution was stirred at −50 ◦C for 1 h and then −5 ◦C for 1 h.
The reaction was quenched by pouring on to ice water (30 mL)
and was then extracted with Et2O (40 mL) and washed with
(2S*, 6R*)-2-(2-Methyl-ethyl)-6-phenyl-4-oxo-tetrahydro-
=
pyran 22d. Colourless oil. mmax (film) 3031, 2963, 1717 (C O),
1
1347, 1252, 1153, 1065 cm−1; H NMR (400 MHz; CDCl3) d
7.31–7.16 (5H, m, Ph), 4.51 (1H, dd, J = 11.5, 2.6 Hz, H-6),
3.39 (1H, ddd, J = 11.5, 6.0, 2.6 Hz, H-2), 2.53 (1H, ddd, J =
14.5, 2.6, 2.1 Hz, H-5eq), 2.40 (1H, dd, J = 14.5, 11.5 Hz, H-
5ax), 2.35 (1H, ddd, J = 14.1, 2.6, 2.1 Hz, H-3eq), 2.28 (1H,
dd, J = 14.1, 11.5 Hz, H-3ax), 1.81 (1H, octet J = 6.8 Hz, H-
13), 0.92 (3H, d, J = 6.8 Hz, H-14 or 15), 0.88 (3H, d, J =
6.8 Hz, H-14 or 15) ppm; 13C NMR (100 MHz; CDCl3) d 207.6
(s), 141.1 (s), 128.5 (d), 127.8 (d), 125.4 (d), 81.9 (d), 78.2 (t),
49.7 (t), 44.6 (t), 33.2 (d), 18.2 (q), 17.9 (q) ppm; m/z (CI+) 218
(59%, M+), 175 (16%, M+ − C3H7), 131 (100%), 104.1 (77%) 77
(31%, Ph), 71 (49%); HRMS: found (M+), 218.1307. C14H18O2
requires (M+), 218.1307.
1
brine (30 mL), dried (MgSO4) and gave 27 (290 mg, 55%). H
NMR (400 MHz; CDCl3) d 7.41 (2H, d, J = 7.3 Hz, H-8), 7.35
(2H, dd, J = 7.3, 7.3 Hz, H-9), 7.29 (1H, d, J = 7.3 Hz, H-10),
5.11 (1H, dd, J = 11.1, 1.7 Hz, H-2), 4.69 (1H, s, OH), 2.56 (1H,
dd, J = 14.9, 11.1 Hz, H-3ax), 2.27 (1H, dd, J = 14.9, 1.7 Hz,
H-3eq) ppm; [a]D (CHCl3, c = 1), −14.7.
(R)-5-Hydroxy-3-oxo-5-phenyl-pentanoic acid tert-butylester
28. To a solution of diisopropylamine (1.34 mL, 9.55 mmol)
in THF (15 mL) at −78 ◦C was added nBuLi (3.82 mL,
9.55 mmol, 2.5 M hexanes) followed by tert-butylacetate
(1.12 mL, 8.32 mmol). After 10 min, methyl (R)-3-hydroxy-3-
phenylpropanoate (0.50 g, 2.77 mmol) was added dropwise over
(2R*, 6R*)-2-(2-Methyl-ethyl)-6-phenyl-4-oxo-tetrahydro-
=
pyran 23d. Colourless oil. mmax (film) 3031, 2962, 1717 (C O),
1
1450, 1366, 1256, 1061 cm−1; H NMR (400 MHz; CDCl3) d
7.38–7.28 (5H, m, Ph), 5.30 (1H, dd, J = 6.0, 5.1 Hz, H-6), 3.46
3 5 6 2
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 5 5 1 – 3 5 6 3

View Article Online
a 5 min period. The solution was stirred at −50 ◦C for 2 h and
then was left to stand at −20 ◦C for 12 h. The reaction was
quenched by pouring on to ice water (30 mL) and was then
extracted with Et2O (40 mL) and washed with brine (30 mL),
dried (MgSO4), and concentrated in vacuo. Purification by flash
column chromatography (20% EtOAc–pet. ether) gave 28 as a
white solid, mp 42–43 ◦C (600 mg, 82%) mmax (film) 3598 (OH),
brine (2 × 30 mL), dried (MgSO4), and concentrated in vacuo.
Purification by flash column chromatography (10% EtOAc–pet.
ether) gave 22d (32 mg, 70%); the data matched that which had
previously been obtained. [a]D (CHCl3, c = 1), +46.8.
Acknowledgements
We thank the EPSRC and the University of Nottingham for a
DTA studentship (W. H. C. M.), AstraZeneca for an unrestricted
research award (P. A. C.) and the EPSRC National Mass
Spectrometry Service, Swansea for accurate mass determination.
=
=
2981, 2933, 1732 (C O), 1710 (C O), 1455, 1370, 1323, 1144,
1
1072 cm−1; H NMR (400 MHz; CDCl3) d 7.36–7.23 (5H, m,
Ph), 5.18 (1H, dd, J = 9.4, 3.4 Hz, H-5), 3.39 (2H, s, H-2), 2.98
(1H, dd, J = 17.5, 9.4 Hz, H-4), 2.90 (1H, dd, J = 17.5, 3.4 Hz,
t
H-4), 1.46 (9H, s, Bu); ppm; 13C NMR (125 MHz; CDCl3)
References
d 203.5, 166.1, 142.6, 128.6, 127.8, 125.7, 82.4, 69.8, 51.6, 51.2,
28.0 ppm; m/z (CI+) 265 (30%, M+ + H), 247 (22%, M+ − OH),
1 For the manipulation of carbohydrates see: S. Hanessian, Total Syn-
thesis of Natural Products: The ‘Chiron’ Approach, ed. J. E. Baldwin,
Pergamon, Oxford, 1983; J. C. Esteveza, A. J. Fairbanks and G. W. J.
Fleet, Tetrahedron, 1998, 54, 13591.
2 For a treatise on the hetero Diels–Alder reaction see: D. L. Boger,
S. M. Weinreb, Hetero Diels–Alder Methodology in Organic Synthesis,
Academic Press, San Diego, 1987.
3 For recent examples of asymmetric intermolecular reactions see:
A. G. Dossetter, T. F. Jamison and E. N. Jacobsen, Angew. Chem.,
Int. Ed., 1999, 38, 2398; M. Johannsen and K. A. Jorgensen, J. Org.
Chem., 1995, 60, 5757; S. E. Schaus, J. Branalt and E. N. Jacobsen,
J. Org. Chem., 1998, 63, 403.
4 For recent examples of the Prins reaction see: C. St. J Barry, S. R.
Crosby, J. R. Harding, R. A. Hughes, C. D. King, G. D. Parker and
C. L. Willis, Org. Lett., 2003, 5, 2429; S. R. Crosby, J. R. Harding,
C. D. King, G. D. Parker and C. L. Willis, Org. Lett., 2002, 4, 3407;
J. J. Jaber, K. Mitsui and S. D. Rychnovsky, J. Org. Chem., 2001, 66,
4679; M. J. Cloninger and L. E Overman, J. Am. Chem. Soc., 1999,
121, 1092; S. A Kozmin, Org. Lett., 2001, 3, 755 For a review of the
Prins reaction see: D. R. Adams and S. D. Bhaynagar, Synthesis,
1977, 661.
t
207 (38%, M+ − Bu), 191 (100%, M+ − OtBu), 149 (21%, M+ −
CO2 Bu); HRMS (CI+): found (M+ + H), 265.1446. C15H20O4
t
requires (M+ + H) 265.1440. Anal. Calcd. for C15H20O4: C, 67.97;
H, 7.46. Found C, 68.16; H 7.63%. [a]D (CHCl3, c = 1), −46.8.
2-(R)-Phenyl-6-(R)-methyl-4-oxo-tetrahydro-pyran-3-(S)-
carboxylic acid tert-butyl ester 29. To a solution of (R)-
5-hydroxy-3-oxo-hexanoic acid tert-butyl ester 26 (90 mg,
0.45 mmol) in CH2Cl2 (5 mL) at room temperature was added
pyridine (70 lL, 1 mmol) and benzaldehyde (60 lL, 0.6 mmol)
followed by titanium tetrachloride (55 lL, 0.5 mmol). The
black solution was stirred at room temperature for 10 min and
was quenched by addition of 5% NaHCO3 (5 mL). The solution
was diluted with Et2O (40 mL) and washed with 5% NaHCO3
(3 × 30 mL), 5% CuSO4 (3 × 30 mL) and brine (2 × 30 mL),
dried (MgSO4), and concentrated in vacuo. Purification by flash
column chromatography (10% EtOAc–pet. ether) gave 29 as a
◦
white solid, mp 88–90 C (50 mg, 55%) mmax (film) 2978, 2932,
−1
1
5 For a recent report of oxonia Cope complication see: S. R. Crosby,
J. R. Harding, C. D. King, G. D. Parker and C. L. Willis, Org. Lett.,
2002, 4, 577.
6 For a review of the Michael reaction see: R. D Little, M. R
Masjedizadeh, O. Wallquist and J. I. McLoughlin, Org. React., 1995,
47, 315.
=
=
1740 (C O), 1714 (C O), 1369, 1288, 1127, cm ; H NMR
(500 MHz; CDCl3) d 7.43–7.27 (5H, m, Ph), 4.84 (1H, d, J =
10.8 Hz, H-2), 4.00 (1H, ddq, J = 10.8, 5.9, 2.9 Hz, H-6),
3.47 (1H, d, J = 10.8, 1.0 Hz, H-3), 2.53 (1H, dd, J = 14.6,
2.9 Hz, H-5eq), 2.40 (1H, ddd, J = 14.6, 10.8, 1.0 Hz, H-5ax),
1.29 (9H,s, H-16), 1.38 (3H, d, J = 5.9 Hz, H-7) ppm; 13C
NMR (125 MHz; CDCl3) d 202.3 (s), 166.6 (s), 138.7 (s), 128.7
(d), 128.6 (d), 127.2 (d), 82.0 (s), 81.1 (d), 73.8 (d), 64.9 (d),
48.7 (t), 27.9 (q), 22.2 (q) ppm; m/z (ES+) 354 (100%, M+ +
Na + CH3CN), 313 (82%, M+ + Na), 298 (38%), 257 (32%);
HRMS: found (M+ + Na), 313.1428. C17H22O4 requires (M+ +
Na) 313.1416; [a]D (CHCl3, c = 1), +4.48. Anal. Calcd. for
C17H22O4: C, 70.32; H, 7.64. Found C, 70.18; H, 7.57%.
7 F. R. Japp and W. Maitland, J. Chem. Soc., 1904, 85, 1473.
8 R. Cornubert and P. Robinet, Bull. Soc. Chim. Fr., 1934, 90.
9 C. A. R. Baxter and D. A. Whiting, J. Chem. Soc. C, 1968, 1174.
10 R. Sivakumar, N. Satyamurthy, K. Ramalingam, D. J. O’Donnell,
K. Ramarajan and K. D. Berlin, J. Org. Chem., 1979, 44, 1559.
11 For the pioneering work of Weiler see: S. N. Huckin and L. Weiler,
Tetrahedron Lett., 1971, 50, 4835; S. N. Huckin and L. Weiler,
Can. J. Chem., 1974, 52, 2157.
12 W. Lehnert, Tetrahedron Lett., 1970, 11, 4723.
13 I. Paterson and S. Osbourne, Tetrahedron Lett., 1990, 31, 2213.
14 P. A. Clarke and W. H. C. Martin, Org. Lett., 2002, 4, 4527.
15 P. A. Clarke, W. H. C. Martin, J. M. Hargreaves, C. Wilson and A. J.
Blake, Chem. Commun., 2005, 1061.
2-(S)-(2-Methyl-ethyl)-6-(R)-phenyl-4-oxo-tetrahydro-pyran
22d. To a solution of the (R)-5-hydroxy-3-oxo-5-phenyl-
pentanoic acid tert-butylester 28 (53 mg, 0.2 mmol) in CH2Cl2
(2 mL) at room temperature was added pyridine (32 lL,
0.4 mmol) and iso-butyraldehyde (22 lL, 0.24 mmol) followed
by titanium tetrachloride (22 lL, 0.2 mmol). The black solution
was stirred at room temperature for 90 min and then TFA
(154 lL, 2.0 mmol) was added and the black solution was
stirred at room temperature for 12 h then pyridine (326 lL,
16 T. Mukaiyama, Org. React., 1982, 28, 203.
17 A. Soriente, M. D. Rosa, R. Villano and A. Scettri, Tetrahedron:
Asymmetry, 2000, 11, 2255.
18 L. F. Tietze, H. Geissler, J. Fennen, T. Brumby, S. Brand and G.
Schulz, J. Org. Chem., 1994, 59, 182.
19 T. H. Chan and P. Brownbridge, J. Am. Chem. Soc., 1980, 102, 3534.
20 L. Shao, H. Kawano, M. Saburi and Y. Uchida, Tetrahedron, 1993,
49, 1997.
◦
2 mmol) was added and the solution was then heated at 35 C
21 A. Yanagisawa, Y. Matsumoto, K. Asakawa and H. Yamamoto,
Tetrahedron, 2002, 58, 8331.
22 X. Xu, Y. Zhang and C. Yuan, Synlett, 2004, 3, 485.
for 2 h. The solution was diluted with Et2O (40 mL) and washed
with 5% NaHCO3 (3 × 30 mL), 5% CuSO4 (3 × 30 mL) and
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 5 5 1 – 3 5 6 3
3 5 6 3