Manganese(III) acetate-mediated alkylation of β-keto esters and β-keto amides: An enantio- and diastereo-selective approach to substituted pyrrolidinones

Article abstract of DOI:10.1039/b209123b

β-Keto esters and β-keto amides can be efficiently alkylated on reaction with enol ethers and manganese(III) acetate in the presence of copper(II) acetate. These intermolecular radical addition reactions can be used to construct quaternary carbon centres in excellent yield and this method has been utilised in a diastereoselective approach to substituted pyrrolidinones.

Full text of DOI:10.1039/b209123b

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Manganese(III) acetate-mediated alkylation of ꢀ-keto esters and
ꢀ-keto amides: an enantio- and diastereo-selective approach to
substituted pyrrolidinones
Gregory Bar, Andrew F. Parsons* and C. Barry Thomas
Department of Chemistry, University of York, Heslington, York, UK YO10 5DD.
E-mail: afp2@york.ac.uk; Fax: ϩ44(01904)432516
Received 18th September 2002, Accepted 7th October 2002
First published as an Advance Article on the web 13th December 2002
β-Keto esters and β-keto amides can be efficiently alkylated on reaction with enol ethers and manganese() acetate in
the presence of copper() acetate. These intermolecular radical addition reactions can be used to construct
quaternary carbon centres in excellent yield and this method has been utilised in a diastereoselective approach to
substituted pyrrolidinones.
Introduction
A variety of organic carbonyl compounds can be oxidised by
manganese() acetate to form carbon-centred radicals.1–4 This
includes 1,3-dicarbonyl compounds such as β-keto amides and
particularly, β-keto esters. Reaction with manganese() acetate
produces (electrophilic) α-carbonyl radicals, which can add to a
number of electron-rich double bonds to form new carbon–
carbon bonds. In contrast to related tributyltin hydride-medi-
ated reactions, the resulting radical adducts are usually oxidised
by a second equivalent of manganese() acetate or an altern-
ative co-oxidant, principally copper() acetate. This can lead to
the formation of alkylcopper() intermediates, which can pro-
duce alkenes by oxidative elimination, or alternatively, carbo-
cation intermediates can be formed and these can undergo a
number of ionic reactions including deprotonation and
hydrolysis. Thus, one particularly attractive feature of this oxid-
Scheme 1
ative method of radical generation is that versatile functional
groups (e.g. alkenes or alcohols) can be introduced into the
product after carbon–carbon bond formation.
Manganese() acetate has been widely exploited in cyclis-
ation reactions1,5 and a good number of intermolecular carbon–
carbon bond forming reactions have been reported. Hence, a
range of 1,3-dicarbonyls have been shown to add to electron-
rich alkenes,6–13 alkynes14 and also enol ethers and esters.15–17
These types of reactions have employed 1,3-dicarbonyls with-
out substitution at the α-position except for an isolated report
by Corey and Ghosh.18 This work showed that ethyl 2-oxo-
cyclopentanecarboxylate 1 (and also ethyl 2-oxocyclohexane-
carboxylate) can be alkylated at the α-position on heating with
isopropenyl acetate and manganese() acetate in acetic acid
(Scheme 1). This gave diketone 2 in 64% yield, presumably via
regioselective addition of radical 3 to the enol ester, followed by
oxidation and hydrolysis of the intermediate oxonium ion 4.
With a view to developing a general approach to sterically con-
gested tricarbonyls we now report our studies on the develop-
ment of this methodology using a range of β-keto esters and
β-keto amides, including chiral pyrrolidinones.19
Fig. 1
were carried out in CH2Cl2. Keto-ester 5 was also reacted with
allyl vinyl ether or vinyl acetate in place of butyl vinyl ether. In
both cases, these reactions also produced aldehyde 6 in good
yield (83–86%). Different enol ethers can be employed and reac-
tion of 5 with ethyl (E,Z)-prop-1-enyl ether, 2-methoxypropene
or trimethyl(1-phenylvinyloxy)silane gave aldehyde 7 and
ketones 8 and 9, in 86%, 81% and 97% yields, respectively.
Aldehyde 7 was formed as a 1.3 : 1 mixture of diastereoisomers
as indicated by the 1H NMR spectrum.
Our investigations then turned to the use of alternative
β-keto esters (Fig. 2). Treatment of the cyclopentanone 1, the
cyclooctanone 10 and the cyclopentenone 11 with butyl vinyl
ether or ethyl (E,Z)-propen-1-yl ether in the presence of
manganese() acetate and copper() acetate gave the expected
aldehydes 12, 13 and 14 in 90%, 95% and 85% yield, respect-
ively. In some cases, acetal rather than aldehyde products were
isolated after column chromatography as illustrated by the
formation of acetals 17 (93%) and 18 (88%) from esters 15 and
16, respectively. These acetals can subsequently be hydrolysed
to the corresponding aldehydes on stirring overnight with silica
in dichloromethane containing a small amount of water.
Results and discussion
Our studies began by exploring the reaction of ethyl 2-methyl-
acetoacetate 5 (1 equiv.) with butyl vinyl ether (6 equiv.) in the
presence of manganese() acetate (2.3 equiv.) and copper()
acetate (0.3 equiv.). On heating overnight at 40 ЊC in CH2Cl2,
this produced the expected aldehyde 6 in an excellent 92% yield
after (silica) column chromatography (Fig. 1). When the same
reaction was carried out in glacial acetic acid (at 60 ЊC for 2–4
h) the yield was only 70–76% and so all subsequent reactions
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 3
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 3 7 3 – 3 8 0
373

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one (NaH then BnBr) followed by benzoylation at C-3
produced the chiral pyrrolidinone 21 in 57% yield as a 1.8 : 1
mixture of inseparable diastereoisomers (Scheme 3). Mangan-
Scheme 3
ese()-mediated alkylation of 21 using butyl vinyl ether in the
presence of copper() acetate (under the same conditions as for
19) gave the expected aldehyde 22 in 42% yield as a 7.1 : 1
mixture of inseparable diastereoisomers (as indicated by the 1H
NMR spectrum24). The introduction of a benzyloxymethyl
substituent had therefore resulted in a diastereoselective addi-
tion and the product was formed in a good de of 74%,
especially considering the alkylation is carried out at 40 ЊC.
Unfortunately, however, the yields were not entirely repro-
ducible and it was believed that the benzyl protecting groups
were undergoing side reactions under the oxidising conditions.
As the benzyl protecting groups were believed to be
incompatible with the reaction conditions, the corresponding
dimethylated derivative 23 was prepared (Fig. 3). In this case,
Fig. 2
Following on from the alkylation of achiral β-keto esters, we
then directed our attention to applying this methodology to
the enantio- and diastereoselective formation of quaternary
carbon centres.20 Of particular interest was the formation of
substituted pyrrolidinones and pyrrolidines. These compounds
have attracted considerable interest because of their use as syn-
thetic intermediates, chiral auxiliaries and ligands as well as the
fact that a large number of these compounds exhibit a variety
of biological activities.21 For example, Moloney and co-workers
have prepared
a range of functionalised pyrrolidinones,
from pyroglutamic acid, using ionic alkylation reactions.22
These type of reactions can however, lead to poly-alkylation,
O- rather than C-alkylation and, in some cases, racemisation
of base-sensitive chiral centres. The formation of hindered
quaternary centres can also be problematic because of steric
effects. In contrast, manganese() acetate-mediated radical
alkylations offer the potential for regioselective alkylation of
pyrrolidinones, leading to the introduction of functionalised
side chains at quaternary centres, under non-basic conditions.
Our initial studies involved the alkylation of 3-benzoyl-1-
methylpyrrolidin-2-one 19 (Scheme 2), which was prepared in
Fig. 3
reaction with butyl vinyl ether in the presence of manganese()
acetate and copper() acetate in boiling dichloromethane, pro-
duced aldehyde 24 in 58% yield as a 4 : 1 mixture of inseparable
isomers (as indicated by the 1H NMR spectrum). So even
though a relatively small methoxymethyl substituent was pres-
ent at C-5, the de of aldehyde 24 was still around 60%. In
contrast to the alkylation of 21, this reaction did give repro-
ducible results and so the alkylation of 23 was investigated
using other enol ethers. Hence, reaction with 2-methoxypro-
pene gave methyl ketone 25 in 78% yield while alkylation using
trimethyl(1-phenylvinyloxy)silane afforded phenyl ketone 26 in
81% yield. In these cases, the alkylations gave 6 : 1 and 7.3 : 1
mixtures of inseparable diastereoisomers, after column
chromatography.
This method of alkylation is also applicable to pyrrolidinone
precursors bearing different carbonyl groups at the C-3 position
(Fig. 4). Reaction of the dimethylpropionyl precursor 27 with
2-methoxypropene and trimethyl(1-phenylvinyloxy)silane gave
the expected tricarbonyls 28 and 29 in 71% and 90% yields,
respectively. A similar reaction of methyl ester 30 with trime-
thyl(1-phenylvinyloxy)silane gave the phenyl ketone 31 in an
excellent 91% yield. The diastereoselectivities of these alkyl-
ations were similar to those observed for related reactions using
the benzoyl derivative 23 (i.e. 4–8 : 1).
We also investigated the manganese()-mediated reaction of
benzoylpyrrolidinone 23 with alkenes rather than enol ethers.
On reaction of 23 with styrene (5 equiv.) in the presence of
manganese() acetate (2.3 equiv.) and copper() acetate
(0.3 equiv.) in boiling dichloromethane, this unexpectedly gave
Scheme 2
50% yield by deprotonation (using LiHMDS at Ϫ78 ЊC) and
acylation of 1-methylpyrrolidin-2-one using benzoyl chloride.
On reaction of 19 with butyl vinyl ether (5 equiv.) in the
presence of manganese() acetate (2.3 equiv.) and copper()
acetate (0.3 equiv.) in boiling dichloromethane, the desired
alkylated pyrrolidinone 20 was isolated in 70% yield after
column chromatography. N-Alkyl-β-keto amides, as well as
β-keto esters can therefore be alkylated to form sterically con-
gested quaternary centres.23 This encouraging result then led us
to explore the alkylation of related pyrrolidinones bearing a
chiral centre at the C-5 position. Hence, N- and O-benzylation
of commercially available (S)-5-(hydroxymethyl)pyrrolidin-2-
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 3 7 3 – 3 8 0
374

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Scheme 4
reaction of 34 with butyl vinyl ether in the presence of
manganese() acetate and copper() acetate in boiling di-
chloromethane, the acetate derivative 35 was produced in 22%
yield (as a single diastereoisomer) together with a mixture of
unidentifiable products in low yield. A similar result was
obtained when using α-methylstyrene (rather than butyl vinyl
ether) and acetate 35 was isolated in 33% yield. For efficient
alkylation of α-substituted β-keto amides it therefore appears
that a carbon- rather than a nitrogen-based substituent should
be present at the α-position. Further applications of this
methodology together with mechanistic studies will be the
subject of future investigations.
Fig. 4
hemiacetal 32 in a good yield of 81% (as a mixture of 2 main
diastereoisomers as indicated by the 1H NMR spectrum)
(Fig. 5). This presumably arises from reaction of an intermedi-
ate benzylic cation with water followed by cyclisation of the
resultant benzyl alcohol onto the aromatic ketone. A similar
reaction was observed using α-methylstyrene although this gave
hemiacetal 33 in a much lower yield of 14%.
Experimental
General
IR spectra were recorded on an ATI Mattson Genesis FTIR
1
spectrometer. H and 13C NMR spectra were recorded on a
Brüker AMX 300 spectrometer. The carbon spectra were
assigned using DEPT experiments. Coupling constants (J) were
recorded in Hertz to the nearest 0.5 Hz. Mass spectra were
recorded on a Fisons Instruments VG Analytical Autospec
Mass Spectrometer. The optical rotation was recorded on a
Jasco DIP-370 polarimeter (sodium D-line; 589 nm). Thin layer
chromatography (TLC) was performed on Merck aluminium-
backed silica gel plates. Compounds were visualised under a
UV lamp, using alkaline potassium permanganate solution
and/or iodine. Column chromatography was performed using
silica gel (Matrix Silica 60, 70–200 micron Fisons or ICN flash
silica 60, 32–63 microns). Optical rotations are given in 10Ϫ1 deg
Fig. 5
The efficiency and diastereoselectivities of these mangan-
ese()-mediated reactions compares favourably with the
reported ionic alkylations, which are carried out at low-temper-
ature. As for related ionic reactions, it was expected that the
major diastereoisomer from each of these reactions involved
addition of the enol ether (or alkene) to the opposite side of the
pyrrolidinone ring to the bulky methoxymethyl substituent (on
steric grounds). The 1H NMR spectra and NOESY experiments
for 31, which gave the correlations shown in Fig. 6, for the major
and minor diastereoisomers, supported this assignment.
cm2 gϪ1
.
General procedure for acylation of pyrrolidinones
To a solution of 1-methylpyrrolidin-2-one, (5S)-5-(benzyloxy-
methyl)-1-benzylpyrrolidin-2-one28
or
(5S)-5-(methoxy-
methyl)-1-methylpyrrolidin-2-one29 (0.30–1.0 g, 3.5–7.0 mmol,
1 equiv.) in dry THF (10–80 cm3) at Ϫ78 ЊC is added benzoyl
chloride or pivaloyl chloride (0.15–1.03 g, 1.06–7.34 mmol, 1.05
equiv.) followed by LiHMDS (1 M solution in dry THF; 2.2–
14.3 cm3, 2.2–14.34 mmol, 2.05 equiv.) dropwise in <5 minutes
giving a yellow solution, which is stirred at the same temper-
ature for a further 1 h. For the formation of 30, LiHMDS (1 M
solution in dry THF; 3.5 cm3, 3.5 mmol, 1 equiv.) is added to a
solution of the pyrrolidinone (0.5 g, 3.5 mmol) in THF (40 cm3)
at Ϫ78 ЊC and after 1 h at the same temperature, methyl chloro-
formate (0.33 g, 3.5 mmol, 1 equiv.) is added and the solution
stirred for 0.25 h. The reaction is then quenched by the addition
of aqueous HCl or saturated aqueous NaHCO3 (10 cm3) at
Ϫ78 ЊC and the resulting mixture is extracted with ethyl acetate
(60 cm3). Brine (10 cm3) is added to the aqueous phase, which is
extracted with ethyl acetate (3 × 30 cm3). The organic extracts
are collected and washed with saturated aqueous NaHCO3
(10 cm3), brine (10 cm3) and dried (MgSO4). Solvent evapor-
ation followed by column chromatography (silica) afforded the
acylated products 20, 21, 23, 27 and 30 (0.09–0.99 g, 13–68%) as
oils.
Fig. 6
Conclusions
Manganese() acetate can be used to promote the efficient
introduction of functionalised (aldehyde or ketone) side-chains
at the α-position of α-substituted β-keto esters and amides,
including pyrrolidinones. The approach compares favourably
with alternative metal-mediated methods of alkylation of
1,3-dicarbonyls25 and this “one-pot” synthesis also offers an
attractive alternative to the classical base-mediated alkylation
of β-keto esters and amides (which can be low yielding because
of competitive O-alkylation26,27). Good diastereoselectivities
are obtained on alkylation of pyrrolidinones at 40 ЊC and the
ability to prepare tricarbonyl derivatives by alkylation under
non-basic conditions is of particular note; this approach could
find application in the alkylation of base-sensitive pyrrol-
idinone substrates. There are limitations to the procedure, for
instance, we have found that similar alkylations are not possible
for piperazine-2,5-dione derivatives such as 34 (Scheme 4). On
3-Benzoyl-1-methylpyrrolidin-2-one (19). 49%; oil, Rf 0.3
(6 : 4, dichloromethane–ethyl acetate); νmax (CHCl3) 3014 (m),
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 3 7 3 – 3 8 0
375

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1674 (s), 1448 (w), 1265 (m) cmϪ1; δH (300 MHz, CDCl3) 8.14–
8.10 (2H, m, CH aromatics), 7.65–7.42 (3H, m, CH aromatics),
CH–C(᎐O)Ph], 28.8 (N–CH ), 25.9 (CH–CH –CH–N). Minor
᎐
3 2
diastereoisomer: δH (300 MHz, CDCl3) 8.12–8.10 (2H, m,
CH aromatics), 7.60–7.35 (3H, m, CH aromatics), 4.47 [1H, t,
4.47 (1H, dd, J = 5 and 9 Hz, O᎐C–CH–COPh), 3.65–3.57
᎐
(1H, m, CH2–CH–COPh), 3.44–3.36 (1H, m, CH2–CH–COPh),
2.87 (3H, s, N–CH3), 2.68–2.58 (1H, m, N–CH2), 2.32–
J = 7.5 Hz, O᎐C–CH–C(᎐O)Ph], 3.76–3.69 (1H, m, CH –O–
᎐ ᎐
3
CH2–CH ), 3.57–3.44 (1H, m, CH3–O–CH2–CH), 3.40–3.25
(1H, m, CH3–O–CH2–CH), 3.39 (3H, s, CH3–O–CH2–CH),
2.91 (3H, s, N–CH3), 2.39–2.33 (2H, m, CH2–CH–COPh);
2.19 (1H, m, N–CH2); δC (75 MHz, CDCl ) 196.8 (O᎐C–Ph),
᎐
3
170.5 (O᎐C–N–CH ), 136.6 (O᎐C–Cphenyl), 133.9 (2 × CH
᎐
᎐
3
aromatics), 130.0 (CH aromatic), 128.9 (2 × CH aromatics),
δC (75 MHz, CDCl ) 196.4 (O᎐C–Ph), 170.6 (O᎐C–N–CH ),
᎐ ᎐
3 3
50.9 (O᎐C–CH–COPh), 48.6 (CH–CH2–CH2–N), 30.4
136.6 (O᎐C–Cphenyl), 133.9 (2 × CH aromatics), 130.0 (CH
aromatic), 128.9 (2 × CH aromatics), 76.1 (CH3–O–CH2–CH),
᎐
᎐
(N–CH3), 22.3 (CH–CH2–CH2–N); m/z (EI) 203 (Mϩ, 28%),
105 (100), 98 (48); Found: Mϩ, 203.0945. C12H13NO2 requires
for Mϩ, 203.0946.
59.5 (CH –O–CH –CH), 58.5 (CH –O–CH –CH), 50.4 [O᎐C–
᎐
3
2
3
2
CH–C(᎐O)Ph], 29.8 (N–CH ), 25.1 (CH–CH –CH–N); m/z
᎐
3
2
(CI, NH3) 265 (M ϩ NH4ϩ, 5%), 248 (M ϩ Hϩ, 100), 105 (7);
Found: M ϩ Hϩ, 248.1284. C14H18NO3 requires for M ϩ Hϩ,
248.1287.
(5S )-3-Benzoyl-1-benzyl-5-[(benzyloxy)methyl]pyrrolidin-2-
one (21). 68%; isolated as an inseparable 2.0 : 1 mixture of
diastereoisomers as indicated by the NMR spectra; colourless
oil; Rf 0.6 (9 : 1, dichloromethane–ethyl acetate); νmax (CHCl3)
3065 (m), 3011 (s, br), 2863 (w, br), 1673 (s, br), 1449 (s), 1230
(s), 1114 (s) cmϪ1. Major diastereoisomer: δH (300 MHz, CDCl3)
8.16–8.09 (2H, m, CH aromatics), 7.61–7.16 (13H, m, CH aro-
matics), 4.90 (1H, d, J = 15 Hz, CPhenyl–CH2–N), 4.69 (1H, dd,
J = 9 and 6.5 Hz, O᎐C–CH–C᎐O), 4.45 (1H, d, J = 12 Hz,
(5S )-3-(2,2-Dimethylpropanoyl)-5-(methoxymethyl)-1-meth-
ylpyrrolidin-2-one (27). 30%; isolated as a 1.6 : 1 mixture of
inseparable diastereoisomers as indicated by the NMR spectra;
colourless oil; Rf 0.3 (6 : 4, dichloromethane–ethyl acetate); νmax
(CHCl3) 3038 (w), 3012 (m), 2971 (m), 2931 (m), 1711 (s), 1679
(s), 1228 (s) cmϪ1. Major diastereoisomer: δH (300 MHz, CDCl3)
4.16–4.00 (1H, m, O᎐C–CH–COtBu), 3.80–3.71 (1H, m, CH –
᎐
᎐
CPhenyl–CH2–O), 4.39 (1H, d, J = 12 Hz, CPhenyl–CH2–O), 4.05
(1H, d, J = 15 Hz, CPhenyl–CH2–N), 3.85–3.70 (1H, m, Ph–CH2–
O–CH2–CH ), 3.53 (1H, dd, J = 10 and 3.5 Hz, CH3–O–CH2–
CH), 3.40 (1H, dd, J = 10 and 3.5 Hz, CH3–O–CH2–CH),
᎐
3
O–CH2–CH ), 3.65–3.57 (1H, m, CH3–O–CH2–CH), 3.56–3.46
(1H, m, CH3–O–CH2–CH), 3.36 (3H, s, CH3–O–CH2–CH),
2.85 (3H, s, N–CH3), 2.35–2.21 (1H, m, CH2–CH–COtBu),
2.06–1.95 (1H, m, CH2–CH–COtBu), 1.21 [9H, s, C(CH3)3];
δC (75 MHz, CDCl ) 214.1 (O᎐C–tBu), 172.2 (O᎐C–N–CH ),
2.74–2.65 (1H, m, N–CH–CH –CH –C᎐O), 2.17–2.08 (1H, m,
᎐
2
2
N–CH–CH –CH–C᎐O); δ (75 MHz, CDCl ) 197.1 (O᎐C–Ph),
᎐
᎐
᎐
᎐
2
C
3
3
3
171.6 (O᎐C–N–CH ), 138.2 (CH –CPhenyl), 136.9 (CH2–CPhenyl),
73.3 (CH3–O–CH2–CH), 59.6 (CH3–O–CH2–CH), 58.8 (CH3–
᎐
3
2
136.7 (O᎐C–Cphenyl), 133.9 (2 × CH aromatics), 130.0 (CH
O–CH –CH), 48.5 (O᎐C–CH–COtBu), 45.2 [C(CH ) ], 28.7
᎐
᎐
2
3 3
aromatic), 129.0 (2 × CH aromatics), 128.9 (4 × CH aromat-
ics), 128.3 (3 × CH aromatics), 128.2 (3 × CH aromatics), 73.6
(Ph–CH2–O–CH2–CH), 70.2 (Ph–CH2–O–CH2–CH), 56.2
(N–CH3), 28.1 (CH–CH2–CH–N), 26.0 (3 × CH3). Minor
diastereoisomer: δ (300 MHz, CDCl ) 4.16–4.00 (1H, m, O᎐C–
᎐
H
3
CH–COtBu), 3.72–3.65 (1H, m, CH3–O–CH2–CH ), 3.56–3.46
(1H, m, CH3–O–CH2–CH), 3.45–3.36 (1H, m, CH3–O–CH2–
CH), 3.37 (3H, s, CH3–O–CH2–CH), 2.88 (3H, s, N–CH3),
2.35–2.21 (1H, m, CH2–CH–COtBu), 1.93–1.79 (1H, m, CH2–
CH–COtBu), 1.21 [9H, s, C(CH3)3]; δC (75 MHz, CDCl3) 213.5
(O᎐C–tBu), 171.8 (O᎐C–N–CH ), 75.9 (CH –O–CH –CH),
(Ph–CH2–O–CH2–CH), 50.6 (O᎐C–CH–C᎐O), 45.4 (Ph–
᎐
᎐
CH2–N), 26.1 (N–CH–CH –CH–C᎐O). Minor diastereo-
᎐
2
isomer: δH (300 MHz, CDCl3) 8.16–8.09 (2H, m, CH aromat-
ics), 7.61–7.16 (13H, m, CH aromatic), 4.86 (1H, d, J = 15 Hz,
CPhenyl–CH –N), 4.52 (1H, dd, J = 9.0 and 6.5 Hz, O᎐C–CH–C᎐
᎐
᎐
᎐
᎐
2
3
3
2
O), 4.45 (1H, d, J = 12 Hz, CPhenyl–CH2–O), 4.39 (1H, d,
59.4 (CH –O–CH –CH), 58.4 (CH –O–CH –CH), 48.6 (O᎐C–
᎐
3 2 3 2
J = 12 Hz, CPhenyl–CH2–O), 4.28 (1H, d, J = 15 Hz, CPhenyl
–
CH–COtBu), 45.2 [(C(CH3)3], 29.4 (N–CH3), 27.4 (CH–CH2–
CH–N), 26.0 (3 × CH3); m/z (CI, NH3) 228 (M ϩ Hϩ, 100%);
Found: M ϩ Hϩ, 228.1598. C12H22NO3 requires for M ϩ Hϩ,
228.1599.
CH2–N), 3.85–3.70 (1H, m, Ph–CH2–O–CH2–CH ), 3.68
(1H, dd, J = 10 and 5.5 Hz, CH3–O–CH2–CH), 3.61 (1H, dd,
J = 10 and 5.5 Hz, CH3–O–CH2–CH), 2.46–2.25 (2H, m,
N–CH–CH –CH–C᎐O); δ (75 MHz, CDCl ) 196.3 (O᎐C–Ph),
᎐
᎐
2
C
3
170.9 (O᎐C–N–CH ), 138.2 (CH –CPhenyl), 137.2 (CH2–CPhenyl),
Methyl
(5S )-5-(methoxymethyl)-1-methyl-2-oxo-3-pyrrol-
᎐
3
2
136.6 (O᎐C–Cphenyl), 133.9 (2 × CH aromatics), 130.0 (CH
idinecarboxylate (30). 13%; isolated as an inseparable 1.6 : 1
mixture of diastereoisomers as indicated by the NMR spectra;
colourless oil; Rf 0.2 (1 : 1, dichloromethane–ethyl acetate);
νmax (CHCl3) 3009 (m, br), 2955 (w, br), 2929 (w, br), 1737
᎐
aromatic), 129.0 (2 × CH aromatics), 128.7 (4 × CH aromat-
ics), 128.2 (3 × CH aromatics), 127.9 (3 × CH aromatics), 73.8
(Ph–CH2–O–CH2–CH), 60.8 (Ph–CH2–O–CH2–CH), 56.0
(Ph–CH2–O–CH2–CH), 50.5 (O᎐C–CH–C᎐O), 46.2 (Ph–
(s), 1688 (s), 1435 (m), 1403 (m), 1250 (m), 1109 (m) cmϪ1
.
᎐
᎐
CH –N), 25.2 (N–CH–CH –CH–C᎐O); m/z (CI, NH ) 400
Major diastereoisomer: δH (300 MHz, CDCl3) 3.75–3.55
᎐
2
2
3
(M ϩ Hϩ, 100%); Found: M ϩ Hϩ, 400.1911. C26H26NO3
requires for M ϩ Hϩ, 400.1913.
(4H, m, O᎐C–CH–CO CH and CH3–O–CH2–CH ), 3.51–
᎐
2
3
3.26 (6H, m, O᎐C–CH–COOCH , CH –O–CH –CH and CH –
᎐
3
3
2
3
O–CH2–CH), 2.80 (3H, s, N–CH3), 2.51–2.33 (1H, m, CH2–
CH–COOCH3), 2.15–1.92 (1H, m, CH2–CH–COOCH3);
(5S )-3-Benzoyl-5-(methoxymethyl)-1-methylpyrrolidin-2-one
(23). 57%; isolated as an inseparable 1.75 : 1 mixture of
diastereoisomers as indicated by the NMR spectra; Rf 0.4 (6 : 4,
dichloromethane–ethyl acetate); νmax (CHCl3) 3691 (w, br),
3026 (m), 2928 (m), 1674 (s, br), 1448 (m), 1402 (m), 1231 (s)
cmϪ1. Major diastereoisomer: δH (300 MHz, CDCl3) 8.12–
8.10 (2H, m, CH aromatics), 7.60–7.35 (3H, m, CH aromatics),
δ (75 MHz, CDCl ) 170.0 (O᎐C–N–CH ), 169.1 (O᎐C–OCH ),
᎐
᎐
C
3
3
3
71.8 (CH3–O–CH2–CH), 58.3 (CH3–O–CH2–CH), 57.2
(CH3–O–CH2–CH), 51.6 (O᎐C–OCH ), 46.8 (O᎐C–CH–
᎐
᎐
3
CO2CH3), 27.5 (N–CH3), 25.1 (CH–CH2–CH–N). Minor
diastereoisomer: δ (300 MHz, CDCl ) 3.75–3.55 (4H, m, O᎐C–
᎐
H
3
CH–COOCH and CH –O–CH –CH ), 3.51–3.26 (6H, m, O᎐
᎐
3
3
2
4.56 [1H, dd, J = 9 and 6 Hz, O᎐C–CH–C(᎐O)Ph], 3.83–
C–CH–COOCH3, CH3–O–CH2–CH and CH3–O–CH2–CH),
2.80 (3H, s, N–CH3), 2.33–2.23 (1H, m, CH2–CH–COOCH3),
2.15–1.92 (1H, m, CH2–CH–COOCH3); δC (75 MHz, CDCl3)
᎐
᎐
3.79 (1H, m, CH3–O–CH2–CH ), 3.57–3.44 (1H, m, CH3–O–
CH2–CH), 3.40–3.25 (1H, m, CH3–O–CH2–CH), 3.38 (3H, s,
CH3–O–CH2–CH), 2.86 (3H, s, N–CH3), 2.79–2.69 (1H,
m, CH2–CH–COPh), 2.09–2.00 (1H, m, CH2–CH–COPh);
169.7 (O᎐C–N–CH ), 168.8 (O᎐C–OCH ), 73.8 (CH –O–CH –
᎐
᎐
3
3
3
2
CH), 58.1 (CH3–O–CH2–CH), 57.0 (CH3–O–CH2–CH), 51.7
δC (75 MHz, CDCl ) 196.9 (O᎐C–Ph), 170.9 (O᎐C–N–CH ),
(O᎐C–OCH ), 46.6 (O᎐C–CH–CO CH ), 28.2 (N–CH ), 24.3
᎐ ᎐
3 2 3 3
᎐
᎐
3
3
136.8 (O᎐C–Cphenyl), 133.8 (2 × CH aromatics), 130.0 (CH
(CH–CH2–CH–N); m/z (CI, NH3) 202 (M ϩ Hϩ, 100%);
Found: M ϩ Hϩ, 202.1075. C9H16NO4 requires for M ϩ Hϩ,
202.1079.
᎐
aromatic), 128.9 (2 × CH aromatics), 73.5 (CH3–O–CH2–CH),
59.6 (CH –O–CH –CH), 58.6 (CH –O–CH –CH), 50.4 [O᎐C–
᎐
3
2
3
2
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 3 7 3 – 3 8 0
376

View Article Online
General procedure for the manganese(III) acetate-mediated
alkylations
O᎐C–CH –C), 2.34 (3H, s, CH –COCH ), 1.57 (3H, s, CH –C–
᎐
2 3 2 3
C᎐O), 1.23 (3H, t, J = 7 Hz, O–CH –CH ); δ (75 MHz, CDCl )
᎐
2
3
C
3
206.1 [CH –COCH ], 197.5 (Ph–C᎐O), 172.7 (O᎐C–O), 136.9
᎐
᎐
3
2
To a solution of the β-keto ester or β-keto amide (0.05–0.30 g,
0.20–1.50 mmol, 1 equiv.) in degassed dichloromethane (5–
10 cm3) was added the enol ether, enol ester or styrene (0.10–
1.35 g, 1.01–8.32 mmol, 5–6 equiv.) followed by manganese()
acetate dihydrate (0.12–0.93 g, 0.43–3.45 mmol, 2.1–2.3 equiv.)
and copper() acetate monohydrate (0.01–0.09 g, 0.06–0.41
mmol, 0.3 equiv.). The solution was heated to reflux overnight
(typically 18 h). Dichloromethane (40 cm3) was then added and
the resulting suspension removed by filtration. The solution
was washed with water (10 cm3), dried (MgSO4) and following
evaporation the crude product was purified using column
chromatography (silica) to give the alkylated products (0.03–
0.36 g, 42–97%) as oils.
[Cphenyl–COCH2], 133.8, 129.0, 128.4 (CH aromatics), 62.0
(O–CH2–CH3), 57.6 [O᎐C–(CH3)C–CO2], 45.0 [COCH2],
᎐
26.8 (CH3–CO–C), 21.1 (CH3–C–CO), 14.3 (O–CH2–CH3);
m/z (CI, NH3) 280 (M ϩ NH4ϩ, 57%), 263 (M ϩ Hϩ, 100);
Found: M ϩ Hϩ, 263.1286. C15H19O4 requires for M ϩ Hϩ,
263.1283.
Ethyl 1-(1-methyl-2-oxoethyl)-2-oxocyclopentanecarboxylate
(12). 90%; isolated as a 1 : 1.7 mixture of diastereoisomers as
indicated by the NMR spectra; oil; Rf 0.5 (dichloromethane);
νmax (CHCl3) 3490 (w, br), 3028 (s), 2983 (s), 2729 (w, br), 1754
(s), 1465 (s), 1403 (s), 1369 (s), 1231 (s), 1129 (s), 1025 (s) cmϪ1
.
Major diastereoisomer: δH (300 MHz, CDCl3) 9.70 (1H, s,
HC᎐O), 4.17 (2H, q, J = 7 Hz, O–CH –CH ), 3.31 (1H, q,
᎐
2
3
Ethyl 2-methyl-3-oxo-2-(2-oxoethyl)butanoate (6). 92%;
colourless oil; Rf 0.45 (7 : 3, dichloromethane–ethyl acetate);
νmax (CHCl3) 3060 (w, br), 2985 (w, br), 1786 (m), 1716 (s, br),
1461 (m), 1277 (s, br) cmϪ1; δH (300 MHz, CDCl3) 9.63 (1H, s,
J = 7.5 Hz, O᎐CH–CH–CH ), 2.65–2.35 (2H, m, CH –CH –
᎐
3
2
2
CH –C᎐O), 2.35–1.90 (4H, m, CH –CH –CH –C᎐O), 1.25 (3H,
᎐
᎐
2
2
2
2
t, J = 7.0 Hz, O–CH –CH ), 1.10 (3H, d, J = 7.5 Hz, O᎐CH–
᎐
2
3
CH–CH ); δ (75 MHz, CDCl ) 214.3 (C᎐O), 202.2 (H–C᎐O),
᎐
᎐
3
C
3
HC᎐O), 4.14 (2H, q, J = 7 Hz, O–CH –CH ), 2.93 and 2.83
᎐
2
3
170.3 (O᎐C–OC H ), 62.2 (O–CH –CH ), 61.6 (O᎐C–C–CO ),
᎐
᎐
2
5
2
3
2
(2H, 2 × d, J = 19 Hz, O᎐CH–CH –C), 2.18 (3H, s, CH –C᎐O),
᎐
᎐
2
3
49.7 (O᎐CH–CH–CH ), 38.7 (CH –CH –CH –C᎐O), 30.3,
᎐
᎐
3
2
2
2
1.44 (3H, s, CH –C–C᎐O), 1.19 (3H, t, J = 7.0 Hz, O–CH –
᎐
3
2
20.3 (CH –CH –CH –C᎐O and CH –CH –CH –C᎐O), 14.3
᎐
᎐
2
2
2
2
2
2
CH ); δ (75 MHz, CDCl ) 203.7 (CH –C᎐O), 198.2 (H–C᎐O),
᎐
᎐
3
C
3
3
(O–CH –CH ), 9.9 (O᎐CH–CH–CH ). Minor diastereoisomer:
᎐
2
3
3
170.6 (O᎐C–O), 60.9 (O–CH –CH ), 56.0 [O᎐C–(CH )C–C-
᎐
᎐
2
3
3
δH (300 MHz, CDCl ) 9.49 (1H, s, HC᎐O), 4.18 (2H, q,
᎐
3
(᎐O)O], 47.6 (O᎐CH–CH –C), 25.0 (CH –C᎐O), 19.4 (CH –
᎐
᎐
᎐
2
3
3
J = 7.0 Hz, O–CH –CH ), 3.32 (1H, q, J = 7.5 Hz, O᎐CH–CH–
᎐
2
3
ϩ
C–C᎐O), 12.9 (O–CH –CH ); m/z (CI, NH ) 203 (M ϩ NH ,
᎐
2
3
3
4
CH ), 2.65–2.35 (2H, m, CH –CH –CH –C᎐O), 2.35–1.90 (4H,
᎐
3
2
2
2
100%), 187 (M ϩ Hϩ, 85), 169 (43); Found: M ϩ Hϩ, 187.0967.
C9H15O4 requires for M ϩ Hϩ, 187.0970.
m, CH –CH –CH –C᎐O), 1.27 (3H, t, J = 7.0 Hz, O–CH –
᎐
2
2
2
2
CH ), 1.23 (3H, d, J = 7.5 Hz, O᎐CH–CH–CH ); δ (75 MHz,
᎐
3
3
C
CDCl ) 214.3 (C᎐O), 201.9 (H–C᎐O), 169.9 (O᎐C–OC H ),
᎐
᎐
᎐
3
2
5
Ethyl 2-acetyl-2,3-dimethyl-4-oxobutanoate (7). 86%; isolated
as a 1.3–1 : 1 mixture of diastereoisomers as indicated by the 1H
NMR spectra; pale yellow oil; Rf 0.5 (7 : 3, dichloromethane–
ethyl acetate); νmax (CHCl3) 3574 (w, br), 2993 (w, br), 2943 (w,
br), 1785 (s), 1723 (s), 1387 (m), 1303 (m), 1217 (m), 1116 (m),
1040 (m), 928 (m) cmϪ1; δH (300 MHz, CDCl3) 9.61, 9.60 (1H,
62.0 (O–CH –CH ), 61.4 (O᎐C–C–CO ), 51.1 (O᎐CH–CH–
᎐
᎐
2
3
2
CH ), 38.4 (CH –CH –CH –C᎐O), 30.1, 20.2 (CH –CH –
᎐
3
2
2
2
2
2
CH –C᎐O and CH –CH –CH –C᎐O), 14.3 (O–CH –CH ), 9.9
᎐
᎐
2
2
2
2
2
3
(O᎐CH–CH–CH ); m/z (CI, NH ) 230 (M ϩ NH ϩ, 100%), 213
᎐
3
3
4
(M ϩ Hϩ, 73), 195 (25); Found: M ϩ Hϩ, 213.1122. C11H17O4
requires for M ϩ Hϩ, 213.1127.
2 × s, 2 × HC᎐O), 4.15 (2H, q, J = 7 Hz, O–CH –CH ), 3.13,
᎐
2
3
3.05 (1H, 2 × q, J = 7.5 Hz, O᎐CH–CH–CH ), 2.16 (3H, s,
᎐
3
Ethyl 2-oxo-1-(2-oxoethyl)cyclooctanecarboxylate (13). 95%;
oil; Rf 0.7 (7 : 3, dichloromethane–ethyl acetate); νmax (CHCl3)
3028 (m), 2936 (m, br), 2861 (w), 1752 (s, br), 1727 (s, br),
1466 (m), 1228 (s) cmϪ1; δH (300 MHz, CDCl3) 9.70 (1H, t, J =
CH –C᎐O), 1.41, 1.36 (3H, 2 × s, CH –C–C᎐O), 1.20, 1.19 (3H,
᎐
᎐
3
3
2 × t, J = 7.0 Hz, 2 × O–CH2–CH3), 1.03, 1.01 (3H, 2 × d,
J = 7.5 Hz, O᎐CH–CH–CH ); δ (75 MHz, CDCl ) 203.8, 203.3
᎐
3
C
3
(2 × CH –C᎐O), 200.8, 200.7 (2 × H–C᎐O), 170.3, 170.1
᎐
᎐
3
1.5 Hz, HC᎐O), 4.13 (2H, q, J = 7 Hz, O–CH –CH ), 3.05 and
᎐
2
3
(2 × O᎐C–O), 61.0, 60.7 (2 × O–CH –CH ), 60.6 [O᎐C–
᎐
᎐
2
3
2.50 (2H, 2 × dd, J = 17 and 1.5 Hz, C–CH2–CHO), 2.65–2.58
(1H, m, –CHCO), 2.30–2.20 (1H, m, –CHCO), 2.10–1.10 (13H,
m, 5 × –CH2– inclusive of t, J = 7.0 Hz, O–CH2–CH3); δC (75
(CH )C–C(᎐O)O], 48.3, 48.1 (2 × O᎐CH–CH–CH ), 25.7, 25.3
᎐
᎐
3
3
(2 × CH –C᎐O), 16.5, 15.5 (2 × CH –C–C᎐O), 13.0 (O–CH –
᎐
᎐
3
3
2
CH ), 8.7, 8.4 (2 × O᎐CH–CH–CH ); m/z (CI, NH ) 201
᎐
3
3
3
MHz, CDCl ) 212.6 (C᎐O), 200.0 (H–C᎐O), 171.7 (O᎐C–
᎐
᎐
᎐
3
(M ϩ Hϩ, 100%); Found: M ϩ Hϩ, 201.1124. C10H17O4 requires
for M ϩ Hϩ, 201.1127.
OC H ), 62.3 (O–CH –CH ), 60.8 (O᎐C–C–CO ), 44.5 (O᎐
᎐
᎐
2
5
2
3
2
CH–CH2), 37.3, 30.6, 30.4, 30.2, 26.0, 22.6 (6 × –CH2–), 14.3 (2
× O–CH2–CH3); m/z (EI) 240 (Mϩ, 3%), 212 (11), 194 (21), 151
(24), 143 (13), 137 (22), 130 (17), 109 (54), 97 (64), 81 (33), 55
(100), 41 (96); Found: Mϩ, 240.1356. C13H20O4 requires for Mϩ,
240.1361.
Ethyl 2-acetyl-2-methyl-4-oxopentanoate (8). 81%; colourless
oil; Rf 0.7 (7 : 3, dichloromethane–ethyl acetate); νmax (CHCl3)
2986 (m), 1715 (s, br), 1449 (w), 1360 (m), 1278 (m), 1202 (m),
1111 (m), 1022 (m) cmϪ1; δH (300 MHz, CDCl3) 4.11 (2H, q,
J = 7 Hz, O–CH2–CH3), 3.03 and 2.95 (2H, 2 × d, J = 18.5 Hz,
Methyl 4-methoxy-2-oxo-1-(2-oxoethyl)cyclopent-3-enecarb-
oxylate (14). 85%; colourless oil; Rf 0.3 (96 : 4, dichloro-
methane–ethyl acetate); νmax (CHCl3) 3027 (w, br), 2955 (w, br),
1739 (s), 1699 (s), 1596 (s), 1360 (s), 1228 (s), 1169 (m), 993 (m)
CH CO–CH –C), 2.18 (3H, s, CH –C᎐O), 2.07 [3H, s, CH –
᎐
3
2
3
3
C(᎐O)CH ], 1.39 (3H, s, CH –C–C᎐O), 1.17 (3H, t, J = 7.0 Hz,
᎐
᎐
2
3
O–CH2–CH3); δC (75 MHz, CDCl ) 206.0, 205.3 [CH –C᎐O
᎐
3
3
cmϪ1; δ (300 MHz, CDCl ) 9.79 (1H, s, HC᎐O), 5.29 (1H, t, J =
and CH –C(᎐O)CH ], 172.4 (O᎐C–O), 61.9 (O–CH –CH ),
᎐
᎐
3
2
2
3
᎐
H
3
57.1 [O᎐C–(CH )C–CO ], 49.3 (O᎐C–CH –C), 30.5 (CH –CO–
1 Hz, HC᎐C–OCH ), 3.91 (3H, s, O᎐C–OCH ), 3.71 (3H, s,
᎐
᎐
3
2
2
3
᎐
᎐
3
3
CH ), 26.8 (CH –CO–C–CH ), 20.3 (CH –C–C᎐O), 14.3
HC᎐C–OCH ), 3.48 [1H, d, J = 19 Hz, C–CH –C(OCH )᎐C],
᎐
2
3
3
3
᎐
᎐
3
3
2
(O–CH2–CH3); m/z (CI, NH3) 201 (M ϩ Hϩ, 100%); Found:
M ϩ Hϩ, 201.1126. C10H17O4 requires for M ϩ Hϩ, 201.1127.
3.48 [1H, dd, J = 19 and 1 Hz, C–CH –C(OCH )᎐C], 2.68 (1H,
᎐
2
d, J = 18.5 Hz, O᎐CH–CH ), 2.50 (1H, dd, J =318.5 and 1 Hz,
᎐
2
O᎐CH–CH ); δ (75 MHz, CDCl ) 200.0 (C᎐C–C᎐O), 199.6
᎐
᎐
᎐
2
C
3
Ethyl 2-acetyl-2-methyl-4-oxo-4-phenylbutanoate (9). 97%;
yellow oil; Rf 0.4 (96 : 4, dichloromethane–ethyl acetate); νmax
(H–C᎐O), 191.3 (C᎐C–O–CH ), 170.3 (O᎐C–O), 101.8 (HC᎐C–
᎐ ᎐ ᎐ ᎐
3
OCH ), 59.7 (C᎐C–O–CH ), 56.1 [CH –C(CO CH )CH ], 53.5
᎐
3
3
2
2
3
2
(CHCl3) 3028 (w), 1712 (s), 1687 (s), 1230 (m), 908 (m) cmϪ1
;
(O᎐C–O–CH ), 48.5 (O᎐CH–CH ), 39.5 [C–CH –C(OCH )᎐
᎐ ᎐ ᎐
3 2 2 3
δH (300 MHz, CDCl3) 7.97–7.94 (2H, m, aromatics), 7.59–7.54
(1H, m, aromatic), 7.47–7.42 (2H, m, aromatics), 4.21 (2H, q,
J = 7 Hz, O–CH2–CH3), 3.69 and 3.62 (1H, 2 × d, J = 18.5 Hz,
C]; m/z (CI, NH3) 230 (M ϩ NH4ϩ, 47%), 213 (M ϩ Hϩ, 100);
Found: M ϩ Hϩ, 213.0760. C10H13O5 requires for M ϩ Hϩ,
213.0763.
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 3 7 3 – 3 8 0
377

View Article Online
Ethyl 2-acetyl-4-(acetyloxy)-2-chloro-4-butoxybutanoate (17).
93%; isolated as a 1 : 1 mixture of inseparable diastereoisomers
as indicated by the NMR spectra; colourless oil; Rf 0.8 (99 : 1,
dichloromethane–ethyl acetate); νmax (CHCl3) 2961 (w, br), 2938
(w, br), 2874 (w, br), 1734 (s), 1239 (m), 1239 (m), 1087 (m),
1012 (m), 801 (m) cmϪ1; δH (300 MHz, CDCl3) (1 : 1 mixture of
diastereoisomers) 6.04–5.98 (1H, m, AcO–CH–COBu), 4.25–
4.11 (2H, m, O–CH2–CH3), 3.60–3.50 and 3.47–3.37 [2H, 2 ×
m, CH–O–CH2–(CH2)2–CH3], 2.70–2.39 (2H, m, C–CH2–CH–),
Hz, C–CH –C–C(᎐O)Ph], 2.72 (1H, dd, J = 13 and 7.5 Hz, N–
᎐
2
CH–CH –CH–C᎐O), 2.60 [1H, d, J = 16.5 Hz, C–CH –C–
᎐
2
2
C(᎐O)Ph], 2.17 (1H, dd, J = 13 and 7.5 Hz, N–CH–CH –CH–
᎐
2
C᎐O); δ (75 MHz, CDCl ) 198.7 (O᎐CH), 197.3 (O᎐C–Ph),
᎐
᎐
᎐
C
3
172.7 (O᎐C–N–CH ), 136.3 (CH –CPhenyl), 135.0 (CH2–CPhenyl),
᎐
3
2
133.5 (O᎐C–CPhenyl), 131.8, 128.4, 127.8, 127.5, 127.3, 127.2,
᎐
127.1, 126.8 (CH aromatics), 72.4 (Ph–CH2–O–CH2–CH),
67.6 (Ph–CH –O–CH –CH), 58.0 (O᎐C–C–C᎐O), 54.0 (Ph–
᎐
᎐
2
2
CH2–O–CH2–CH), 45.5 (CH2CHO), 44.3 (Ph–CH2–N), 30.6
2.26 and 2.21 (3H, s, CH –C᎐O), 2.00 and 1.99 (3H, s, CH –
(N–CH–CH –C–C᎐O); m/z (CI, NH ) 442 (M ϩ Hϩ, 100%);
᎐
᎐
3
3
2
3
CO2), 1.55–1.35 (2H, m, CH2–CH2–CH2), 1.33–1.15 (5H, m,
CH2–CH2–CH2 and OCH2CH3), 0.82 (3H, br t, J = 7.5 Hz, O–
CH2–CH2–CH2–CH3); δC (75 MHz, CDCl3) (1 : 1 mixture of
Found: M ϩ Hϩ, 442.2026. C28H28NO4 requires for M ϩ Hϩ,
442.2018.
The presence of the minor isomer was indicated from the 1H
diastereoisomers) 197.2, 196.0 (2 × CH –C᎐O), 170.6 [2 × CH –
and 13C NMR spectra: δH (300 MHz, CDCl ) 9.65 (1H, s, O᎐
᎐
᎐
3
3
3
C(᎐O)O–], 167.1, 166.7 (2 × O᎐C–OC H ), 95.9, 95.3 (BuO–
CH ); δC (75 MHz, CDCl ) 198.8 (O᎐CH), 196.8 (O᎐C–Ph),
᎐ ᎐
3
᎐
᎐
2
5
CH–OAc), 73.0, 72.8 [O–CH –(CH ) –CH ], 70.5, 70.2 (2 × O᎐
171.6 (O᎐C–N–CH ), 72.2 (Ph–CH –O–CH –CH), 57.7 (O᎐C–
᎐ ᎐
3 2 2
᎐
2
2
2
3
C–C–Cl), 63.5, 63.4 (2 × O–CH2–CH3), 41.0, 41.7 (2 × C–
CH –CH–), 31.6, 31.5 (2 × –CH –), 26.2, 26.1 (2 × CH –C᎐O–
C–C᎐O), 54.9 (Ph–CH –O–CH –CH), 30.9 (N–CH–CH –C–
᎐
2 2 2
C᎐O).
᎐
᎐
2
2
3
C–Cl), 24.7, 24.6 [2 × CH –C(᎐O)O–], 21.4 (O–CH –CH ),
᎐
3
2
3
19.5, 19.3 (2 × –CH2–), 14.1, 14.0 [2 × O–CH2–(CH2)2–CH3];
m/z (CI, NH3) 340 (35M ϩ NH4ϩ, 1%), 263 (100), 229 (20).
2-[(5S)-3-Benzoyl-5-(methoxymethyl)-1-methyl-2-oxopyrrol-
idin-3-yl]acetaldehyde (24). 58%; 4 : 1 mixture of inseparable
diastereoisomers as indicated by the 13C NMR spectrum; oil; Rf
0.2 (6 : 4, dichloromethane–ethyl acetate); νmax (CHCl3) 3008 (w,
br), 2929 (w, br), 2880 (w, br), 1692 (s), 1401 (w), 1262 (w), 1129
(w) cmϪ1. Major diastereoisomer: δH (300 MHz, CDCl3) 9.74
1-Butoxy-2-(2,2,5-trimethyl-4,6-dioxo-1,3-dioxan-5-yl)ethyl
acetate (18). 88%; colourless oil; Rf 0.3 (96 : 4, dichloro-
methane–ethyl acetate); νmax (CHCl3) 3027 (s), 2961 (s, br), 2875
(s, br), 1752 (s, br), 1382 (s, br), 1323 (s, br), 1202 (s, br), 1154
(s, br), 1010 (s, br) cmϪ1; δH (300 MHz, CDCl3) 5.75 (1H,
t, J = 5 Hz, AcO–CH–COBu), 3.51 and 3.35 [2H, 2 × dt,
J = 9.5 and 7.5 Hz, CH–O–CH2–(CH2)2–CH3], 2.50 and 2.43
(2H, 2 × dd, J = 14 and 5 Hz, C–CH2–CH–), 1.98 (3H, s, CH3–
CO2), 1.71 (3H, s, CH3–C–CH3), 1.69 (3H, s, CH3–C–CH3),
(1H, br s, O᎐C–H ), 7.89–7.85 (2H, m, CH aromatics), 7.44–
᎐
7.30 (3H, m, CH aromatics), 3.79–3.65 (1H, m, CH3–O–CH2–
CH ), 3.57 (1H, dd, J = 10.5 and 3.5 Hz, CH3–O–CH2–CH),
3.37 (1H, dd, J = 10.5 and 4.5 Hz, CH3–O–CH2–CH), 3.30 (3H,
s, CH –O–CH –CH), 3.14 (1H, dd, J = 17 and 1 Hz, O᎐CH–
᎐
3
2
CH2–C), 2.91 (3H, s, CH3–N), 2.71 (1H, dd, J = 17 and 1 Hz,
1.56 (3H, s, CH –C–C᎐O), 1.52–1.40 and 1.31–1.16 (2 × 2H, m,
O᎐CH–CH –C), 2.61 (1H, dd, J = 13.5 and 7 Hz, N–CH–CH –
᎐
᎐
3
2
2
–CH2–CH2–CH2–CH3), 0.82 (3H, t, J = 7.5 Hz, CH2–CH3);
C–C᎐O), 2.21 (1H, dd, J = 13.5 and 7 Hz, N–CH–CH –C–C᎐
᎐ ᎐
2
O); δC (75 MHz, CDCl ) 198.7 (O᎐C–H), 197.2 (O᎐C–Ph),
᎐ ᎐
3
δC (75 MHz, CDCl ) 170.7 [CH –C(᎐O)–O], 169.8 and 169.5
᎐
3
3
(2 × CO2), 105.6 (CH3–C–CH3), 95.2 (AcO–CH–COBu), 69.9
(O–CH –CH –CH –CH ), 45.3 (CH –C–C᎐O), 43.8 (C–CH –
172.1 (O᎐C–N–CH ), 134.1 (O᎐C–CPhenyl), 131.6 (CH aro-
᎐ ᎐
3
matic), 128.2 (2 × CH aromatics), 127.3 (2 × CH aromatics),
71.5 (CH –O–CH –CH), 58.2 (CH –O–CH –CH), 57.7 (O᎐C–
᎐
2
2
2
3
3
2
CH), 31.6 (O–CH2–CH2–CH2–CH3), 30.1 and 28.6 (CH3–C–
CH ), 26.3 (CH –C–C᎐O), 21.3 (CH –CO ), 19.3 (O–CH –
᎐
3
2
3
2
C–C᎐O), 56.5 (CH O–CH ), 46.4 (CH –CHO), 30.9 (N–CH–
᎐
᎐
3
3
3
2
2
3
2
2
CH2–CH2–CH3), 14.1 (O–CH2–CH2–CH2–CH3); m/z (CI,
CH –C–C᎐O), 27.9 (N–CH ); m/z (CI, NH ) 290 (M ϩ Hϩ,
᎐
2 3 3
NH3) 334 (M ϩ NH4ϩ, 7%), 216 (100); Found: M ϩ NH4
334.1866. C15H28NO7 requires for M ϩ NH4ϩ, 334.1865.
,
100%); Found: M ϩ Hϩ, 290.1392. C16H20NO4 requires for
M ϩ Hϩ, 290.1392.
ϩ
The presence of the minor isomer was indicated from the 1H
2-(3-Benzoyl-1-methyl-2-oxopyrrolidin-3-yl)acetaldehyde
and 13C NMR spectra: δ (300 MHz, CDCl ) 9.63 (1H, br s, O᎐
᎐
H
3
(20). 70%; oil, Rf 0.05 (9 : 1, dichloromethane–ethyl acetate);
νmax (CHCl3) 3583 (w, br), 3027 (m, br), 2957 (m, br), 2877 (w,
br), 1723 (m), 1673 (s), 1272 (m, br) cmϪ1; δH (300 MHz, CDCl3)
CH ), 7.75–7.72 (2H, m, CH aromatics), 1.84 (1H, dd, J = 13
and 6.5 Hz, N–CH–CH –C–C᎐O); δ (75 MHz, CDCl ) 198.7
᎐
2
C
3
(O᎐C–H), 197.8 (O᎐C–Ph), 171.0 (O᎐C–N–CH ), 135.9 (O᎐C–
᎐
᎐
᎐
᎐
3
9.66 (1H, s, O᎐CH ), 7.78–7.75 (2H, m, CH aromatics), 7.49–
CPhenyl), 131.0 (CH aromatic), 127.4 (2 × CH aromatics), 127.1
(2 × CH aromatics), 71.2 (CH3–O–CH2–CH), 57.8 (CH3–O–
᎐
7.09 (3H, m, CH aromatics), 3.51–3.32 (3H, m, N–CH2–CH2–C
and C–CH–CHO), 2.99–2.72 (5H, m, N–CH3, C–CH–CHO
and N–CH2–CH–C), 2.09–1.99 (1H, m, N–CH2–CH–C); δC (75
CH2–CH), 57.7 (O᎐C–C–C᎐O), 56.6 (CH3O–CH2), 48.7
᎐
᎐
(CH –CHO), 31.8 (N–CH–CH –C–C᎐O), 27.6 (N–CH ).
᎐
2
2
3
MHz, CDCl ) 198.2 (O᎐C–H), 197.7 (O᎐C–Ph), 170.9 (O᎐C–
᎐
᎐
᎐
3
N–CH ), 135.6 (O᎐C–Cphenyl), 131.2 (CH aromatic), 127.4
(5S )-3-Benzoyl-5-(methoxymethyl)-1-methyl-3-(2-oxopropyl)-
pyrrolidin-2-one (25). 78%; isolated as a 6 : 1 mixture of
inseparable diastereoisomers as indicated by the 13C NMR
spectrum; oil, Rf 0.3 (6 : 4, dichloromethane–ethyl acetate); νmax
(CHCl3) 3055 (w), 3012 (s, br), 2929 (m), 1691 (s), 1674 (s), 1402
(m), 1229 (s) cmϪ1. Major diastereoisomer: δH (300 MHz,
CDCl3) 7.90–7.72 (1H, m, CH aromatic), 7.49–7.21 (4H, CH
aromatics), 3.74–3.63 (1H, m, CH3–O–CH2–CH ), 3.52–3.46
(3H, m, CH3–O–CH2–CH and CH3–CO–CH2–C), 3.27 (3H, s,
CH3–O–CH2–CH), 2.89 (3H, s, CH3–N), 2.73 (1H, d, J = 18 Hz,
CH3–CO–CH2–C), 2.59 (1H, dd, J = 14 and 6 Hz, N–CH–CH2–
᎐
3
(2 × CH aromatics), 127.3 (2 × CH aromatics), 57.8 (O᎐C–C–
᎐
COPh), 47.7 (C–CH –C᎐O), 46.2 (C–CH –CH –N), 29.4
᎐
2
2
2
(N–CH3), 28.5 (CH–CH2–CH2–N); m/z (EI) 246 (M ϩ Hϩ,
100%), 204 (32); Found: M ϩ Hϩ, 246.1133. C14H16NO3
requires for M ϩ Hϩ, 246.1131.
2-[(5S)-3-Benzoyl-5-(benzyloxymethyl)-1-benzyl-2-oxopyrrol-
idin-3-yl]acetaldehyde (22). 42%; 7.1 : 1 mixture of insepar-
1
able diastereoisomers as indicated by the H NMR spectrum;
colourless oil; Rf 0.4 (9 : 1, dichloromethane–ethyl acetate); νmax
(CHCl3) 3026 (s), 2866 (w, br), 1692 (s, br), 1447 (w), 1258 (w,
br), 1103 (w, br) cmϪ1. Major diastereoisomer: δH (300 MHz,
C–C᎐O), 2.32 (1H, dd, J = 14 and 8.5 Hz, N–CH–CH –C–C᎐
᎐
᎐
2
O), 2.04 (3H, s, CH3–CO–CH2–C); δC (75 MHz, CDCl3) 205.0
(CH –CO–CH –C), 198.1 (O᎐C–Ph), 172.1 (O᎐C–N–CH ),
CDCl ) 9.78 (1H, br s, O᎐CH ), 7.91–7.88 (2H, m, CH aromat-
᎐
᎐
᎐
3
3
2
3
ics), 7.60–6.90 (13H, m, CH aromatic), 4.95 (1H, d, J = 15 Hz,
CPhenyl–CH2–N), 4.36 (1H, d, J = 12 Hz, CPhenyl–CH2–O), 4.32
(1H, d, J = 12 Hz, CPhenyl–CH2–O), 4.06 (1H, d, J = 15 Hz,
CPhenyl–CH2–N), 3.70–3.55 (1H, m, Ph–CH2–O–CH2–CH ),
3.45–3.30 (2H, m, Ph–CH2–O–CH2–CH), 3.07 [1H, d, J = 16.5
135.5 (O᎐C–CPhenyl), 130.9 (CH aromatic), 127.8 (2 × CH aro-
matics), 127.1 (2 × CH aromatics), 72.8 (CH3–O–CH2–CH),
᎐
59.4 (O᎐C–C–C᎐O), 58.3 (CH –CO–CH ), 58.1 (CH –O–CH –
᎐
᎐
2
3
3
2
CH), 56.6 (CH3–O–CH2–CH), 46.7 (CH2–CO–CH3), 30.9
(N–CH–CH –C–C᎐O), 28.4 (N–CH ); m/z (CI, NH ) 304
᎐
2
3
3
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 3 7 3 – 3 8 0
378

View Article Online
(M ϩ Hϩ, 100%); Found: M ϩ Hϩ, 304.1553. C17H22NO4
requires for M ϩ Hϩ, 304.1549.
The presence of the minor diastereoisomer was indicated by
the 1H and 13C NMR spectra: δH (300 MHz, CDCl3) 2.59–2.37
(2H, br m, N–CH–CH2–C), 1.13 [9H, s C(CH3)3]; δC (75 MHz,
The presence of the minor isomer was indicated from the 1H
and 13C NMR spectra: δH (300 MHz, CDCl3) 7.75–7.72 (1H, m,
CH aromatic), 2.17 (1H, dd J = 14 and 6 Hz, N–CH–CH2–C–
CDCl ) 209.0 [COC(CH ) ], 205.8 (CH COCH ), 171.9 (O᎐C–
᎐
3
3
3
2
3
N), 72.9 (CH3–O–CH2–CH), 44.1 (CH2CO), 29.9 (N–CH–
CH –C–C᎐O), 27.5 (N–CH ), 27.0 [C(CH ) ].
C᎐O); δ (75 MHz, CDCl3) 205.0 (CH3–CO–CH2–C), 198.6
᎐
᎐
C
2
3
3 3
(O᎐C–Ph), 170.2 (O᎐C–N–CH ), 136.9 (O᎐C–CPhenyl), 131.9
᎐
᎐
᎐
3
(CH aromatic), 127.8 (2 × CH aromatics), 127.1 (2 × CH aro-
matics), 71.5 (CH –O–CH –CH), 59.4 (O᎐C–C–C᎐O), 58.5
(CH2–CO–CH3), 58.1 (CH3–O–CH2–CH), 56.7 (CH3–O–
(5S )-3-(2,2-Dimethylpropanoyl)-5-(methoxymethyl)-1-methyl-
3-(2-oxo-2-phenylethyl)pyrrolidin-2-one (29). 90%; isolated as an
8 : 1 mixture of inseparable isomers as indicated by the H
᎐
᎐
3
2
1
CH –CH), 46.7 (CH –CO–CH ), 32.3 (N–CH–CH –C–C᎐O),
27.6 (N–CH3).
NMR spectrum; oil; Rf 0.4 (9 : 1, dichloromethane–ethyl acet-
ate); νmax (CHCl3) 3013 (w, br), 1695 (s), 1449 (m), 1401 (m),
1228 (s) cmϪ1. Major diastereoisomer: δH (300 MHz, CDCl3)
7.86–7.84 (2H, m, CH aromatics), 7.49–7.43 (1H, m, CH aro-
matic), 7.37–7.32 (2H, m, CH aromatics), 3.82 (1H, d, J = 17.5
Hz, Ph–CO–CH2–C), 3.61–3.51 (2H, m, CH3–O–CH–CH and
CH3–O–CH2–CH ), 3.40 (1H, dd, J = 10 and 4.5 Hz, CH3–O–
CH–CH), 3.30 (3H, s, CH3–O–CH2–CH), 2.95 (1H, d, J = 17.5
Hz, Ph–CO–CH2–C), 2.80 (3H, s, CH3–N), 2.66 (1H, dd, J = 14
᎐
2
2
3
2
(5S )-3-Benzoyl-5-(methoxymethyl)-1-methyl-3-(2-oxo-2-phe-
nylethyl)pyrrolidin-2-one (26). 81%; isolated as a 7.3 : 1 mixture
of inseparable isomers as indicated by the NMR spectra; oil; Rf
0.5 (7 : 3, dichloromethane–ethyl acetate); νmax (CHCl3) 3059 (w,
br), 3026 (m), 2927 (w, br), 1685 (s), 1597 (w), 1448 (m), 1402
(w), 1263 (m), 1231 (m) cmϪ1. Major diastereoisomer: δH (300
MHz, CDCl3) 8.10–7.82 (2H, m, CH aromatics), 7.61–7.32
(8H, m, CH aromatics), 4.15 (1H, d, J = 20 Hz, Ph–CO–CH2–
C), 3.80–3.71 (1H, m, CH3–O–CH2–CH ), 3.59 (1H, dd, J = 11
and 4.5 Hz, CH3–O–CH2–CH), 3.49 (1H, dd, J = 11 and 6.5 Hz,
CH3–O–CH2–CH), 3.39 (1H, d, J = 20 Hz, Ph–CO–CH2–C),
3.35 (3H, s, CH3–O–CH2–CH), 2.97 (3H, s, CH3–N), 2.80 (1H,
and 8 Hz, N–CH–CH –C–C᎐O), 2.42 (1H, dd, J = 14 and 8 Hz,
᎐
2
N–CH–CH –C–C᎐O), 1.19 [9H, s, C(CH ) ]; δ (75 MHz,
᎐
2
3
3
C
CDCl ) 210.9 [O᎐C–C(CH ) ], 198.0 (CH –COPh), 174.4 (O᎐
᎐
᎐
3
3
3
2
C–N–CH3), 137.3 (CH2–COCPhenyl), 133.6 (CH aromatic),
128.9 (2 × CH aromatics), 128.8 (2 × CH aromatics), 73.4
(CH –O–CH –CH), 60.3 (O᎐C–C–C᎐O), 59.5 (CH –O–CH –
᎐
᎐
3
2
3
2
dd, J = 15 and 6 Hz, N–CH–CH –C–C᎐O), 2.36 (1H, dd, J = 15
CH), 57.8 (CH3–O–CH2–CH), 46.1 [C(CH3)3], 43.0 (CH2–CO–
᎐
2
and 9 Hz, N–CH–CH –C–C᎐O); δ (75 MHz, CDCl3) 199.9
Ph), 31.5 (N–CH–CH –C–C᎐O), 29.1 (N–CH3), 28.2
᎐
᎐
2
C
2
(CH –COPh), 197.8 (O᎐C–Ph), 173.7 (O᎐C–N–CH ), 137.6
[C(CH3)3]; m/z (CI, NH3) 346 (M ϩ Hϩ, 25%), 228 (M ϩ Hϩ–
CH2COPh, 100); Found: M ϩ Hϩ, 346.2017. C20H28NO4
requires for M ϩ Hϩ, 346.2018.
᎐
᎐
2
3
(CH2–COCPhenyl), 137.2 (O᎐C–CPhenyl), 134.0 (CH aromatic),
᎐
132.3 (CH aromatic), 129.4 (2 × CH aromatics), 129.2 (2 × CH
aromatics), 128.7 (4 × CH aromatics), 75.0 (CH3–O–CH2–
CH), 59.9 (CH –O–CH –CH), 59.4 (O᎐C–C–C᎐O), 58.5 (CH –
The presence of the minor diastereoisomer was indicated by
the 1H and 13C NMR spectra: δH (300 MHz, CDCl3) 8.00–7.98
(2H, m, CH aromatics), 7.49–7.43 (1H, m, CH aromatic), 7.37–
7.32 (2H, m, CH aromatics), 4.06 (1H, d, J = 17.5 Hz, Ph–CO–
CH–C), 3.61–3.51 (2H, m, CH3–O–CH–CH and CH3–O–CH2–
CH ), 3.40 (1H, dd, J = 10 and 4.5 Hz, CH3–O–CH–CH), 3.30
(3H, s, CH3–O–CH2–CH), 3.03 (1H, d, J = 17.5 Hz, Ph–CO–
᎐
᎐
3
2
3
O–CH2–CH), 44.9 (CH2–CO–Ph), 33.0 (N–CH–CH2–C–CO),
30.2 (N–CH3). Minor diastereoisomer: δH (300 MHz, CDCl3)
8.10–7.82 (2H, m, CH aromatics), 7.61–7.32 (8H, m, CH aro-
matics), 4.42 (1H, d, J = 20 Hz, Ph–CO–CH2–C), 3.92–3.84
(1H, m, CH3–O–CH2–CH ), 3.59 (1H, dd, J = 11 and 4.5 Hz,
CH3–O–CH2–CH), 3.49 (1H, dd, J = 11 and 6.5 Hz, CH3–O–
CH2–CH), 3.43 (1H, d, J = 20 Hz, Ph–CO–CH2–C), 3.32 (3H, s,
CH3–O–CH2–CH), 3.17 (1H, dd, J = 15 and 9 Hz, N–CH–
CH–C), 3.02 (1H, dd, J = 15 and 5 Hz, N–CH–CH–C–C᎐O),
᎐
2.82 (3H, s, CH3–N), 2.08 (1H, dd, J = 15 and 5 Hz, N–CH–
CH–C–C᎐O), 1.16 [9H, s, C(CH ) ]; δ (75 MHz, CDCl ) 210.0
᎐
3
3
C
3
CH –C–C᎐O), 2.94 (3H, s, CH –N), 1.84 (1H, dd, J = 15 and 8
[O᎐C–C(CH ) ], 198.1 (CH –COPh), 57.9 (CH –O–CH –CH),
᎐
3 3 2 3 2
46.0 [C(CH3)3], 43.0 (CH2–CO–Ph), 28.5 [C(CH3)3].
᎐
2
3
Hz, N–CH–CH –C–C᎐O); δ (75 MHz, CDCl3) 199.9 (CH2–
᎐
2
C
COPh), 197.8 (O᎐C–Ph), 173.7 (O᎐C–N–CH ), 137.6 (CH –
᎐
᎐
3
2
COCPhenyl), 137.2 (O᎐C–CPhenyl), 134.0 (CH aromatic), 131.8
(CH aromatic), 129.4 (2 × CH aromatics), 129.2 (2 × CH aro-
matics), 128.7 (4 × CH aromatics), 73.2 (CH3–O–CH2–CH),
Methyl (5S )-5-(methoxymethyl)-1-methyl-2-oxo-3-(2-oxo-2-
phenylethyl)pyrrolidine-3-carboxylate (31). 91%; isolated as a
5.6 : 1 mixture of inseparable isomers as indicated by the NMR
spectra; colourless oil; Rf 0.45 (1 : 1, dichloromethane–ethyl
acetate); νmax (CHCl3) 3693 (w, br), 3008 (m, br), 1736 (s), 1686
(s), 1231 (w) cmϪ1. Major diastereoisomer: δH (300 MHz,
CDCl3) 7.88–7.85 (2H, m, CH aromatics), 7.52 (1H, m, CH
aromatic), 7.40–7.35 (2H, m, CH aromatics), 4.01 (1H, d,
᎐
59.7 (CH –O–CH –CH), 59.4 (O᎐C–C–C᎐O), 58.3 (CH –O–
᎐
᎐
3
2
3
CH –CH), 46.7 (CH –CO–Ph), 34.4 (N–CH–CH –C–C᎐O),
᎐
2
2
2
29.3 (N–CH3); m/z (CI, NH3) 366 (M ϩ Hϩ, 100%); Found:
M ϩ Hϩ, 366.1706. C22H24NO4 requires for M ϩ Hϩ, 366.1705.
(5S )-3-(2,2-Dimethylpropanoyl)-5-(methoxymethyl)-1-methyl-
3-(2-oxopropyl)pyrrolidin-2-one (28). 71%; isolated as a 4 : 1
mixture of inseparable isomers as indicated by the NMR spec-
tra; pale yellow oil; Rf 0.3 (7 : 3 dichloromethane–ethyl acetate);
νmax (CHCl3) 2970 (m, br), 2930 (w, br), 2253 (m), 1699 (s), 1682
(s), 1475 (m, br), 1397 (m, br) cmϪ1. Major diastereoisomer:
δH (300 MHz, CDCl3) 3.54 (2H, m, CH3–CO–CH2–C and CH3–
O–CH2–CH ), 3.45–3.37 (1H, m, CH3–O–CH2–CH), 3.33–3.25
(4H, m, CH3–O–CH2–CH and CH3–O–CH2–CH), 3.11 (1H, d,
J = 17 Hz, CH3–CO–CH2–C), 2.80 (3H, s, CH3–N), 2.59–
2.37 (2H, br m, N–CH–CH2–C–CO), 2.13 (3H, s, CH3–CO–
CH2–C), 1.15 [9H, s, C(CH3)3]; δC (75 MHz, CDCl3) 209.9
J = 18.5 Hz, Ph–CO–CH –C), 3.70–3.55 (5H, m, O᎐C–OCH ,
᎐
2 3
CH3–O–CH2–CH and CH3–O–CH–CH), 3.48 (1H, m, CH3–O–
CH–CH), 3.31 (3H, s, CH3–O–CH2–CH), 3.16 (1H, d, J = 18.5
Hz, Ph–CO–CH2–C), 2.90 (3H, s, CH3–N), 2.62 (1H, dd, J =
14 and 4 Hz, N–CH–CH –C–C᎐O), 2.62 (1H, dd, J = 14 and
᎐
2
9 Hz, N–CH–CH –C–C᎐O); δ (75 MHz, CDCl3) 196.0
᎐
2
C
(CH –COPh), 170.7 (O᎐C–N–CH ), 170.5 (O᎐C–OCH ), 135.3
᎐
᎐
2
3
3
(CH2–COCPhenyl), 132.5 (CH aromatic), 127.7 (2 × CH aromat-
ics), 127.3 (2 × CH aromatics), 74.8 (CH3–O–CH2–CH), 58.1
(O᎐C–C–C᎐O), 56.5 (CH –O–CH –CH), 52.0 (O᎐C–OCH ),
᎐
᎐
᎐
3
2
3
51.9 (CH3–O–CH2–CH), 43.4 (CH2–CO–Ph), 30.9 (N–CH–
CH –C–C᎐O), 29.0 (N–CH ). Minor diastereoisomer: δ (300
᎐
2
3
H
[OC–C(CH ) ], 205.4 (CH –COCH ), 172.8 (O᎐C–N–CH ),
MHz, CDCl3) 7.99–7.98 (2H, m, CH aromatics), 7.52 (1H, br s,
CH aromatic), 7.40–7.35 (2H, m, CH aromatics), 4.15 (1H, d,
J = 18.5 Hz, Ph–CO–CH2–C), 3.89–3.79 (1H, m, CH3–O–CH2–
᎐
3
3
2
3
3
71.8 (CH –O–CH –CH), 59.1 (CH –C᎐O), 58.1 (O᎐C–C–C᎐
᎐
᎐
᎐
3
2
3
O), 56.8 (CH3–O–CH2–CH), 56.4 (CH3–O–CH2–CH), 45.2
[C(CH ) ], 44.5 (CH –CO), 29.5 (N–CH–CH –C–C᎐O), 27.4
CH ), 3.70–3.55 (4H, m, O᎐C–OCH and CH –O–CH–CH),
᎐
3 3
᎐
3
3
2
2
(N–CH3), 26.7 [C(CH3)3]; m/z (CI, NH3) 284 (M ϩ Hϩ, 100%),
228 (M ϩ Hϩ Ϫ CH2COMe, 40); Found: M ϩ Hϩ, 284.1861.
C15H26NO4 requires for M ϩ Hϩ, 284.1862.
3.48 (1H, m, CH3–O–CH–CH), 3.28 (3H, s, CH3–O–CH2–CH),
3.15 (1H, d, J = 18.5 Hz, Ph–CO–CH2–C), 3.04 (1H, dd,
J = 14 and 8 Hz, N–CH–CH–C–C᎐O), 2.84 (3H, s, CH –N),
᎐
3
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 3 7 3 – 3 8 0
379

View Article Online
1.68 (1H, dd, J = 14 and 8 Hz, N–CH–CH–C–C᎐O); δ (75
᎐
References
C
MHz, CDCl ) 196.3 (CH –COPh), 170.6 (O᎐C–N–CH ), 170.4
᎐
3
2
3
1 B. B. Snider, Chem. Rev., 1996, 96, 339.
2 T. Linker, J. Prakt. Chem., 1997, 339, 488.
3 (a) G. G. Melikyan, Aldrichimica Acta, 1998, 31, 50; (b) G. G.
Melikyan, Organic Reactions, ed., L. A. Paquette, John Wiley,
New York, 1997, 49, 427.
(O᎐C–OCH ), 135.2 (CH –COCPhenyl), 132.4 (CH aromatic),
᎐
3
2
127.7 (2 × CH aromatics), 127.0 (2 × CH aromatics), 71.4
(CH –O–CH –CH), 58.1 (O᎐C–C–C᎐O), 56.6 (CH –O–CH –
᎐
᎐
3
2
3
2
CH), 52.4 (O᎐C–OCH ), 51.9 (CH –O–CH –CH), 43.7 (CH –
᎐
3
3
2
2
4 A. F. Parsons, An Introduction to Free Radical Chemistry, Blackwell
Science, Oxford, 2000.
5 For a recent example see: B. B. Snider and R. B. Smith, Tetrahedron,
2002, 58, 25.
CO–Ph), 30.9 (N–CH–CH –C–C᎐O), 27.6 (N–CH ); m/z (CI,
᎐
2
3
NH3) 320 (M ϩ Hϩ, 100%); Found: M ϩ Hϩ, 320.1496.
C17H22NO5 requires for M ϩ Hϩ, 320.1498.
6 J. Y. Nédélec and K. Nohair, Synlett, 1991, 659.
7 H. Nishino, S-I. Tategami, T. Yamada, J. D. Korp and K. Kurosawa,
Bull. Chem. Soc. Jpn., 1991, 64, 1800.
8 E. I. Heiba and R. M. Dessau, J. Org. Chem., 1974, 39, 3456.
9 R. Lavilla, A. Spada, I. Carranco and J. Bosch, J. Org. Chem., 2001,
66, 1487.
10 R. Kumabe, H. Nishino, M. Yasutake, V.-H. Nguyen and
K. Kurosawa, Tetrahedron Lett., 2001, 42, 69.
11 M. Allegretti, A. D’Annibale and C. Trogolo, Tetrahedron, 1993, 49,
10705.
12 G. Midgley and C. B. Thomas, J. Chem. Soc., Perkin Trans. 2, 1987,
1103.
(8R)-1-Hydroxy-8-(methoxymethyl)-7-methyl-1,3-diphenyl-2-
oxa-7-azaspiro[4.4]nonan-6-one (32). 81%; isolated as a 6 : 1
mixture of diastereoisomers as indicated by the NMR spectra.
Major diastereoisomer; colourless oil; Rf 0.4 (9 : 1, dichloro-
methane–ethyl acetate); [α]2D0 = 26.8 (0.175 g/10 cm3 in CHCl3);
νmax (CHCl3) 3304 (m, br), 3015 (s), 2893 (s, br), 1667 (s), 1448
(m), 1392 (m), 1046 (s) cmϪ1; δH (300 MHz, CDCl3) 7.65–7.68
(2H, m, CH aromatics), 7.52–7.44 (3H, m, CH aromatics),
7.39–7.23 (5H, m, CH aromatics), 5.59–3.49 (1H, m, CH3–O–
CH2–CH ), 5.33 (1H, dd, J = 10.5 and 6.5 Hz, O–CHPhCH2),
3.09 (3H, s, CH3–O–CH2–CH), 2.88 (3H, s, CH3–N), 2.79–2.70
(3H, m, Ph–CH–CH2–C and CH3–O–CH–CH), 2.36 (1H, dd,
J = 12 and 6.5 Hz, CH3–O–CH–CH), 1.97 (1H, dd, J = 13.5 and
13 G. Bar, A. F. Parsons and C. B. Thomas, Tetrahedron, 2001, 57,
4719.
14 P. C. Montevecchi and M. L. Navacchia, Tetrahedron, 2000, 56,
9339.
15 E. J. Corey and A. K. Ghosh, Chem. Lett., 1987, 223.
16 J. M. Mellor and S. Mohammed, Tetrahedron, 1993, 49, 7547.
17 J. M. Mellor and S. Mohammed, Tetrahedron, 1993, 49, 7557.
18 E. J. Corey and A. K. Ghosh, Tetrahedron Lett., 1987, 28, 175.
8 Hz, N–CH–CH–C–C᎐O), 1.50 (1H, dd, J = 13.5 and 7 Hz, N–
᎐
CH–CH–C–C᎐O); δ (75 MHz, CDCl3) 176.2 (NCO), 142.5,
᎐
C
141.1, 128.8, 128.7, 128.4, 128.1, 127.3, 127.1 (C and CH aro-
matics), 107.5 [O–C(OH)–Ph], 81.0 [O–CH(Ph)CH2], 74.6
19 Part of this work has been reported as
a preliminary
(CH –O–CH –CH), 59.3 (CH –O–CH –CH), 57.1 (O᎐C–C–
communication: G. Bar, A. F. Parsons and C. B. Thomas, Synlett,
2002, 1069.
᎐
3
2
3
2
C–OH), 56.7 (CH3–O–CH2–CH), 46.1 (C–CH2–CH–Ph), 31.3
20 For related asymmetric manganese()-based approaches using
chiral auxiliaries see: (a) F. Garzino, A. Méou and P. Brun,
Tetrahedron Lett., 2000, 41, 9803; (b) B. B. Snider and Q. Zhang,
Tetrahedron Lett., 1992, 33, 5921; (c) Q. Zhang, R. M. Mohan,
L. Cook, S. Kazanis, D. Peisach, B. M. Foxman and B. B. Snider,
J. Org. Chem., 1993, 58, 7640; (d ) P. A. Zoretic, X. Weng, M. S.
Biggers, M. L. Caspar and D. G. Davis, Tetrahedron Lett., 1992, 33,
2637; (e) R. Galeazzi, G. Mobbili and M. Orena, Tetrahedron, 1996,
52, 1069; ( f ) B. Cardillo, R. Galeazzi, G. Mobbili and M. Orena,
Synlett, 1995, 1159; (g) R. Galeazzi, S. Geremia, G. Mobbili and
M. Orena, Tetrahedron: Asymmetry, 1996, 7, 3573.
21 For recent references see for example: (a) M. G. Moloney, Nat. Prod.
Rep., 1999, 16, 485; (b) P. W. H. Chan, I. F. Cottrell and M. G.
Moloney, J. Chem. Soc., Perkin Trans. 1, 2001, 2997; (c) P. W. H.
Chan, I. F. Cottrell and M. G. Moloney, J. Chem. Soc., Perkin Trans.
1, 2001, 3007; (d ) J. E. Baldwin, A. M. Fryer and G. J. Pritchard,
J. Org. Chem., 2001, 66, 2588; (e) A. Ali, V. U. Ahmad, B. Ziemer
and J. Liebscher, Tetrahedron: Asymmetry, 2000, 11, 4365;
( f ) Y. Aoyagi and R. M. Williams, Tetrahedron, 1998, 54, 13045.
22 M. J. Beard, J. H. Bailey, D. T. Cherry, M. G. Moloney, S. B. Shim,
K. A. Statham, M. J. Bamford and R. B. Lamont, Tetrahedron, 1996,
52, 3719.
(N–CH–CH –C–C᎐O), 29.6 (N–CH ); m/z (CI, NH ) 368
᎐
2
3
3
(M ϩ Hϩ, 8%), 350 (M ϩ Hϩ Ϫ H2O, 100); Found: M ϩ Hϩ,
368.1861. C22H26NO4 requires for M ϩ Hϩ, 368.1862.
The presence of the minor diastereoisomer [Rf 0.3 (9 : 1, di-
chloromethane–ethyl acetate)] was indicated by the NMR
spectra: δH (300 MHz, CDCl3) 5.61 (1H, dd, J = 9.5 and 5 Hz,
O–CHPhCH2), 3.08 (3H, s, CH3–O–CH2–CH), 2.87 (3H, s,
CH –N), 2.16–2.05 (1H, m, N–CH–CH–C–C᎐O), 1.72–1.61
᎐
3
(1H, m, N–CH–CH–C–C᎐O); δ (75 MHz, CDCl3) 176.4
᎐
C
(NCO), 107.5 [O–C(OH)–Ph], 81.3 [O–CH(Ph)CH2], 74.3
(CH –O–CH –CH), 59.3 (CH –O–CH –CH), 57.8 (O᎐C–C–
᎐
3
2
3
2
C–OH), 55.9 (CH3–O–CH2–CH), 47.0 (C–CH2–CH–Ph), 29.6
(N–CH–CH –C–C᎐O), 29.0 (N–CH ).
᎐
2
3
(5R)-2-Benzoyl-5-isopropyl-1,4-dimethyl-3,6-dioxopiperazin-
2-yl acetate (35). 22–33%; single diastereoisomer; solid; mp
153–155 ЊC; Rf 0.7 (6 : 4, dichloromethane–ethyl acetate); νmax
(CHCl3) 3054 (w, br), 2968 (w, br), 1758 (w), 1675 (s), 1394 (m),
1228 (m) cmϪ1; δH (300 MHz, CDCl3) 8.34–8.25 (2H, m, aro-
matics), 7.65–7.55 (1H, m, aromatics), 7.51–7.45 (2H, m, aro-
23 It is interesting to note that a related intramolecular cyclisation of
an α-methyl β-amido ester was unsuccessful: D. T. Davies, N. Kapur
and A. F. Parsons, Tetrahedron Lett., 1998, 39, 4397.
matics), 3.92 [1H, d, J = 3.5 Hz, N–CH(iPr)–C᎐O], 3.02 (3H, s,
᎐
24 In these types of compounds, the peaks for the two hydrogen atoms
at C-4 are often well separated for each of the two diastereoisomers:
J. Ezquerra, C. Pedregal, A. Rubio, B. Yruretagoyena, A. Escribano
and F. Sánchez-Ferrando, Tetrahedron, 1993, 49, 8665.
N–CH3), 2.73 (3H, s, CH–N–CH3), 2.44–2.33 (1H, m, CH3–
CH–CH3), 2.18 (3H, s, CH3–CO2), 1.22 (3H, d, J = 7 Hz, CH3–
CH–CH3), 1.10 (3H, d, J = 7 Hz, CH3–CH–CH3); δC (75 MHz,
CDCl ) 192.5 (PhC᎐O), 168.6 (CH CO ), 166.3 (iPrC–C᎐O),
᎐
᎐
3
3
2
25 (a) J. Iqbal, R. R. Srivastava and M. A. Khan, Tetrahedron Lett.,
1990, 31, 1485; (b) V. Nair, J. Mathew and J. Prabhakaran, Chem.
Soc. Rev., 1997, 127; (c) X.-P. Gu, N. Nishida, I. Ikeda and
M. Okahara, J. Org. Chem., 1987, 52, 3192; (d ) X.-P. Gu, T. Okuhara,
I. Ikeda and M. Okahara, Synthesis, 1988, 535; (e) I. Ikeda, X.-P.
Gu, T. Okuhara and M. Okahara, Synthesis, 1990, 32; ( f ) Y. Hori,
T.-A. Mitsudo and Y. Watanabe, Tetrahedron Lett., 1986, 27, 5389.
26 P.-K. Chiu and M. P. Sammes, Tetrahedron, 1990, 46, 3439.
27 For an alternative approach to 1,4-dicarbonyl compounds from
β-keto esters see: J. B. Brogan and C. K. Zercher, J. Org. Chem.,
1997, 62, 6444.
160.2 (C–C᎐O), 134.6 (O᎐C–CPhenyl), 133.5 (2 × CH aromatics),
᎐
᎐
131.3 (CH aromatic), 128.1 (2 × CH aromatics), 91.3 (AcO–C–
COPh), 67.4 [(CH3)2CH–CH], 34.0 (N–CH3), 32.2 [(CH3)2-
CH–CH], 29.3 (N–CH3), 21.0 (CH3–CO2), 19.9 (CH3–CH–
ϩ
CH3), 17.8 (CH3–CH–CH3); m/z (CI, NH3) 364 (M ϩ NH4
,
2%), 347 (M ϩ Hϩ, 3), 304 (M ϩ Hϩ–CH C᎐O, 9), 287
᎐
3
(M ϩ Hϩ Ϫ CH3CO2H, 100%); Found: M ϩ Hϩ, 347.1594.
C18H23N2O5 requires for M ϩ Hϩ, 347.1607.
28 L. J. Breña-Valle, R. C. Sánchez and R. Cruz-Almanza, Tetrahedron:
Asymmetry, 1996, 7, 1019.
29 P. D. Williams, D. S. Perlow, L. S. Payne, M. K. Holloway, P. K. S.
Siegl, T. W. Schorn, R. J. Lynch, J. J. Doyle, J. F. Strouse, G. P.
Vlasuk, K. Hoogsteen, J. P. Springer, B. L. Bush, T. A. Halgren,
A. D. Richards, J. Kay and D. F. Veber, J. Med. Chem., 1991, 34, 887.
Acknowledgements
This work was supported by BP Amoco Chemicals, the
European Union (under the ERASMUS scheme) and The
University of York.
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 3 7 3 – 3 8 0
380