Stereoselective routes to substituted β-amino carbonyl compounds via heterodiene [4π+2π] cycloadditions of auxiliary-based C2 symmetric ketene acetals

Article abstract of DOI:10.1016/S0040-4020(02)01523-5

Heterodiene [4π+2π] cycloadditions of (S,S)-4,5-diaryl-2-methylene-1,3-dioxolanes 1 to a series of β-amido-α,β-unsaturated carbonyl compounds are diastereoselective (d.r.≥4:1). The products can be purified by trituration or crystallisation and hydrolysed with acid to generate the corresponding β-amido carbonyl compounds, the overall sequence effecting an auxiliary-based enantioselective conjugate addition of an acetate enolate, leading to β-aminoacid derivatives.

Full text of DOI:10.1016/S0040-4020(02)01523-5

Tetrahedron 59 (2003) 341–352
Stereoselective routes to substituted b-amino carbonyl
compounds via heterodiene [4p12p] cycloadditions of
auxiliary-based C2 symmetric ketene acetals
Peter Leeming,a Colin A. Ray,a Stephen J. Simpson,a Timothy W. Wallacea
,
*
and Richard A. Wardb
aDepartment of Chemistry, University of Salford, Salford M5 4WT, UK
bSynthetic Chemistry, GlaxoSmithKline Medicines Research Centre, Gunnels Wood Road, Stevenage SG1 2NY, UK
Received 28 August 2002; revised 29 October 2002; accepted 21 November 2002
Abstract—Heterodiene [4pþ2p] cycloadditions of (S,S)-4,5-diaryl-2-methylene-1,3-dioxolanes 1 to a series of b-amido-a,b-unsaturated
carbonyl compounds are diastereoselective (d.r.$4:1). The products can be purified by trituration or crystallisation and hydrolysed with acid
to generate the corresponding b-amido carbonyl compounds, the overall sequence effecting an auxiliary-based enantioselective conjugate
addition of an acetate enolate, leading to b-aminoacid derivatives. q 2003 Elsevier Science Ltd. All rights reserved.
The [4pþ2p] cycloaddition of a,b-unsaturated carbonyl
compounds (1-oxabutadienes) to alkenes can be an effective
route to dihydropyrans and other synthetically useful
materials.1 Our interest in exploiting reactions of this
type2 led us to prepare a series of homochiral C2-symmetric
ketene acetals 1, starting with the corresponding diols 2 and
proceeding via the derived bromoacetals 3, for use as
electron-rich dienophiles, and we established that such
systems could serve as recyclable acetate enolate equiva-
lents.3 In an illustration of our strategy, the aldehyde 4 was
transformed into the functionalised a-cyclohomogeranyl
system (S)-5 in three steps, the first being a diastereoselec-
tive [4pþ2p] cycloaddition to the ketene acetal (S,S)-1a.4
We considered that a similar strategy (Scheme 1) might
provide access to homochiral b-amino carbonyl com-
pounds, especially those with synthetic value such as
substituted b-aminoacids5 and piperidines.6 Related hetero-
diene cycloadditions have been used before for the
preparation of racemic aminosugars7 and carbapenem
11 were prepared from the respective methoxymethylene
compounds 8 and 9,13 and on the basis of the evidence
presented by Bayles et al.,8 the isolated product in each case
was assigned the (E)-geometry. A third heterodiene, the
diketone 12,14 was accessible from 2,4-pentanedione in a
single operation. Various [4pþ2p] permutations of these
materials provided cycloadducts in the form of dihydro-
pyran-derived ortholactones (Table 1). In an initial
experiment, the alkene 6 was treated with a slight excess
of the ketoester 10 in THF at room temperature. The
resulting cycloaddition took 3 days to reach completion, and
a simple isolation procedure gave the ortholactone (^)-13 in
precursors,8 but a variant combining exploitable levels of
asymmetric induction and a recyclable auxiliary remained
an attractive target.9 We therefore undertook a study with
this objective and herein report our findings in detail.10
In the first part of our study, various cycloadditions were
attempted using the ketene acetals 1,3 611 and 712 as 2p
components. For use as heterodienes, the ketoesters 108 and
Keywords: heterodiene cycloaddition; ketene acetal; chiral auxiliary; b-
amino acid; pyrano[4,3-b]pyridine.
1
acceptable yield. The H NMR spectrum of 13 included
signals at d (ppm) 5.11 (1H, dd, J¼5.5, 9.5 Hz) and 6.64
*
Corresponding author. Address: Department of Chemistry, UMIST, P.O.
Box 88, Manchester M60 1QD, UK. Tel.: þ44-161-200-4521; fax: þ44-
161-200-4559; e-mail: tim.wallace@umist.ac.uk
(1H, br d, J¼9.5 Hz), which were assigned to the C-4
0040–4020/03/$ - see front matter q 2003 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(02)01523-5

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P. Leeming et al. / Tetrahedron 59 (2003) 341–352
Scheme 1.
methine and amide NH, respectively; signals corresponding
to these were characteristic all of the cycloadducts
subsequently isolated. The cycloaddition of the ketoester
10 and the cyclic ketene acetal 7 was complete within 2 h,
giving the spirocyclic ortholactone (^)-14. Although more
favourable conditions were employed, it is assumed that the
fast reaction of the ketoester 10 with the ketene acetal 7,
compared to that of 6, is primarily due to steric differences,
the reacting p-bond being significantly less encumbered in
the cyclic system 7.
The reaction of equimolar quantities of the ketoester 10 and
the ketene acetal (S,S)-1a (THF, 2158C) gave, after 3 days,
a crude mixture of the cycloadducts 15 and 16 with a
diastereoisomeric ratio (d.r.) of ca. 4:1 as judged by
1
250 MHz H NMR spectroscopy. One crystallisation from
Figure 1. X-Ray structure of the cycloadduct 20.
isohexane allowed isolation of the major adduct 15 (60%,
d.e. .95% by HPLC). An apparent by-product, detected in
early samples of the reaction mixture, was identified (by
synthesis) as the monoacetate 17, formed by hydrolysis of
unreacted ketene acetal 1a during isolation or analysis.15
The cycloaddition between (S,S)-1a and the benzyl ester 11
(entry 4), proceeded more slowly than that of 10 but with
similar diastereoselectivity. Detailed analysis of the purified
cycloadduct 18 using high field NMR correlation techniques
(COSY, HMQC) indicated its constitution and, by com-
parison, its relationship with the methyl ester 15. The
diketone 12 reacted slowly with the ketene acetal (S,S)-1a
(2158C, 5 days) yielding the mixed cycloadducts 20 and 21
(67%). The major product 20 crystallised from isohexane as
colourless needles, mp 112–1158C, and a crystal was
analysed by X-ray crystallography. Although this material
turned out to be poorly diffracting, the resulting data
unequivocally confirmed the gross structure and (4S)
configuration (Fig. 1).
purity after crystallisation compared favourably with those
derived from 1a. The structural parallel between the phenyl
and tolyl series were readily apparent when their high field
NMR spectra were compared, and the (4S) configuration of
24 was therefore assigned by comparison with 20. Similarly,
the (4S) assignment for 22, which was verified by a short
synthetic sequence as described below, strongly supports
the structures assigned to 15 and 18. Given the ready
availability of the auxiliary diol (S,S)-hydrobenzoin 2b, the
diphenyl ketene acetal 1b is the most convenient source of
this type of cycloadduct.
Ortholactones are readily hydrolysed by acid,16 and the
cycloadducts described in Table 1 were converted into
esters by treatment with 0.1 M sulfuric acid in THF for a
few hours. The ketoester cycloadducts 13 and 14 afforded
the respective esters 26 and 27 as ca. 55:45 mixtures of
diastereoisomers, as judged by 1H NMR spectroscopy
(Scheme 2). The cycloadducts 20, 22 and 24 derived from
the diaryl ketene acetals 1 were similarly transformed into
the respective ring-opened derivatives 28–30 in fair yields,
and it was established that 24 could also be hydrolysed to 30
using citric acid instead of sulfuric acid (Scheme 3). The
diastereoisomeric purity of the diketone products 28 and 30
appeared to be the same as that of their precursors. The keto
In previous studies, cycloadditions of the diphenyl ketene
acetal 1b have been less effective than those of the ditolyl
compound 1a, both in terms of the level of diastereoselec-
tion observed and the ease with which the resulting
cycloadducts could be purified.3,4 However, in the reactions
of 1b with the ketoester 10 and diketone 12 (entries 6 and 7),
the yields of the respective cycloadducts 22 and 24 and their

P. Leeming et al. / Tetrahedron 59 (2003) 341–352
Table 1. Heterodiene cycloadditions of b-acetamidoenones 10–12 with ketene acetals
343
Entry
Starting material
Diene
Solvent
Temperature (8C)
Time (h)
Products
Isolated material
Acetal
Ratio
Ratio
Yield (%)
1
2
3
4
5
6
7
6
7
10
10
10
11
12
10
12
0.9:1
10:1
1:1
1:1
1:1
THF
–
þ20
þ20
215
215
215
220
220
72
2
72
96
120
72
120
13
14
64
63
60
62
67
61
63
1a
1a
1a
1b
1b
THF
THF
THF
THF
THF
15þ16
18þ19
20þ21
22þ23
24þ25
$19:1
4.1:1
$4:1
$19:1
$19:1
1:1
1.1:1
diester 29 was obtained as a 1:1 mixture of C-2
diastereoisomers.
bility to hydrolysis of 2-hydroxyethyl esters, engendered by
the catalytic influence of the local hydroxyl function.17
Transesterification of 29 using methanol and potassium
carbonate proceeded at room temperature, giving the methyl
ester 31 (65%) and simultaneously making the diol (S,S)-2b
available for recycling (Scheme 4). The alternative route
from 29 to 31 involved the removal of the auxiliary by
catalytic hydrogenation, which cleanly provided the acid 32
and hence, by methylation, the ester 31. However, this
method also sacrificed the original auxiliary, from which
only diphenylethane 33 remained. The hydrogenolytic
sequence was repeated with the diketoester 30, providing
the ester 35 in 70% yield over two steps.
Two methods were developed for the removal of the
auxiliary moiety, using the ester-amides 29 and 30. The
more economical method takes advantage of the suscepti-
Confirmation of the absolute stereochemistry of the
cycloadduct 22 was obtained by subjecting the derived
ester 31 to triethylsilane reduction, as described by Bayles
et al.8 The 1H NMR spectrum of the major product (2)-36
corresponded to that of racemic material,8 and its specific
rotation confirmed its antipodal relationship with
(2R,3S,4R)-36, a precursor of the b-lactam antibiotic,
thienamycin.18
The extension of the above strategy to nitrogen heterocyclic
systems was attempted with the uracil derivative 37,19
which reacted diastereoselectively with (S,S)-1a to give the
spirocyclic pyrano[4,3-d]pyrimidines 38 and 39 (50%, d.r.
4.26:1 by HPLC) (Scheme 5). The structures of these
cycloadducts were readily assigned by comparison of their
distinctive 1H NMR spectra with those of structurally
similar analogues derived from chromone-3-carbaldehyde.3
An attempt to transform the piperidine 4020 into the
potentially useful heterodiene 41 by oxidation with DDQ
gave a poor yield; the lability of the product may have been
a contributing factor. However, the viability of the proposed
heterodiene cycloadditions was established by treating 41
with ethoxyethene, which gave the expected endo- and exo-
cycloadducts 42 and 43 (52%, d.r. 3.4:1), and with 2-
methoxypropene, which gave the corresponding adducts 44
and 45 (77%, d.r. 3.6:1) (Scheme 6). These cycloadducts
were readily identified by spectroscopy, the 1H NMR
signals due to the respective C-5 and C-8 hydrogens being
particularly characteristic.2 A second piperidine heterodiene
was prepared from the N-tosyl piperidone 46, this time
introducing the unsaturation via the selenium technique.21
This gave a good yield of the aldehyde 47, but it too proved
unstable. In a trial cycloaddition with ethoxyethene, the
aldehyde 47 was converted into the endo- and exo-
cycloadducts 48 and 49 with the expected level of

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P. Leeming et al. / Tetrahedron 59 (2003) 341–352
Scheme 2. Reagents: (i) 0.1 M aq. H2SO4, THF, 208C, 14 h (60–75%).
Scheme 3. Reagents; (i) 0.1 M aq. H2SO4, THF, 208C, 1–1.5 h (56–65%).
Scheme 4. Reagents: (i) MeOH, K2CO3, 208C, 16 h (65%); (ii) H2, Pd–C, MeOH, 3–4 h; (iii) CH2N2, Et2O, EtOH (X¼OMe, 61% over two steps; X¼Me,
70% over two steps); (iv) Et3SiH, CF3CO2H, CH2Cl2, 208C, 48 h (81%).
diastereoselection (3.5:1) but in low total yield (30%). Due
to the problems associated with the lability of the aldehydes
41 and 47, further efforts in this area will focus on the use of
alternative heterodienes.
Mechanistically, the facial selectivity manifested in the
preferential formation of the (4S)-cycloadducts 20 and 22
from the respective dienes 10 and 12 is consistent with
the concerted cycloaddition models depicted in Figure 2.
The most favoured reacting (s-cis) conformations
Scheme 5. Reagents: (i) 1 equiv. 1a, THF, 2158C, 72 h (50%; d.r. 81:19).
available to the heterodienes 10–12 are assumed to be the

P. Leeming et al. / Tetrahedron 59 (2003) 341–352
345
Scheme 6. Reagents; (i) DDQ, CH2Cl2, 208C, 16 h (41, 22%); (ii) (a) PhSeCl, CH2Cl2, pyridine, 08C, 20 min, then aq. HCl, then 30% H2O2, 08C (47, 63%);
(iii) excess RO(Y)CvCH2, CH2Cl2, 208C, 14–28 days (42/43, 52%; 44/45, 77%; 48/49, 30%; d.r.$3:1 in each case).
and Kratos Concept S1 (high resolution) instruments using
the ammonia CI method, or on a Micromass Platform II
coupled to a Hewlett–Packard HP1100 HPLC system for
LC/MS work. Data for most of the peaks of intensity ,20%
of that of the base peak are omitted. Analytical HPLC and
LC/MS were run using the following (generic) conditions
on the Hewlett Packard system: Column, Luna 3
micrometer C18(2) 50£2.0 mm; mobile phase, A 1000 mL
H2Oþ0.5 mL trifluoroacetic acid (TFA), B 1000 mL
MeCNþ0.5 mL TFA; %B 0 to 95% in 0 to 8 min (linear
gradient) then 0% B for 2 min prior to next run; flow rate,
1 mL min21, temperature, 408C; injection volume, 1 mL;
detection wavelength user selectable, default 220 nm.
Optical rotations were measured at 589 nm using an AA-
10 polarimeter (Optical Activity Ltd.).
Starting materials and solvents were routinely purified by
conventional techniques23 and most reactions were carried
Figure 2. Mechanistic models for the concerted cycloaddition of (S,S)-1 to
b-acetamidoenones 10 and 12.
out under nitrogen or argon. Organic solutions were dried
using anhydrous magnesium sulfate and concentrated by
rotary evaporation. Analytical thin layer chromatography
(TLC) was carried out on Camlab Polygram SIL G/UV254
plates. The chromatograms were visualised by the use of
UV light or the following developing agents; ethanolic
vanillin or potassium permanganate. Unless otherwise
indicated, preparative (column) chromatography was car-
ried out using the flash technique24 on 60H silica gel (Merck
9385), Florisilw (60–100 mesh) or basic alumina. Compo-
sitions of solvent mixtures are quoted as ratios of volume.
‘Petroleum’ refers to a light petroleum fraction, bp 40–
608C, unless otherwise stated. Isohexane (Fisher) is mainly
2-methylpentane. ‘Ether’ refers to diethyl ether.
hydrogen-bonded arrangements shown in the Figure. This is
supported for the esters 10 and 11 by the 13C NMR studies
described by Bayles et al.,8 which indicated that the
preparative routes to these compounds predominantly give
rise to the E-geometry, and for 12 by the results of
calculations.22 Synthetically, the sequence shown in
Scheme 1 has been shown to provide a stereoselective
route to a variety of functionalised b-amino carbonyl
systems based on a recyclable auxiliary strategy.
1. Experimental
1.1. General
1.1.1. (S,S)-4,5-Bis(2-methylphenyl)-2-methylene-1,3-
dioxolane 1a. The following is a modified version of the
procedure described previously.4 To a stirred solution of the
(S,S)-bromoacetal (2)-2a3 (250 mg, 0.72 mmol) in anhy-
drous THF (15 mL) at 2158C was added solid potassium t-
butoxide (300 mg, 2.67 mmol) and, a few minutes later, a
solution of methyltrioctylammonium chloride (Fluka
69485; 200 mg, 0.49 mmol) in anhydrous THF (2 mL).
The reaction mixture was maintained at 2158C for 16–18 h
after which time no bromoacetal was detected by HPLC
analysis. The reaction mixture was filtered through a short
plug of basic alumina, and the filtrate containing the (S,S)
ketene acetal (2)-1a (assumed 192 mg, 90%) was used
directly. A concentrated sample had dH 1.82 (6H, s,
2£ArMe), 3.45 (2H, s, CvCH2), 5.35 (2H, s, CHAr), 7.05
(2H, dd, J¼1, 7.5 Hz, 3,30-ArH), 7.18–7.30 (4H, m,
All compounds are racemic unless their names are preceded
by stereochemical descriptors. Melting points were deter-
mined using an Electrothermal apparatus and are uncor-
rected. Unless otherwise stated, IR spectra were of neat thin
films on NaCl plates, recorded on a Perkin–Elmer 1710FT
spectrometer. NMR spectra were measured on a Bruker
AC300 spectrometer (1H at 300 MHz, 13C at 75 MHz),
Bruker DPX250 (1H at 250 MHz, 13C at 63 MHz) and
Bruker Advance 400 (1H at 400 MHz, 13C at 100 MHz)
instruments for solutions in deuteriochloroform with tetra-
methylsilane as the internal standard; J values are quoted to
the nearest 0.5 Hz. Assignments for 13C spectra are tentative
unless the use of correlation techniques is indicated. Mass
spectra were measured on a Finnegan 4500 (low resolution)

346
P. Leeming et al. / Tetrahedron 59 (2003) 341–352
4,40,5,50-ArH), 7.54 (2H, dd, J¼1.5, 8 Hz, 6,60-ArH). HPLC
analysis of a THF solution of 1a showed a single peak,
corresponding to the hydrolysis product 17.
12.14 In a round-bottomed flask fitted with a mechanical
stirrer was placed anhydrous trimethyl orthoformate (15.9 g,
0.15 mol), 2,4-pentanedione (10.0 g, 0.10 mol) and acetic
anhydride (24.8 g, 0.24 mol). The reaction mixture was
heated under reflux for 4 h. The residual acetic anhydride
was removed by azeotropic distillation with toluene and the
residue was filtered through silica using ether. The filtrate
was evaporated and taken up in THF (10 mL). To this
solution was added acetamide (8.87 g, 0.15 mol) and the
reaction mixture heated under reflux for 4 h. Evaporation
and chromatography (elution with ether) provided the title
compound 12 (5.5 g, 33%) as an orange crystalline solid, mp
648C [lit.14 needles, mp 628C (ethyl acetate)]; nmax 3263,
1728, 1650, 1576, 1167 cm21; dH (250 MHz) 2.28 (3H, s,
amide Me), 2.40 (3H, s, ketone Me), 2.52 (3H, s, ketone
Me), 8.35 (1H, d, J¼11 Hz, 1-H), 12.0 (1H, br s, NH); m/z
170 (MþHþ, 100%).
1.1.2. (S,S)-4,5-Diphenyl-2-methylene-1,3-dioxolane 1b.3
This was prepared as a solution in THF using the method
described for 1a, starting with the (S,S)-bromoacetal (2)-
2b3 and assuming a yield of 90%.
1.1.3. Benzyl 3-methoxy-2-(1-oxoethyl)prop-2-enoate
9.13 To a round-bottomed flask fitted with a magnetic stirrer
was added anhydrous trimethyl orthoformate (15.9 g,
0.15 mol), benzyl acetoacetate (19.2 g, 0.10 mol) and acetic
anhydride (24.5 g, 0.24 mol). The mixture was heated under
reflux until complete by TLC (24 h). Concentration of the
reaction mixture followed by chromatography gave the title
compound 9 (4.25 g, 18%) as an orange solid (E and Z
isomers, ratio ca. 1:1) which was used without further
purification; nmax 3543, 1713, 1633, 1588, 1276, 1197,
1138, 1071 cm21; dH (250 MHz) (major isomer) 2.39 (3H,
s, Me), 3.97 (3H, s, OMe), 5.21 (2H, s, OCH2Ph), 7.30–7.40
(5H, m, Ar), 7.58 (1H, s, 10-H); (minor isomer) 2.31 (3H, s,
Me), 4.01 (3H, s, OMe), 5.27 (2H, s, OCH2Ph), 7.30–7.40
(5H, m, Ar), 7.61 (1H, s, 10-H); m/z (ES) 235 (MþHþ,
100%).
1.1.7. Methyl 4-acetylamino-6,6-bis(2-methoxyethoxy)-
5,6-dihydro-2-methyl-4H-pyran-3-carboxylate 13. To a
solution of 1,1-bis(2-methoxyethoxy)ethene 611 (204 mg,
1.16 mmol) in THF (10 mL) at room temperature was added
the diene 10 (250 mg, 1.35 mmol). The reaction was
monitored by TLC and appeared to be complete after
72 h. The reaction mixture was concentrated and filtered
through an alumina plug to provide the title compound 13
(268 mg, 64%) as an orange solid (MþHþ, 362.1821.
C16H28NO8 requires 362.1815); nmax 3378, 1712, 1635,
1118, 1062, 1042 cm21; dH (300 MHz) 1.79 (3H, s,
MeCON), 2.10–2.25 (2H, obscured m, 5-H2), 2.18 (3H, s,
2-Me), 3.24 (3H, s, OMe), 3.26 (3H, s, OMe), 3.43–3.50
(2H, m, OCH2C), 3.55–3.70 (6H, m, 3£OCH2C), 3.58 (3H,
s, CO2Me), 5.11 (1H, dd, J¼5.5, 9.5 Hz, 4-H), 6.64 (2H, br
d, J¼9.5 Hz, NH); m/z 362 (MþHþ, 100%), 286 (50), 227
(60).
1.1.4. Methyl 3-acetylamino-2-(1-oxoethyl)prop-2-eno-
ate 10.8 To a solution of methyl 3-methoxy-2-(1-oxoethyl)-
prop-2-enoate 813 (700 mg, 4.43 mmol) in THF (10 mL)
under argon was added acetamide (260 mg, 4.40 mmol).
The reaction mixture was heated at 1008C for 4 h and then
concentrated in vacuo. The residue was purified by
chromatography, eluting with petroleum–ethyl acetate
(4:1), and the major product was crystallised from
petroleum ether to obtain the pure title compound 10
(420 mg, 52%) as a light yellow waxy solid which was used
without further purification; nmax 3435, 1739, 1718, 1373,
1240, 1025, 764 cm21; dH (300 MHz) 2.23 (3H, s,
MeCON), 2.53 (3H, s, 20-H3), 3.77 (3H, s, CO2Me), 8.51
(1H, d, J¼12 Hz, CvCH), 12.0 (1H, br s, NH); m/z 203
(MþNHþ4 , 100%), 186 (MþHþ, 60); Rf 0.42 (petroleum–
ethyl acetate 2:1).
1.1.8. Methyl 4-acetylamino-5,6-dihydro-2-methyl-
spiro[4H-pyran-6,20-[1,3]dioxolan]-3-carboxylate 14. To
t-butanol (75 mL) under argon was added potassium metal
(2.0 g, 51 mmol) in small portions and the solution heated to
908C. Once the potassium metal had dissolved to form the t-
butoxide, 2-bromomethyl-1,3-dioxolane (4.36 g, 26 mmol)
was added. After 1 h the resultant ketene acetal 712 was
distilled, together with some t-butanol, directly into an
adjoining flask containing heterodiene 10 (0.50 g,
2.7 mmol). The reaction was stirred at room temperature
until no heterodiene was visible by TLC (2 h). The volatiles
were removed in vacuo and the residue purified by rapid
flash chromatography, eluting with petroleum–ethyl acetate
(4:1), to obtain the title compound 14 (460 mg, 63%) as an
off-white solid, mp 104–1058C (MþHþ, 272.1135.
C12H18NO6 requires 272.1134); nmax (Nujol) 3375, 1706,
1632, 1530, 1322, 1266, 1092, 1012, 951, 859 cm21; dH
(300 MHz) 1.91 (3H, s, MeCON), 2.05–2.25 (2H, m, 5-H2),
2.21 (3H, s, 2-Me), 3.67 (3H, s, CO2Me), 4.0–4.3 (4H, m,
40-H2 and 50-H2), 5.26 (1H, dd, J¼5, 9.5 Hz, 4-H), 5.97 (1H,
d, J¼9.5 Hz, NH); m/z 272 (MþHþ, 100%); Rf 0.55
(petroleum–ethyl acetate 4:1).
1.1.5. Benzyl 3-acetylamino-2-(1-oxoethyl)prop-2-enoate
(E)-11. To a solution of 9 (E and Z isomers; 1.6 g,
6.8 mmol) in THF (5 mL) under argon was added acetamide
(0.60 g, 10.2 mmol). The mixture was heated under reflux
for ca. 15 h, allowed to cool and the solvent evaporated.
Chromatography of the residue, eluting with ether, gave an
orange waxy solid identified as (E)-11 (1.0 g, 56%)
(MþHþ, 262.1072. C14H16NO4 requires 262.1079); nmax
3261, 1714, 1651, 1574, 1240, 1178, 1068, 995, 783, 753,
699 cm21; dH (250 MHz) (major isomer; signals attributed
to the minor isomer are shown in brackets) 2.24 [2.25] (3H,
s, MeCON), 2.54 [2.55] (3H, s, 20-H3), 5.25 [5.30] (2H, s,
CH2O), 7.30–7.40 (5H, m, Ar), 8.57 [8.53] (1H, d,
J¼12 Hz, 3-H), 12.0 (1H, br s, NH); dC (63 MHz) 23.9
(amide Me), 31.6 (C-20), 66.5 (CH2O), 108.3 (C-2), 126.9,
128.25, 128.3, 128.5, 128.6, (5£ArCH), 135.9 (ArC-1),
146.6 (C-3), 165.7 (ester CO), 169.2 (amide CO), 201.5 (C-
10); m/z 262 (MþHþ, 100%), 186 (64), 107 (84).
1.1.9. Methyl 4-acetylamino-5,6-dihydro-2-methyl-
40S,50S-bis(2-methylphenyl)spiro[4H-pyran-6,20-
[1,3]dioxolan]-3-carboxylates 15 and 16. To a solution of
the ketene acetal (S,S)-1a (168 mg, 0.63 mmol) in THF
1.1.6. N-(2-(1-Oxoethyl)-3-oxobut-1-enyl)ethanamide

P. Leeming et al. / Tetrahedron 59 (2003) 341–352
347
(10 mL) at 2158C was added the diene 10 (117 mg,
0.63 mmol). The reaction mixture was maintained at
2158C for 72 h after which no diene was visible by TLC,
and the 300 MHz 1H NMR spectrum suggested a d.r. of ca.
4:1. The mixture was concentrated, taken up in DCM
(1 mL) and filtered through an alumina plug, eluting with
petroleum–ethyl acetate (4:1). Crystallisation from isohex-
ane–ether (1:1) provided the title compound (4S,40S,50S)-15
(164.5 mg, 60%) as a colourless solid (d.r.$19:1 by
250 MHz NMR) (MþHþ, 452.2073. C26H30NO6 requires
452.2073); nmax 3305, 1713, 1633, 1574, 1530, 1324, 1244,
1223, 1130, 1097, 1003, 761 cm21; dH (250 MHz) 1.68 (3H,
s, ArMe), 1.78 (3H, s, ArMe), 1.89 (3H, s, MeCON), 2.44
(3H, s, 2-Me), 2.40–2.50 (2H, obscured m, 5-H2), 3.74 (3H,
s, CO2Me), 5.28 (1H, d, J¼9 Hz, 40-H or 50-H), 5.30–5.40
(1H, m, 4-H), 5.54 (1H, d, J¼9 Hz, 40-H or 500-H), 6.00 (1H,
d, J¼9 Hz, NH), 7.06 (2H, d, J¼7.5 Hz, 3,3 -ArH), 7.20–
7.35 (4H, m, 4,40,5,50-ArH), 7.57 (2H, d, J¼8 Hz, 6,60-ArH);
m/z 452 (MþHþ, 20%), 267 (100), 203 (50), 186 (70);
HPLC retention time 5.88 min (purity $95%). The follow-
ing signals were tenta0tively assigned to the minor
diastereoisomer (4R,40S,5 S)-16: dH (250 MHz) 1.65 (3H,
s, ArMe), 1.74 (3H, s, ArMe).
J¼12 Hz, 0OCHPh), 5.37–5.45 (1H, m, 4-H), 5.54 (1H, d,
J¼9 Hz, 4 -H), 5.97 (1H, d, J¼9.5 Hz, NH), 7.02–7.07 (2H,
m, 3,30-ArH), 7.18–7.40 (9H, m, ArH), 7.57 (2H, br d,
J¼8 Hz, 6,60-ArH); dC (100 MHz) 19.2 (ArMe), 20.6
(ArMe), 23.8 (amide Me), 23.9 (2-Me), 35.3 (C-5), 41.4
(C-4), 66.2 (OCH2), 82.2 (C-40), 84.1 (C-50), 103.3 (C-3),
119.4 (C-6), 126.7–136.5 (several peaks, Ar), 165.3 (C-2),
167.1 (ester CO), 169.1 (amide CO) [NMR signals were
assigned with reference to H–1H (COSY) and H–13C
correlation (HMQC) spectra. Assignments for C-2, C-5 and
C-6 are tentative]; m/z (FAB) 528 (MþHþ, 20%), 481 (20),
368 (100), 156 (25); HPLC retention times 5.87 min (minor
isomer, area 11.89), 6.67 min (major isomer, area 48.88).
pTrituration with isohexane gave material with d.r. 14:1
[HPLC retention times 5.87 min (minor isomer, area 5.1),
6.67 min (major 0isomer, area 70.7)]. The minor diastereoi-
somer (4R,40S,5 S)-19 had dH (400 MHz) 5.55 (1H, d,
J¼9 Hz, 40-H) and 6.02 (1H, d, J¼9.5 Hz, NH).
1
1
1.1.12. 4-Acetylamino-3,4-dihydro-6-methyl-40S,50S-
bis(2-methylphenyl)-5-(1-oxoethyl)spiro[2H-pyran-2,20-
[1,3]dioxolans] 20 and 21. To a solution of ketene acetal
(S,S)-1a (168 mg, 0.63 mmol) in THF (10 mL) at 2158C
was added the diene 12 (110 mg, 0.63 mmol). After 5 days
at 2158C analysis by HPLC revealed the absence of any
starting material, and the 250 MHz NMR spectrum
indicated a d.r. of $4:1. The reaction mixture was
concentrated and the residue was taken up in DCM
(1 mL) and filtered through a plug of basic alumina, eluting
with more DCM0. Evaporation of the solvent gave the title
compound (4S,4 S,50S)-20 (184 mg, 67%) as a solid (d.r.
$4:1 by 250 MHz NMR). Crystallisation from isohexane
gave 20 as colourless needles, mp 112–1158C (d.r. $19:1
by 400 MHz NMR) (MþHþ, 436.2119. C26H30NO5
requires 436.2124); nmax (Nujol) 3308, 1677, 1585, 1320,
1257, 1242, 1224, 1129, 1098, 1002, 935, 880, 762,
728 cm21; dH (400 MHz) 1.70 (3H, s, ArMe), 1.79 (3H, s,
ArMe), 1.93 (3H, s, MeCON), 2.28 (3H, s, MeCOC), 2.37
(3H, s, 6-Me), 2.45 (1H, dd, J¼2, 14 Hz, 3-0H), 2.50 (1H, dd,
J¼6, 14 Hz, 3-H), 5.27 (1H, d, J¼9 Hz, 4 or 50-H), 5.38–
5.44 (1H, m, 4-H), 5.55 (1H, d, J¼9 Hz, 40 or 50-H), 6.17
(1H, d, J¼10 Hz, NH), 7.04–7.08 (2H, m, 3,30-ArH), 7.20–
7.35 (4H, m, 4,40,5,50-ArH), 7.57 (2H, dd, J¼2, 8 Hz, 6,60-
ArH); dC (100 MHz) 19.2 (two peaks, MeAr), 21.0 (6-Me),
23.9 (amide Me), 29.7 (MeCO.C), 35.4 (C-3), 42.2 (C-4),
81.8 (C-40 or C-50), 83.8 (C-40 or C-50), 111.1 (C-5), 118.6
(C-2), 126.3–136.1 (several peaks, ArC), 163.3 (C-6), 169.0
(amide CO), 199.5 (ketone CO) [NMR signals were
1.1.10. 1,2-Bis(2-methylphenyl)-ethane-1,2-diol 1-acetate
17. To a solution of ketene acetal (S,S)-1a (50 mg,
0.19 mmol) in THF (5 mL) was added 0.1 M sulfuric acid
(2 mL). After stirring for 1 h the reaction mixture was
concentrated in vacuo, taken up in DCM, washed with
saturated aq. sodium hydrogen carbonate (5 mL), dried and
evaporated. Trituration with isohexane provided the title
compound 17 (40 mg, 75%) as a colourless solid (MþHþ,
285.1486. C12H21O3 requires 285.1491); nmax 3435, 1737,
1645, 1240, 1026, 757 cm21; dH (300 MHz) 1.78 (3H, s,
ArMe), 1.86 (3H, s, ArMe), 2.10 (3H, s, COMe), 5.19 (1H,
d, J¼8.5 Hz, H-2), 6.04 (1H, d, J¼8.5 Hz,0H-1), 6.91 (2H, d,
J¼7.5 Hz, 30,300-H), 7.070–0 7.21 (4H, m, 4 ,400,50,500-H), 07.44
(1H, dd, J¼1.5, 7.5 Hz, 6 -H), 7.59 (1H, d, J¼7.5 Hz, 6 -H);
dC (75 MHz) 18.9 (MeAr), 23.4 (MeAr), 29.0 (MeCO), 72.6
(2-C), 76.2 (1-C), 125.7, 125.9 (50-C, 500-C), 127.3, 127.5,
127.9, 128.0 (40-C, 400-C, 60-C, 600-C), 130.2 (30-C, 300-C),
135.3, 135.7, 136.4, 137.1 (10-C, 100-C, 20-C, 200-C), 170.1
(CvO); m/z 302 (MþNHþ4 , 30%), 285 (MþHþ, 5), 243
(22), 242 (100); HPLC retention time 5.17 min.
1.1.11. Benzyl 4-acetylamino-5,6-dihydro-2-methyl-
40S,50S-bis(2-methylphenyl)spiro[4H-pyran-6,20-
[1,3]dioxolan]-3-carboxylates 18 and 19. To a solution of
the ketene acetal (S,S)-1a (83 mg, 0.31 mmol) in THF
(10 mL) at 2158C was added the diene 11 (80 mg,
0.31 mmol). The reaction was maintained at 2158C for
96 h after which no diene was present by HPLC analysis,
and the 250 MHz NMR spectrum suggested a d.r. of ca. 4:1.
The reaction mixture was concentrated, taken up in DCM
(1 mL) and filtered through an alumina plug eluting with
ether–isohexane (2:1). Concentration of the filtrate gave the
title compound (4S,40S,50S)-18 (101 mg, 62%) as a cream-
coloured solid (d.r. 4.1:1 by HPLC)p (MþHþ, 528.2394.
C32H34NO6 requires 528.2386); nmax 3258, 1715, 1652,
1574, 1275, 1240, 1178, 1077 cm21; dH (400 MHz) 1.69
(3H, s, ArMe), 1.77 (3H, s, MeCON), 1.79 (3H, s, ArMe),
2.39–2.48 (2H, m, 5-H2), 2.45 (3H, s, 2-Me), 5.06 (1H, d,
J¼12 Hz, OCHPh), 5.29 (1H, d, J¼9 Hz, 50-H), 5.33 (1H, d,
1
assigned with reference to a H–13C correlation (HMQC)
spectrum; assignments for C-2, C-5 and C-6 are tentative];
m/z 436 (MþHþ, 10%), 242 (30), 76 (100). The following
signals were tentatively assigned to the minor diastereoi-
somer (4R,40S,50S)-21: dH (400 MHz) 1.67 (3H, s, ArMe),
1.76 (3H, s, ArMe), 1.94 (3H, s, MeCON), 5.34 (1H, d,
J¼9 Hz, 40 or 50-H), 7.88 (2H, dd, J¼2, 8 Hz, 6,60-ArH).
The identity of the cycloadduct hydrolysis product 28
(analytical HPLC retention time 4.89 min), 17 (5.17 min)
and 20 (5.79 min) were confirmed by the following LC-MS
data [retention times (min), MþH, assignment]: 5.94, 436,
20; 5.56, 256, 17; 5.07, 454, 28.
1.1.13. Crystal data for 20.25 Monoclinic; C2;
˚
˚
˚
a¼21.201(4) A,
b¼9.944(2) A,
c¼13.660(2) A,

348
P. Leeming et al. / Tetrahedron 59 (2003) 341–352
3
2
˚
V¼2708.6(8) A ; Z¼4; goodness-of-fit on F 1.170; final R
indices [I.2s(I)] R1¼0.1274, wR2¼0.3262; R indices (all
data) R1¼0.1897, wR2¼0.3972. The crystal quality was
very poor and due to a paucity of observed data all carbon
atoms were refined isotropically.
6.17 (1H, d, J¼10 Hz, NH), 7.18–7.28 (4H, m, ArH), 7.33–
7.38 (6H, m, ArH); dC (75 MHz) 20.5 (6-Me), 23.4 (amide
Me), 29.2 (MeC0O.C), 34.9 (C-3), 41.9 (C-4), 85.1 (C-40 or
C-50), 87.4 (C-4 or C-50), 111.3 (C-5), 118.9 (C-2), 126.7,
126.8, 128.8, 129.1, 135.4, 136.9 (Ar), 163.3 (C-6), 169.0
(amide CO), 199.5 (ketone CO) (assignments based on
comparison with the tolyl analogue 20); m/z 409 (25%), 408
(MþHþ, 100), 239 (71), 170 (53).
1.1.14. Methyl 4-acetylamino-5,6-dihydro-2-methyl-
40S,50S-diphenylspiro[4H-pyran-6,20-[1,3]dioxolan]-3-
carboxylates 22 and 23. To a solution of the ketene acetal
(S,S)-1b (236 mg, 1.0 mmol) in THF (5 mL) at 2208C was
added a solution of heterodiene 10 (185 mg, 1.0 mmol) in
THF (10 mL). The reaction mixture was maintained at
2208C until the reaction was complete by 1H NMR
spectroscopy (72 h). The reaction mixture was concentrated
in vacuo, dissolved in DCM (5 mL) and filtered through
alumina, eluting with more DCM. Concentration and
trituration with isohexane provided an orange solid, which
was suspended in hot isohexane (2 mL) and treated
dropwise with DCM until the solution clarified. The solution
was then allowed to cool in a refrigerator, which gave the
title compound (4S,40S,50S)-22 as a white solid (260 mg,
61%), d.r. $19:1 by 300 MHz 1H NMR spectroscopy
(MþHþ, 424.1771. C24H26NO6 requires 424.1760); nmax
3302, 1713, 1632, 1515, 1324, 1245, 1127, 1100, 1005, 868,
760, 701 cm21; dH (300 MHz) 1.88 (3H, s, MeCON) [minor
product 1.89], 2.38 (3H, s, 6-Me), 2.36–2.41 (2H, obscured
m, 3-H2), 3.70 (3H, s, CO2Me), 4.95 (1H, d, J¼8.5 Hz, 40-H
or 50-H) [minor product 4.87], 5.29 (1H, d, J¼9 Hz, 40-H or
50-H) [minor product 5.08], 5.30–5.40 (1H, m, 4-H), 5.98
(1H, d, J¼9.5 Hz, NH), 7.16–7.28 (4H, m, ArH), 7.32–7.37
(6H, m, ArH); dC (75 MHz) 20.2 (2-Me), 23.7 (amide Me),
34.70(C-5), 41.0 (C-4), 51.8 (OMe), 85.1 (C-40 or C-50), 87.3
(C-4 or C-50), 103.3 (C-3), 119.3 (C-6), 126.6, 126.7, 128.8,
129.0, 135.4, 137.1 (Ar), 164.5 (C-2), 167.6 (ester CO),
169.0 (amide CO) (assignments based on comparison with
benzyl analogue); m/z 424 (MþHþ, 22%), 239 (85), 186
(100). The mother liquor from the crystallisation of 22
1.1.16. 2-Acetyl-3-acetylaminopentanedioic acid 1-
methyl ester 5-(2-methoxyethyl) ester 26. To a solution
of the cycloadduct 13 (20 mg, 0.06 mmol) in THF (5 mL),
was added 0.1 M sulfuric acid (1 mL). The reaction mixture
was stirred at room temperature. After overnight stirring (ca.
14 h) TLC indicated that the reaction was complete, and the
mixture was concentrated, taken up in DCM (5 mL), washed
with saturated aq. sodium hydrogen carbonate (5 mL), dried
and evaporated to provide the title compound 26 (10 mg,
1
60%) as a colourless solid (d.r. ca. 1.2:1 by 300 MHz H
NMR spectroscopy) (MþHþ, 304.1389. C13H22NO7
requires 304.1396); nmax 3387, 1730, 1260 cm21; dH
(300 MHz) (major isomer; distinguishable values for
minor isomer are shown in brackets) 1.89 (3H, s,
MeCON), 2.27 [2.23] (3H, s, 20-H3), 2.56–2.66 (1H, m, 4-
H), 2.70–2.80 (1H, m, 4-H), 3.34 (3H, s, CH2OMe), 3.52–
3.59 (2H, m, 200-H2), 3.72 [3.70] (3H, s, CO2Me), 4.02 (1H,
d, J¼4 Hz, 2-H), 4.18–4.25 (2H, m, 100-H2), 4.97–5.07
[4.82–4.92] (1H, m, 3-H), 6.65 [6.50] (1H, br d, J¼8 Hz,
NH); m/z 321 (MþNHþ4 , 30%), 304 (40), 242 (90).
1.1.17. 2-Acetyl-3-acetylaminopentandioic acid 1-methyl
ester 5-(2-hydroxyethyl) ester 27. To a solution of the
cycloadduct 14 (100 mg, 0.37 mmol) in THF (5 mL) under
argon was added 0.1 M sulfuric acid (3.7 mL). On addition
of the acid the colour of the reaction mixture changed from
orange to pale yellow, and after 0.5 h TLC indicated that the
reaction was complete. The reaction mixture was concen-
trated, extracted with ethyl acetate (2£5 mL), washed with
saturated aqueous sodium hydrogen carbonate (5 mL), dried
and evaporated. The residue was chromatographed (elution
with ethyl acetate) to obtain the title compound 27 (80 mg,
provided0 a sample enriched in the minor product
(4R,40S,5 S)-23, enabling its characteristic 1H NMR signals
to be assigned as indicated above.
1.1.15. 4-Acetylamino-3,4-dihydro-6-methyl-40S,50S-
diphenyl-5-(1-oxoethyl)spiro[2H-pyran-2,20-[1,3]dioxo-
lan] 24 and 25. To a solution of the ketene acetal (S,S)-1b
(95.2 mg, 0.40 mmol) in THF (10 mL) at 2208C was added
a solution of heterodiene 12 (72 mg, 0.43 mmol) in THF
(2 mL). The mixture was maintained at 2208C until the
75%) as an off-white solid (d.r. ca. 1.2:1 by 300 MHz H
1
NMR spectroscopy) (MþHþ, 290.1252. C12H20NO7
requires 290.1240); nmax 3418, 1733, 1652, 1551, 1262,
1207, 1084, 1023 cm21; dH (300 MHz) (major isomer;
distinguishable values for minor isomer in brackets) 1.93
(3H, s, MeCON), 2.29 [2.26] (3H, s, 20-H3), 2.55–2.75 (2H,
m, 4-H2), 3.76 [3.73] (3H, s, CO2Me), 3.7–3.9 (2H, m, 200-
H2), 4.05–4.35 (3H, m, 2-H and 100-H2), 5.1–5.2 [4.95–
5.05] (1H, m, 3-H), 6.81 (1H, t, J¼9 Hz, NH) [6.69 (1H, br
d, J¼9 Hz, NH)]; m/z 290 (MþHþ, 100%), 272 (25), 164
(45).
1
reaction was complete by H NMR spectroscopy (120 h).
The reaction mixture was concentrated in vacuo, dissolved
in DCM (5 mL) and filtered through alumina, eluting with
more DCM. Concentration and trituration with isohexane
provided an orange solid, which was suspended in hot
isohexane and treated dropwise with DCM until the solution
clarified. The solution was then allowed to cool0 in a
refrigerator, which gave the title compound (4S,40S,5 S)-24
as the major product (102 mg, 63%), d.r. $19:1 by
300 MHz 1H NMR spectroscopy (MþHþ, 408.1802.
C24H26NO5 requires 408.1811); nmax 3305, 1733, 1651,
1580, 1279, 1243, 1179, 1000, 937, 869, 761, 700 cm21; dH
(300 MHz) 1.91 (3H, s, MeCON), 2.25 (3H, s, MeCOC),
2.30 (3H, s, 6-Me), 2.39 (1H, dd, J¼2, 14 Hz, 3-H), 02.47
(1H, dd, J¼6, 14 Hz, 3-H), 4.95 (1H, d, J¼9 Hz, 40 or 5 -H),
5.29 (1H, d, J¼9 Hz, 40 or 50-H), 5.35–5.42 (1H, m, 4-H),
1.1.18. 4-Acetyl-3-acetylamino-5-oxohexanoic acid 1,2-
bis(2-methylphenyl)-2-hydroxyethyl ester 28. To a sol-
ution of the cycloadduct 20 (23 mg, 0.05 mmol) in THF
(2 mL) was added 0.1 M sulfuric acid (0.5 mL). The
reaction mixture was stirred at room temperature for 1 h,
at which point HPLC analysis indicated that the reaction
was complete. The reaction mixture was concentrated, taken
up in DCM (5 mL), washed with saturated aq. sodium
hydrogen carbonate (2£5 mL), dried and evaporated to
provide the title compound 28 (13 mg, 56%) as a white solid

P. Leeming et al. / Tetrahedron 59 (2003) 341–352
349
(MþHþ, 454.2219. C26H32NO6 requires 454.2229); nmax
3424, 1737, 1651, 1241, 1179 cm21; dH (300 MHz) 1.80
(3H, s, ArMe), 1.87 (3H, s, ArMe), 1.92 (3H, s, MeCON),
2.15 (3H, s, 20-Me), 2.24 (3H, s, 6-Me), 2.60 (1H, dd, J¼7,
15 Hz, 2-H), 2.70 (1H, dd, J¼7, 15 Hz, 2-H), 4.07 (1H, d,
J¼6 Hz, 4-H), 5.10–5.20 (1H, m, 3-0H0 ), 5.24 (1H, d,
J¼9 Hz, 200-H), 6.11 (1H, d, J¼9 Hz, 1 -H), 6.74 (1H, d,
J¼10 Hz, NH), 6.90–7.00 (2H, m, 3,30-ArH), 7.07–7.23
(4H, m, 4,40,5,50-ArH), 7.046 (1H, br d, J¼8 Hz, 6-ArH),
7.60 (1H, br d, J¼8 Hz, 6 -ArH); m/z 454 (MþHþ, 10%),
436 (15), 230 (100), 212 (25); analytical HPLC retention
time 4.88 min.
50%) which was identical by NMR spectroscopy to the
product obtained by method 1.
1.1.21. Dimethyl 2-acetyl-3-acetylaminopentanedioate
31. Method 1. To a solution of 29 (50 mg, 0.11 mmol) in
anhydrous methanol (5 mL) was added potassium carbonate
(103 mg, 0.73 mmol). The mixture was stirred overnight
and then concentrated, diluted with DCM (5 mL), washed
with 0.1 M hydrochloric acid (5 mL), dried and evaporated.
Chromatography, eluting with ethyl acetate, provided the
diol (S,S)-2b (16 mg, 66%) and a sample of the diester 31
(19 mg, 65%) which was identical (TLC, NMR) to the
material produced by method 2 (see below). The recovered
diol 2b was identical (TLC, NMR) to an authentic sample,
and had an enantiomeric purity of .80% when estimated
by 300 MHz 1H NMR spectroscopy in the presence of
4 equiv. of (R)-(2)-2,2,2-trifluoro-1-(9-anthryl)ethanol, as
described.3
1.1.19. 2-Acetyl-3-acetylaminopentanedioic acid 5-(2-
hydroxy-1,2-diphenyl)ethyl ester 1-methyl ester 29. To
a solution of the cycloadduct (4S,40S,50S)-22 (100 mg,
0.24 mmol) in THF (5 mL) was added 0.1 M sulfuric acid
(2.5 mL, 0.25 mmol). The reaction mixture was stirred at
room temperature for 1.5 h at which point 1H NMR analysis
indicated that the reaction was complete. The mixture was
concentrated, taken up in DCM (5 mL), washed with
saturated aq. sodium hydrogen carbonate (3 mL), dried
and evaporated to obtain the title compound 0029 (68 mg,
65%) as a white solid mixture of (2R,3S,1 S,200S) and
(2S,3S,100S,200S) diastereoisomers (ratio ca. 1:1 by NMR)
(MþHþ, 442.1858. C24H28NO4 requires 442.1866); nmax
3418, 1737, 1718, 1669, 909, 734 cm21; dH (300 MHz) 1.88
and 1.89 (total 3H, 2£s, MeCON), 2.21 and 2.24 (total 3H,
2£s, 20-Me), 2.58–2.78 (2H, m, 4-H2), 3.69 and 3.73 (total
3H, 2£s, CO2Me), 3.85–3.89 (total 1H, m, 2-H), 4.90 and
4.91 (total 1H, 2£d, J¼8 Hz, 200-H), 5.0–5.1 and 5.1–5.2
(total 1H, 2£m, 3-H), 5.79 and 5.80 (total 1H, 2£d, J¼8 Hz,
100-H), 6.62 and 6.73 (total 1H, 2£d, J¼9.5 Hz, NH), 7.03–
7.10 (4H, m, ArH), 7.12–7.18 (6H, m, ArH); m/z 442
(MþHþ, 2%), 228 (29), 214 (45), 186 (77), 169 (24), 160
(22), 134 (49), 77 (100).
Method 2. To a solution of 29 (50 mg, 0.11 mmol) in
anhydrous methanol (5 mL) was added 5% Pd/C catalyst
(1 mg) and the reaction mixture was stirred under an
atmosphere of hydrogen at room temperature until no
starting material could be detected by TLC (3–4 h). The
solution was filtered through Celitew and evaporated.
Washing the resultant solid with isohexane removed the
by-product (1,2-diphenylethane 33) and provided 2-acetyl-
3-acetylaminopentanedioic acid 1-methyl ester 32 (18 mg)
as a white solid which 1H NMR spectroscopy indicated was
a mixture (ca. 1:1) of diastereoisomers [dH (d6-acetone)
1.84, 1.86 (each 3H, s, MeCON), 2.23, 2.26 (each 3H, s, 20-
H3), 3.70, 3.71 (each 3H, s, OMe)]. The sample of 32 was
dissolved in ethanol (10 mL) and treated dropwise with a
slight excess of diazomethane in ether (Caution—Hazar-
dous; prepared26 from Diazaldw). After 5 min the reaction
was quenched by the dropwise addition of 4 M acetic acid
until the yellow colour of the reaction mixture faded. The
solution was concentrated, diluted with ethyl acetate
(8 mL), washed with saturated aq. sodium hydrogen
hydrogen carbonate, and dried. Evaporation gave the title
compound 31 (18 mg, 61%) as a white solid [1:1 mixture of
(2R,3S) and (2S,3S) diastereoisomers] (MþHþ, 260.1134.
C11H18NO6 requires 260.1134); nmax 3407, 1734,
1660 cm21; dH (300 MHz) 1.92 (3H, s, MeCON), 2.25,
2.28 (total 3H, 2£s, 20-H3), 2.5–2.8 (2H, m, 4-H2), 3.66,
3.68, 3.72, 3.74 (total 6H, 4£s, OMe), 4.01–4.07 (total 1H,
m, 2-H), 4.80–4.90, 4.95–5.05 (total 1H, 2£m, 3-H), 6.47,
6.63 (total 1H, 2£d, J¼9.5 Hz, NH); m/z 260 (MþHþ, 100).
1.1.20. 4-Acetyl-3-acetylamino-5-oxohexanoic acid 1,2-
diphenyl-2-hydroxyethyl ester 30. Method 1. To a solution
of the cycloadduct (4S,40S,50S)-24 (102 mg, 0.25 mmol) in
THF (5 mL) was added 0.1 M sulfuric acid (2.5 mL). The
reaction mixture was stirred at room temperature for 1.5 h at
1
which point H NMR analysis indicated that the reaction
was complete. The mixture was concentrated, taken up in
DCM (5 mL), washed with saturated aq. sodium hydrogen
carbonate (3 mL), dried and evaporated to obtain the title
compound (3S,100S,200S)-30 (60 mg, 56%) as an off-white
solid, d.r. $19:1 by 300 MHz 1H NMR spectroscopy
(MþHþ, 426.1916. C24H28NO6 requires 426.1917); nmax
3367, 1729, 1702, 1659, 1261, 1177, 758, 700 cm21; dH
(300 MHz) 1.88 (3H, s, MeCON), 2.12 (3H, s, 20-Me), 2.21
(3H, s, 6-Me), 2.60 (1H, dd, J¼9, 15 Hz, 2-H), 2.65 (1H, dd,
J¼8.5, 15 Hz, 2-H), 4.04 (1H, d, J¼5 Hz, 4-H), 4.90 (1H, d,
J¼8 Hz, 200-H), 5.05–5.15 (1H, m, 3-H), 5.83 (1H, d,
J¼8 Hz, 100-H), 6.71 (1H, d, J¼9.5 Hz, NH), 7.05–7.12
(4H, m, ArH), 7.15–7.20 (6H, m, ArH); m/z 426 (MþHþ,
10%), 232 (45), 214 (85), 212 (100), 170 (58), 119 (49); Rf
0.38 (hexane–ethyl acetate 1:9).
1.1.22. Methyl 4-acetyl-3-acetylamino-5-oxohexanoate
35. To a solution of the ester 30 (40 mg, 0.094 mmol) in
anhydrous methanol (5 mL) was added 5% Pd/C catalyst
(1 mg) and the reaction mixture was stirred under an
atmosphere of hydrogen at room temperature until no
starting material could be detected by TLC (3–4 h). The
solution was filtered through Celitew and evaporated.
Washing the resultant solid with isohexane removed the
by-product (1,2-diphenylethane 33) and provided (3S)-4-
acetyl-3-acetylamino-5-oxohexanoic acid 34 as a white
solid (15 mg) [nmax 3377, 1721, 1620, 1257 cm21; dH
(300 MHz) 1.85 (3H, s, MeCON), 2.16 (3H, s, 20-Me), 2.26
(3H, s, 6-Me)], which was dissolved in ethanol (10 mL) and
treated dropwise with a slight excess of diazomethane in
Method 2. The procedure described in method 1 was
repeated with 24 (11.5 mg) using 1 equiv. 0.1 M aq. citric
acid instead of sulfuric acid. After 48 h the reaction was
complete, and isolation as before gave a sample of 30 (6 mg,

350
P. Leeming et al. / Tetrahedron 59 (2003) 341–352
ether (Caution—Hazardous; prepared26 from Diazaldw).
After 5 min the reaction was quenched by the dropwise
addition of 4 M acetic acid until the yellow colour of the
reaction mixture faded. The solution was concentrated,
diluted with ethyl acetate (8 mL), washed with saturated aq.
sodium hydrogen hydrogen carbonate, and dried. Evapor-
ation gave the title compound (3S)-35 (16 mg, 70%) as a
white solid (MþHþ, 244.1184. C11H18NO5 requires
; dH
762 cm21; dH (300 MHz) (distinguishable values for 39 are
shown in brackets) 1.66 (3H, s, ArMe), 1.77 (3H, s, ArMe),
2.27 (1H, t, J¼12 Hz, 8-Hax), 2.75 (1H, dd, J¼5, 12 Hz, 8-
Heq), 3.07 [3.08] (3H, s, NMe), 3.23 [3.21] (3H, s, NMe),
4.40 (1H, ddd, J¼2, 5, 12 Hz, 8a-H), 5.31 (1H, d, J¼9 Hz,
40-H), 5.58 [5.43] (1H, d, J¼9 Hz, 50-H),06.95–7.10 (2H, m,
3,30-ArH), 7.15–7.30 (4H, m, 4,40,5,5 -ArH), 7.50–7.60
(2H, m, 6,60-ArH), 7.70 [7.62] (1H, d, J¼2 Hz, 5-H); m/z
(FAB) 435 (MþHþ, ,1%), 368 (32), 256 (100), 254 (46),
156 (82); HPLC retention times 5.32 min (minor isomer,
area 6.62), 6.10 min (major isomer, area 28.17).
244.1185); nmax 3278, 1735, 1715, 1655 cm21
(300 MHz) 1.91 (3H, s, MeCON), 2.16 (3H, s, 20-H3),
2.28 (3H, s, 6-H3), 2.55 (1H, dd, J¼8, 16.5 Hz, 2-H), 2.67
(1H, dd, J¼5.5, 16.5 Hz, 2-H), 3.67 (3H, s, OMe), 4.25 (1H,
d, J¼5 Hz, 4-H), 4.93–5.03 (1H, m, 3-H), 6.53 (1H, d,
J¼9.5 Hz, NH); m/z 244 (MþHþ, 100); Rf 0.33 (ethyl
acetate). The isolated sample of 33 was identical (TLC,
NMR) to commercial material (Lancaster Synthesis, 4977).
1.1.26. 1-Carbethoxy-3-hydroxymethylene-4-piperidone
40.20 In a 3-necked flask equipped with a calcium chloride
guard tube, argon inlet, dropping funnel and magnetic stirrer
were placed sodium hydride (60% dispersion in mineral oil;
4.8 g, 0.12 mol), dry ether (100 mL) and ethanol (10 mL).
The reaction vessel was cooled with an ice bath and treated
dropwise with a mixture of 1-carbethoxy-4-piperidone
(10.26 g, 0.06 mol) and ethyl formate (8.90 g, 0.12 mol) in
dry ether (150 mL). The mixture turned lemon in colour and
was stirred at room temperature overnight (16 h). TLC
analysis of the orange mixture indicated the presence of
starting material, so ethanol (10 mL) was added and the
reaction was stirred for a further 2 days. The mixture was
then poured into a separating funnel and the solid residue
was extracted with water (150 mL). The ethereal layer was
extracted once more with water (150 mL) and the aqueous
extracts were combined and acidified with 6 M hydrochloric
acid (140 mL). The aqueous mixture was then extracted
with ether (2£200 mL) and the ethereal extracts were
washed with brine (150 mL), dried and evaporated to give a
viscous orange viscous oil. Purification by vacuum distilla-
tion gave 40 (2.86 g, 24%) as a yellow oil, bp 1308C
(0.6 mm Hg); lit.20 bp 130–1318C (2 mm Hg) (MþNHþ4 ,
299.1059. C13H19N2O4S requires 299.1065); nmax 3400 br,
1719 cm21; dH (300 MHz) 1.25 (3H, t, J¼7 Hz, Me), 2.47
(2H, t, J¼6 Hz, 5-H2), 3.62 (2H, t, J¼6 Hz, 6-H2), 4.15 (2H,
q, J¼7 Hz, OCH2Me), 4.23 (2H, s, 2-H2), 8.50 (1H, br s,
CHOH), 14.1 (1H, br s, OH); m/z (peaks $10%) 217
(MþNHþ4 , 100%), 200 (12).
1.1.23. Methyl 4-acetylamino-2-methyl-6-oxotetrahydro-
pyran-3-carboxylate 36. To a solution of diester 31
(14 mg, 0.054 mmol) in anhydrous DCM (0.5 mL) under
argon at room temperature was added trifluoroacetic acid
(0.5 mL) and triethylsilane (29 mg, 0.25 mmol). The
mixture was stirred for 48 h, after which the reaction
appeared to be complete by TLC. Evaporation followed by
chromatography provided the title compound (2S,3R,4S)-36
(10 mg, 81%) as a yellow oil (MþHþ, 230.1024.
C10H16NO5 requires 230.1028); [a]2D2¼212^1.5 (c 2.0,
CHCl3) {lit.18 for (2R,3S,4R)-36, [a]2D0¼þ22.4 (c 1.35,
CHCl3)}; nmax 3416, 1727, 1662, 1646, 1217, 768,
750 cm21; dH (300 MHz) 1.39 (3H, d, J¼6 Hz, 2-Me),
1.96 (3H, s, MeCON), 2.56 (1H, dd, J¼6.5, 17 Hz, 5-H),
2.58 (1H, dd, J¼8, 10.5 Hz, 3-H), 3.00 (1H, dd, J¼7, 17 Hz,
5-H), 3.75 (3H, s, OMe), 4.49 (1H, dd, J¼6, 10.5 Hz, 2-H),
4.54–4.64 (1H, m, 4-H), 5.75 (1H, br s, NH);27 m/z (CI) 247
(MþNHþ4 , 96%), 230 (MþHþ, 100); m/z (EI) 230 (Mþ1,
100), 186 (22), 171 (27), 170 (100), 156 (20), 128 (70); Rf
0.20 (ethyl acetate).
1.1.24. 1,3-Dimethyl-2,4-dioxopyrimidine-5-carbalde-
hyde 37.19 To a solution of phosphorus oxychloride
(1.64 g, 10.7 mmol) in dry DMF (6 mL) at 08C was added
1,3-dimethyluracil (1.0 g, 7.1 mmol). The reaction mixture
was then heated at 908C for 1 h. The solvent was removed in
vacuo and the residue dissolved in cold water. The resulting
precipitate was collected on a filter and crystallised from
petroleum (bp 60–808C) to obtain the title compound 37
1.1.27. 1-Carbethoxy-3-formyl-5,6-dihydro-4-pyridone
41. A solution of the hydroxymethylene compound 40
(2.76 g, 13.9 mmol) in DCM (50 mL) was treated with 2,3-
dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) (0.5 g). The
mixture was stirred overnight (16 h) and a second portion of
DDQ (0.5 g) was added. The reaction was then diluted with
pentane (60 mL) and filtered. The resulting solution was
evaporated and the residue chromatographed, eluting with
petroleum–ethyl acetate (1:1). The resulting solid was
washed with a 1% solution of sodium bicarbonate, to give
the title compound 41 (387 mg, 22%) as buff-coloured
crystals, mp 74–778C (MþHþ, 198.0766. C9H12NO4 requires
198.0766); nmax (Nujol) 1741, 1667, 1574 cm21; dH
(300 MHz) 1.37 (3H, t, J¼7 Hz, Me), 2.63 (2H, t, J¼7.5 Hz,
5-H2), 4.07 (2H, t, J¼7.5 Hz, 6-H2), 4.37 (2H, q, J¼7 Hz,
OCH2Me), 8.66 (1H, s, 2-H), 9.93 (1H, s, CHO); m/z (peaks
$10%) 215 (MþNHþ4 , 100%), 198 (50), 187 (17), 170 (19).
(0.657 g, 55%) as a crystalline solid; nmax 1633, 1486 cm21
;
dH (300 MHz) 3.37 (3H, s, NMe), 3.51 (3H, s, NMe), 8.05
(1H, s, 6-H), 10.02 (1H, s, CHO); m/z 169 (MþHþ, 100%).
1.1.25. 1,3-Dimethyl-1,7,8,8a-tetrahydro-40S,50S-bis(2-
methylphenyl)spiro[pyrano[4,3-d]pyrimidine-7,20-
[1,3]dioxolan]-2,4-diones 38 and 39. To a solution of the
ketene acetal (S,S)-1a (85 mg, 0.32 mmol) in THF (5 mL) at
2158C was added the aldehyde 3719 (58 mg, 0.32 mmol).
The reaction mixture was maintained at 2158C and
monitored by TLC. After 72 h the reaction appeared to be
complete. Concentration of the reaction mixture provided a
yellow solid which was crystallised from isohexane to
obtain the title compound (8aR,40S,50S)-38 (69.5 mg, 50%)
as a white solid (d.r. 4.26:1 by HPLC; $4:1 by 300 MHz 1H
NMR) (MþHþ, 435.1919. C25H27N2O5 requires 435.1920);
nmax 1702, 1666, 1632, 1334, 1215, 1134, 1004, 902, 885,
1.1.28. 7-Ethoxy-4-oxo-3,4,8,8a-tetrahydro-2H,7H-pyr-
ano[4,3-b]pyridine-1-carboxylic acid ethyl esters 42
and 43. To a solution of the pyridone 41 (0.175 g,

P. Leeming et al. / Tetrahedron 59 (2003) 341–352
351
0.89 mmol) in DCM (20 mL) was added ethoxyethene
(1.28 g, 20 equiv.) and the mixture was stirred at room
temperature. TLC after 2 weeks indicated that the reaction
was incomplete. Ethoxyethene (2 mL) was added and after a
further 2 weeks of stirring at room temperature, TLC
showed that the reaction had gone to completion. The NMR
spectrum of the crude reaction mixture indicated that the
ratio of 42/43 was 77:23. The mixture was evaporated and
the residue purified by flash chromatography over Florisil
(15 g), eluting with petroleum–ethyl acetate (3:1), to give
the mixed cycloadducts 42 and 43 (124 mg, 52%) as a
colourless oil (MþHþ, 270.1342. C13H20NO5 requires
270.1341); nmax 1735 br, 1374, 1238 br, 1046 cm21; (42)
dH (300 MHz) 1.2–1.3 (6H, m, CO2CH2Me, OCH2Me),
1.74 (1H, apparent q, J¼ca. 12 Hz, 7b-Hax), 2.35–2.45 (2H,
m, 3-H2), 2.5–2.6 (1H, m, 8a-Heq), 3.06 (1H, ddd, J¼5,
10.5, 13.5 Hz, 2-Hax), 3.62 (1H, qd, J¼7, 9.5 Hz, OCHMe),
3.97 (1H, qd, J¼7, 9.5 Hz, OCHMe), 4.16 (2H, q, J¼7 Hz,
CO2CH2Me), 4.2–4.3 (1H, m, 2-Heq), 4.77 (1H, ddd, J¼2,
5, 11.5 Hz, 8a-H), 5.26 (1H, dd, J¼2.5, 10 Hz, 7-H), 7.36
(1H, d, J¼2 Hz, 5-H). Flash chromatography of the mixed
(3:1) cycloadducts over alumina, eluting with petroleum–
ethyl acetate (1:1), gave the title compound 43 (MþHþ,
270.1346. C13H20NO5 requires 270.1341); dH (300 MHz)
1.18 (3H, t, J¼7 Hz, OCH2Me), 1.27 (3H, t, J¼7 Hz,
CO2CH2Me), 1.74 (1H, dt, J¼ca. 3, 12 Hz, 7b-Hax), 2.35–
2.55 (3H, m, 3-H2, 7a-Heq), 3.05–3.15 (1H, m, 2-Hax), 3.59
(1H, dq, J¼9.5, 7 Hz, OCHMe), 3.82 (1H, dq, J¼9.5, 7 Hz,
OCHMe), 4.15–4.25 (2H, m, CO2CH2Me), 4.25–4.35 (1H,
m, 2-Heq), 4.80–4.90 (1H, narrow m, 8a-H), 5.23 (1H, br s,
7-H), 7.32 (1H, d, J¼2 Hz, 5-H); m/z 270 (MþHþ, 100%),
215 (35), 207 (20), 198 (21), 187 (22), 170 (28).
1.1.30. 3-Hydroxymethylene-1-p-toluenesulfonyl-4-
piperidone 46. A suspension of sodium hydride (60%
dispersion in mineral oil; 158 mg, 3.96 mmol) in ether
(30 mL) was treated with a few drops of dry ethanol. The
reaction vessel was cooled with an ice bath and treated
dropwise with a mixture of N-tosyl-4-piperidone28 (500 mg,
1.98 mmol) and ethyl formate (2.93 g, 39.5 mmol) in ether
(20 mL). The mixture became yellow in colour and was
stirred at room temperature for 64 h. Ethanol (10 mL) was
then added and the mixture stirred for a further 2 h. Water
(30 mL) was added, the aqueous phase was separated and
the organic phase was extracted again with water (30 mL).
The combined aqueous extract was acidified to pH 3 using
6 M hydrochloric acid and then extracted with DCM
(3£50 mL). The organic phase was washed with brine
(50 mL), dried and reduced in volume. The solution of 46
thus obtained was stored in the freezer until required
(MþNHþ4 , 299.1059. C13H19N2O4S requires 299.1065);
nmax 3400 br, 1719 cm21; dH (300 MHz) 2.41 (3H, s, Me),
2.53 (2H, t, J¼6 Hz, 5-H2), 3.25 (2H, t, J¼6 Hz, 6-H2), 3.84
(2H, s, 2-H2), 7.32 (2H, d, J¼8 Hz, 30-H, 50-H), 7.66 (2H, d,
J¼8 Hz, 20-H, 60-H), 8.53 (1H, s, CHOH), 14.0 (1H, br s,
OH); m/z 299 (MþNHþ4 , 30%), 189 (29), 143 (100), 128
(32), 126 (55), 118 (61).
1.1.31. 3-Formyl-5,6-dihydro-1-p-toluenesulfonyl-4-pyr-
idone 47. To a stirred solution of phenylselenenyl chloride
(398 mg, 2.08 mmol) in DCM (40 mL) at 08C was added
pyridine (172 mg, 2.17 mmol). The solution, which turned
from red to orange in colour, was stirred at 08C for 20 min
and then treated with a solution the hydroxymethylene
compound 46 (556 mg, 1.98 mmol) in DCM (4 mL). This
was stirred at 08C for 20 min. before being washed with
10% hydrochloric acid (2£30 mL). The solution was then
cooled back to 08C and treated with 30% hydrogen peroxide
(0.67 mL). Four more portions of 30% hydrogen peroxide
(each 0.67 mL) were added at intervals of 10, 20, 30 and
30 min, and the mixture was finally stirred for a further
30 min. Water (20 mL) was then added and the organic
layer was washed with saturated sodium bicarbonate
solution (3£20 mL), dried and evaporated to give the
crude title compound 47 (346 mg, 63%) as an orange oil.
Purification by chromatography over silica gel (20 g),
eluting with petroleum–ethyl acetate (1:1), resulted in
loss of material and gave a sample of the aldehyde 47
(25 mg, 4.5%) as a pale yellow oil; dH (300 MHz) 2.45 (3H,
s, Me), 2.59 (2H, t, J¼7.5 Hz, 5-H2), 3.81 (2H, t, J¼7.5 Hz,
6-H2), 7.39 (2H, d, J¼8.5 Hz, 30-H, 50-H), 7.74 (2H, d,
J¼8.5 Hz, 20-H, 60-H), 8.57 (1H, s, 2-H), 9.89 (1H, s, CHO);
m/z 297 (MþNHþ4 , 30%), 280 (MþHþ, 17), 174 (35), 143
(100), 126 (50).
1.1.29. 7-Methoxy-7-methyl-4-oxo-3,4,8,8a-tetrahydro-
2H,7H-pyrano[4,3-b]pyridine-1-carboxylic acid ethyl
ester 44 and 45. To a solution of the pyridone 41 (0.1 g,
0.51 mmol) in DCM (20 mL) was added 2-methoxypropene
(0.735 g, 10 mmol, 20 equiv.) and the mixture was stirred at
room temperature. TLC after 2 weeks indicated that the
reaction was incomplete. 2-Methoxypropene (3 mL) was
added and after a further 2 weeks of stirring at room
temperature, TLC showed that the reaction had gone to
completion. Chromatography over silica gel (50 g), eluting
with petroleum–ethyl acetate (4:1), gave the mixed
cycloadducts 44 and 45 (105 mg, 77%; ratio 3.6:1 by
NMR) as a pale yellow oil. Further chromatography, eluting
with cyclohexane–ether–DCM (2:4:1), afforded the title
compounds 44 (19 mg) and 45 (11 mg) as colourless oils;
(44) (MþHþ, 270.1332. C13H20NO5 requires 270.1341); dH
(300 MHz) 1.27 (3H, t, J¼7 Hz, CO2CH2Me), 1.47 (3H, s,
Me), 1.86 (1H, apparent t, J¼12 Hz, 7b-Hax), 2.30–2.50
(3H, m, 7a-Heq, 3-H2), 3.05–3.20 (1H, m, 2-H), 3.36 (3H, s,
OMe), 4.09–4.22 (2H, m, CO2CH2Me), 4.25–4.35 (1H, m,
2-H), 4.72 (1H, ddd, J¼2, 5, 11 Hz, 8a-H), 7.38 (1H, d,
J¼2 Hz, 5-H); m/z 270 (MþHþ, 73%), 273 (46), 256 (20),
215 (100), 198 (21); (45) (MþHþ, 270.1345. C13H20NO5
requires 270.1341); dH (300 MHz) 1.27 (3H, t, J¼7 Hz,
CO2CH2Me), 1.49 (3H, s, Me), 2.30–2.60 (4H, m, 3-H2, 7-
H2), 2.95–3.15 (1H, m, 2-H), 3.29 (3H, s, OMe), 4.1–4.25
(2H, m, CO2CH2Me), 4.25–4.35 (1H, m, 2-H), 4.83 (1H,
ddd, J¼2, 5, 11.5 Hz, 8a-H), 7.29 (1H, d, J¼2 Hz, 5-H); m/z
270 (MþHþ, 52%), 242 (100), 215 (86), 198 (33), 160 (94),
73 (27).
1.1.32. 7-Ethoxy-1-(toluene-4-sulfonyl)-1,2,3,7,8,8a-hex-
ahydropyrano[4,3-b]pyridin-4-ones 48 and 49. A solution
of the aldehyde 47 (24 mg, 0.09 mmol) in DCM (5 mL) was
treated with a large excess of ethoxyethene and the mixture
stirred at room temperature for 2 weeks. Evaporation to
dryness gave a yellow oil (36 mg) which was passed down a
plug of silica gel to give a pale yellow oil (9 mg, 30%). By
1H NMR spectroscopy the ratio of endo/exo cycloadducts
was ca. 3.5:1. The following signals are those due to the
major diastereoisomer 48; the few distinguishable peaks due
to the minor diastereoisomer 49 are marked thus ( p )

352
P. Leeming et al. / Tetrahedron 59 (2003) 341–352
(MþHþ, 352.1225. C17H22NO5S requires 352.1219); dH
(300 MHz) 1.23 (3H, t, J¼7 Hz, OCH2Me p), 1.25 (3H, t,
J¼7 Hz, OCH2Me), 1.90–2.05 (2H, m, 7b-Hax, 3-Hax), 2.16
(1H, td, J¼2.5, 17.5 Hz, 3-Heq), 2.41 (3H, s, ArMe), 2.67
(1H, ddd, J¼2.5, 5, 13 Hz, 7a-Heq), 3.34 (1H, ddd, J¼2.5,
12.5, 15 Hz, 2-Hax), 3.43 (1H, ddd, J¼2.5, 12.5, 15 Hz, 2-
Hpax), 3.63 (1H, dq, J¼9.5, 7 Hz, OCHMe), 3.86 (1H, ddd,
J¼2.5, 5, 15 Hz, 2-Heq), 3.97 (1H, dq, J¼9.5, 7 Hz,
OCHMe), 4.57 (1H, ddd, J¼2, 5, 11.5 Hz, 8a-H p ), 4.64
(1H, ddd, J¼2, 5, 11.5 Hz, 8a-H),0 5.26 0 (1H, dd, J¼2.5,
10 Hz, 7-H), 7.30 (2H, d, J¼8 Hz, 3 -H, 5 -H), 7.36 (1H, d,
J¼2 Hz, 5-H), 7.71 (2H, d, J¼8 Hz, 20-H, 60-H); m/z 369
(MþNHþ4 , 68%), 352 (65), 297 (65), 280 (100), 198 (36),
196 (42), 174 (60), 143 (38), 126 (48).
See also De Gaudenzi, L.; Apparao, S.; Schmidt, R. R.
Tetrahedron 1990, 46, 277–290, and references cited therein.
8. (a) Bayles, R.; Flynn, A. P.; Galt, R. H. B.; Kirby, S.; Turner,
R. W. Tetrahedron Lett. 1988, 29, 6341–6344. (b) Bayles, R.;
Flynn, A. P.; Galt, R. H. B.; Kirby, S.; Turner, R. W.
Tetrahedron Lett. 1988, 29, 6345–6348.
9. For an alternative approach to this objective, see (a) Sato, M.;
Kitazawa, N.; Nagashima, S.; Kaneko, C.; Inoue, N.; Furuya,
T. Tetrahedron 1991, 47, 7271–7278. (b) Sato, M.; Kitazawa,
N.; Nagashima, S.; Kano, K.; Kaneko, C. Chem. Lett. 1992,
485–488.
10. For a preliminary account of some of this work, see Ray, C. A.;
Wallace, T. W.; Ward, R. A. Tetrahedron Lett. 2000, 41,
3501–3504.
11. Kuryla, W. C.; Hyre, J. E. Organic Syntheses, Wiley: New
York, 1973; Collect. Vol. 5. pp 684–687.
12. (a) McElvain, S. M.; Curry, M. J. J. Am. Chem. Soc. 1948, 70,
3781–3786. (b) See also Diez-Barra, E.; De la Hoz, A.; Diaz-
Ortiz, A.; Prieto, P. Synlett 1992, 893–894.
Acknowledgements
We are grateful to the EPSRC and Glaxo Wellcome (now
GlaxoSmithKline) for studentships, and warmly thank Drs
Ron Galt and Tony Flynn (AstraZeneca) for the generous
provision of information and data relating to the lactone
(^)-36. We also thank Mrs Ruth Howard (Salford) for mass
spectra and Drs Mike Stuckey (Salford) and Peter Moore
(GlaxoSmithKline) for NMR measurements. We also wish
to acknowledge the use of the EPSRC’s Chemical Database
Service at Daresbury.
13. Crombie, L.; Games, D. E.; James, A. W. G. J. Chem. Soc.,
Perkin Trans. 1 1979, 464–471.
14. Claisen, L. Justus Liebigs Ann. Chem. 1897, 297, 1–98.
15. For the exploitation of this hydrolytic process as a route to diol
monoacetates, see: Zhu, P. C.; Lin, J.; Pittman, C. U. J. Org.
Chem. 1995, 60, 5729–5931.
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25. Crystallographic data (excluding structure factors) for com-
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charge, on application to CCDC, 12 Union Road, Cambridge,
CB2 1EZ, UK (fax: þ44-1223-336033 or e-mail: depos-
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