Stereoselective reduction of chiral 2-furoic acid derivatives using group I metals in ammonia

Article abstract of DOI:10.1039/b006390h

A series of chiral auxiliaries have been attached to 2-furoic acid and 3-methyl-2-furoic acid. The performance of these auxiliaries in the Birch reduction was assessed and it was found that placing a C-3 methyl group on the heterocycle was essential for good stereoselectivity. Using bis(methoxymethyl)pyrrolidine high levels of diastereoselectivity could be obtained with a range of electrophiles. A model is also presented which explains the sense of stereoselectivity displayed by this auxiliary. After reduction, the auxiliaries could be removed by reaction with acid to furnish dihydrofuran-based carboxylic acids with high enantiomeric excess. The Royal Society of Chemistry 2000.

Full text of DOI:10.1039/b006390h

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Stereoselective reduction of chiral 2-furoic acid derivatives using
group I metals in ammonia
Timothy J. Donohoe,*a Andrew A. Calabrese,a Clare A. Stevensona and Tamara Ladduwahettyb
1
a Department of Chemistry, The University of Manchester, Oxford Road, Manchester,
UK M13 9PL. E-mail: t.j.donohoe@man.ac.uk
b Merck Sharp and Dohme, Neuroscience Research Centre, Terlings Park, Harlow, Essex,
UK CM20 2QR
Received (in Cambridge, UK) 4th August 2000, Accepted 5th September 2000
First published as an Advance Article on the web 30th October 2000
A series of chiral auxiliaries have been attached to 2-furoic acid and 3-methyl-2-furoic acid. The performance of these
auxiliaries in the Birch reduction was assessed and it was found that placing a C-3 methyl group on the heterocycle
was essential for good stereoselectivity. Using bis(methoxymethyl)pyrrolidine high levels of diastereoselectivity could
be obtained with a range of electrophiles. A model is also presented which explains the sense of stereoselectivity
displayed by this auxiliary. After reduction, the auxiliaries could be removed by reaction with acid to furnish
dihydrofuran-based carboxylic acids with high enantiomeric excess.
Introduction
The partial reduction of aromatic heterocycles is a useful reac-
tion for the synthesis of stereochemically defined ring systems
containing oxygen and nitrogen.1 Although the Birch reduction
has been extensively studied in its application to carbocyclic
Scheme 1 Reagents: i. SOCl2 then (S)-methoxymethylpyrrolidine,
CH2Cl2, NaOH; ii. Na, NH3, then MeI.
compounds,2 the use of this reduction on heterocycles is more
limited. We have recently reported the results of a study
designed to investigate the partial reduction process (usually–
but not always–manifested as the Birch reduction) as applied to
heterocycles such as pyrrole,3 pyridine,4 and furan.5
If we are going to use our methodology in synthesis then it is
imperative that we are able to control absolute stereochemistry
as well as relative. Perhaps the simplest way of controlling
absolute stereochemistry in such reductions is to insert a chiral
auxiliary, bound to an acyl group on the heterocycle, prior to
reduction. This type of system has been studied extensively by
Schultz who reported the stereoselective reductive alkylation of
a variety of auxiliary-laden benzoic acid derivatives.6 In this
Fig. 2
paper we wish to provide a full account of our studies on chiral
derivatives of 2-furoic acid, 1, Fig. 1.7 Although the Birch
product in 61% yield, it was formed as near to a 1:1 mixture of
diastereoisomers (as measured by H NMR and GC analysis)
1
reduction of 2-furoic acid derivatives has been reported before,8
under all conditions investigated (changing the reducing agent
to Li metal gave 61:39 dr, 33% yield). This result is close to
that reported by Kinoshita who also investigated this auxiliary
bound to 2-furoic acid.9
we are aware of only one (marginally successful) attempt to
control the stereoselectivity of this reaction.9 We initially under-
took the sequence described in Fig. 1 as the products 2 and 3
should prove to be useful intermediates in natural product
synthesis.
The mechanism for the reduction is outlined in Fig. 2 and
the salient points are the formation of a reactive dianion by
addition of two electrons to the heterocycle; this can then
deprotonate ammonia and yield a corresponding enolate B. We
postulate the formation of a reactive dianion A because these
Birch reductions proceed without addition of a proton source
such as an alcohol and it seems unlikely that a radical anion
itself would be basic enough to deprotonate ammonia. Reac-
tion of enolate B occurs when an external electrophile is added
to the system and like most extended enolates it displays a
strong penchant for reaction at the alpha position.10 We
reasoned that the lack of selectivity observed in the reduction
of 5 had its origins in the formation of a mixture of enolate
geometric isomers. Under such circumstances, the auxiliary
cannot then be expected to promote the formation of a single
diastereoisomer upon reaction with an electrophile.
Results and discussion
Following the work of Schultz, we began by attaching (S)-
methoxymethylpyrrolidine to 2-furoic acid 4 and performing
a reductive methylation reaction on the known amide 5,
Scheme 1.9 Unfortunately, this reaction gave a mixture of
diastereoisomers and was characterised by low yields of di-
hydrofurans (possibly with ring opened products present in
the reaction mixture). While we were able to isolate the desired
Our tactic for controlling the enolate geometry within B was
to introduce a substituent at C-3 as Schultz had shown that an
Fig. 1
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This journal is © The Royal Society of Chemistry 2000
DOI: 10.1039/b006390h

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ortho-methyl group was sufficient to control enolate geometry
in related benzenoid systems.11 So, 3-methyl-2-furoic acid 7
(commercially available) was coupled (carbonyldiimidazole,
CDI) to (S)-prolinol and then methylated (NaH, MeI) to give
furan 9. Compound 9 was then subjected to a reductive alkyl-
ation reaction as before, Scheme 2. Surprisingly, the outcome
Scheme 3 Reagents: i. NaH, BnBr; ii. Li, NH3, then MeI; iii. 2 M (aq.)
HCl, ∆.
Scheme 2 Reagents: i. CDI, (S)-prolinol; ii. NaH, MeI; iii. Na, NH3,
then MeI.
separation of the diastereoisomers of 12 on chromatography.
The configuration of 13 (and therefore 12) was assigned from
its sign of optical rotation, vide infra.
was similar to that reported in Scheme 1 and under all con-
ditions tried the product was formed as a less than useful
mixture of diastereoisomers. The clearest indication that
reductive alkylation had occurred as shown in Scheme 2 was
Use of a C2 symmetrical chiral auxiliary in the Birch reduction
1
the disappearance of all furyl-H resonances in the H NMR
While this route was promising, we did not pursue reduction
of 11 further because of exciting developments using the C2
symmetrical auxiliary bis(methoxymethyl)pyrrolidine, (com-
mercially available as either enantiomer) Scheme 4.12 Coupling
spectrum of 10 and the presence of two methyl singlets at δ 1.34
and 1.33 ppm. The alkene resonance in compound 10 was not
resolved between the two diastereoisomers and appeared as
a broad singlet (1H) at δ 5.41 ppm.
While attempts to reduce compound 8 (X = OH) were com-
plicated by low yields (possibly due to over reduction caused by
the presence of an acidic, O–H, proton), any products that
we did isolate were formed with significant levels of stereo-
selectivity. This observation led us to believe that the presence
of a methyl group at C-3 was indeed controlling enolate geom-
etry successfully and that the lack of stereoselectivity during
reduction of 9 was caused by rotation about the C–N bond in
the enolate (see Fig. 2 for an example; this rotation means that
the side chain of the auxiliary can shield either face of the
enolate in turn and this effect could lead to a 1:1 mixture of
diastereoisomers whatever the geometry of the enolate). So, we
presumed that reduction of 8 did form a single enolate isomer
(as did 9) but that the alkoxide present in 8 (present on the
side chain of the auxiliary after deprotonation of the OH) pre-
vented rotation about the C–N bond, presumably because of
chelation. Therefore, we prepared O-benzylated derivative 11 in
one step from 8 in the hope that the benzyl group would be
cleaved under the reductive reaction conditions and that the
resulting alkoxide would prevent C–N bond rotation as before
and so give rise to high levels of stereoselectivity. Moreover, as
there is no acidic proton in the reaction medium the yields of
dihydrofuran should be good. In the event, reduction of 11
proceeded smoothly and formed 12 in reasonable yield and with
good diastereoselectivity. The stereoselectivity was measured by
GC on crude material and against an authentic 1:1 standard
and was found to be 93:7 in favour of the isomer shown,
Scheme 3. Lithium metal was preferred over sodium as the
latter metal also promoted some methylation of the alkoxide on
the auxiliary, thus complicating product analysis. Examination
Scheme 4 Reagents: i. SOCl2 then (S,S)-bis(methoxymethyl)pyrrol-
idine; ii. Na, NH3, then RX.
Table 1 Birch reduction of 15
Entry
RX
R
Yield (%)
Dr
Compound
1
2
3
4
5
6
MeI
BnBr
iBuI
EtI
Allyl Br
NH4Cl
Me
Bn
iBu
Et
Allyl
H
98
57
68
74
62
65
30:1
30:1
30:1
30:1
30:1
10:1
16
17
18
19
20
21
of (S,S)-(ϩ)-bis(methoxymethyl)pyrrolidine 14 to acid 7 gave
the amide 15 in excellent yield. This compound was subse-
quently reduced with sodium in liquid ammonia and quenched
with a variety of electrophiles. In all cases the stereoselectivity
of the reaction was excellent and the yields were also better
than with any other auxiliary we had previously tested. It is
no coincidence that reductive methylation of 15 (Table 1, entry
1), which has been repeated several times, has an excellent yield
(98%) while the other entries shown in Table 1 have been
performed only once and may be considered unoptimised. In
each case the diastereoselectivity was difficult to ascertain by
NMR and instead we used GC on the crude reaction mixture
and in conjunction with an authentic 1:1 standard prepared
by coupling of (S,S)-(ϩ)-14 to the corresponding racemic
dihydrofuran acid with bis(2-oxooxazolidin-3-yl)phosphinic
chloride (BOPCl). Although the level of stereoselectivity can-
1
of the H NMR spectrum of 12 made it clear that both reduc-
tive alkylation and debenzylation had occurred. For example,
the only olefinic resonance to be found in the spectrum of 12
was a broad singlet (1H) at δ 5.61 ppm; there were no aromatic
C–H resonances. Moreover, a methyl singlet at δ 1.53 ppm
indicated that reductive methylation had taken place.
The auxiliary was cleaved from 12 with (aq.) HCl in unopti-
mised 42% yield to give acid 13 with 91% ee (as measured by
GC against a racemic standard: the ee measured by optical
rotation was lower at 80%, but could easily be due to the inher-
ent inaccuracies in this analytical technique). The enantiomeric
excess of (ϩ)-13 is slightly higher than the diastereoisomeric
excess of 12 (86% de), which could easily be due to partial
1
not be easily determined by H NMR spectroscopy, we could
obtain a qualitative reading by looking at the region δ 4.0–5.0
ppm where the methine NCH resonances were different for
each diastereoisomer. In addition, the 13C NMR spectra of the
mixtures clearly showed doubling of many of the peaks. As far
as the single isomers were concerned, each could be identified as
J. Chem. Soc., Perkin Trans. 1, 2000, 3724–3731
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Scheme 5 Reagents: i. (S,S)-bis(methoxymethyl)pyrrolidine, CH2Cl2,
NaOH; ii. Na, NH3, then MeI.
peaks in a 41:59 ratio. So, this result conforms to our mech-
anistic model and underscores the importance of substitution
at C-3 of the heterocycle to enforce control of stereochemistry.
Clearly, chelation between the enolate counterion and the ring
oxygen is poor and certainly insufficiently strong to control
enolate geometry.
Removal of the chiral auxiliary
Fig. 3
For our methodology to become useful we need to be able to
remove the auxiliary from the products 16–21. The best way to
achieve this was simply to heat the amides in acid. Heating in
(aq.) 6 M HCl removed the auxiliary in a few hours and,
remarkably, even (aq.) 2 M HCl was sufficient to hydrolyse these
amides, as exemplified with 16 and 17, Scheme 6, Table 2. The
a dihydrofuran by the presence of a (1H) alkene methine reson-
ance around δ 5.5 ppm; this was normally a broad singlet whose
fine structure indicated small coupling to the C-5 methylene
protons and also possibly to the C-3 methyl group. Moreover,
each compound displayed additional peaks in the NMR which
were consistent with the introduction of a group R from the
electrophile RX used in the Birch reduction. Interestingly, both
diastereoisomers of 21 showed a resonance at δ 5.28–5.22 ppm
which had fine structure indicative of (allylic) coupling to other
protons on the dihydrofuran ring.
We propose that the mechanism of reaction is similar to that
described in Fig. 2. The key issue regards the details of how the
chiral auxiliary enforces stereoselectivity upon alkylation of
enolate D or E, Fig. 3. It is clear that one enolate geometric
isomer is formed in this reaction: however, at present we do not
have experimental evidence to indicate which one.
Scheme 6
Table 2 Hydrolysis of 16–19
Entry
R
Yield (%)
% Ee
96
>96
>96
94
Compound
A simple model assumes that the nitrogen in the enolate is
planar. We suppose that enolate D has the trans-geometry (so
that the bulky auxiliary can avoid clashing with the methyl
group) and also that the electrophile chooses to attack D from
the lower face as drawn. Although an arm of the auxiliary
shields each face of the enolate, one arm is much closer to the
enolate α-carbon than the other and this is predicted to be
a more efficient block to approach of the electrophile- on
the upper face as drawn. However, we must be circumspect
because our assumption that the nitrogen atom in the enolate
is flat is unsafe. There are X-ray data in the literature to suggest
that analogous nitrogen atoms within amide enolates are
pyramidalised (in a manner similar to enamines).13 Fortunately,
pyramidalisation of the nitrogen does not create a new
stereogenic centre and while reaction of a trans-enolate through
a variety of different conformations can be envisaged, most do
not alter the sense of selectivity predicted by our model as
described above with a trigonal nitrogen.
It is more difficult to devise a model whereby a cis-enolate
shields the correct face of the enolate. In fact we must invoke
a pyramidalised nitrogen atom, possibly with some rotation
about the C–N axis, see E, Fig. 3. While this rotation would
reduce allylic strain between the methyl group and the auxiliary,
it would also reduce overlap between the nitrogen lone pair
and the π-system. Reaction through this conformation would
predict the correct face selectivity for the enolate, however, we
consider this scenario less likely than the first.
1
2
3
4
5
Me
Bn
Et
iBu
H
86a
80a
74
68
—
13
25
26
27
—
—
a Hydrolysis was carried out in 2 M (aq.) HCl.
enantiomeric excesses of acids 13 and 25–27 were high and were
measured by GC (on a chiral support) and in comparison with
a racemic standard made from 3-methyl-2-furoic acid in three
steps (amide formation with pyrrolidine, Birch reduction and
amide hydrolysis).
Two of the substrates that were treated with acid did not
behave as expected. Compound 21 (R = H) resisted hydrolysis
(2–6 M (aq.) HCl) conditions and prolonged exposure to acid
eventually led to decomposition. This seems surprising as 21
represents one of the least hindered amides in this sequence and
should, therefore, be more reactive to acid hydrolysis.†
Compound 20 was the other amide derivative that did not
yield a carboxylic acid upon reaction with (aq.) HCl, and two
diastereoisomeric lactones 28 and 29 were produced instead,
Scheme 7. Initial experiments showed that while amide 20 could
† We tentatively suggest that the reluctance of 21 to be hydrolysed,
together with the relative ease of hydrolysis of hindered amides 16–20,
can be explained by invoking a mechanism analogous to the AAC
mechanism for hydrolysis of esters. In this scenario, these hindered
amides would eventually protonate on nitrogen and ionise to an
acylium ion (ionisation may be driven by release of steric strain).
Perhaps compound 21 is insufficiently strained to undergo acylium ion
formation and yet still too hindered to undergo acid hydrolysis via a
more conventional mechanism (i.e. attack of water on a protonated
carbonyl group as the rate determining step).
If the first model shown above is correct then use of (S,S)-14
as an auxiliary for the reduction of 2-furoic acid will give rise to
a mixture of stereoisomers as the enolate will be a mixture of
geometric isomers. So, to confirm our hypothesis, compound 23
was prepared from furoyl chloride 22 and subjected to a Birch
reductive methylation reaction, Scheme 5. The product 24 was
isolated in 45% yield and analysed by GC which showed two
1
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J. Chem. Soc., Perkin Trans. 1, 2000, 3724–3731

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in the synthesis of biologically important natural products is
currently being investigated.14
Experimental
General details
All reactions, except aqueous reactions, were carried out under
an atmosphere of dry nitrogen. Proton nuclear magnetic reson-
ance spectra (NMR) were recorded on a Gemini 200 at 200
MHz, a Bruker AC300/Varian XL300 at 300 MHz, a Bruker
AM360 at 360 MHz or a Bruker AC250 at 250 MHz. 13C
nuclear magnetic resonance spectra were recorded on a Gemini
200 at 50 MHz, a Bruker AC300/Varian XL300 at 75 MHz, or a
Bruker AM360 at 90 MHz. Coupling constants (J) are quoted
in Hz. Infrared spectra (IR) were recorded on an ATI Mattson
Genesis FTIR as evaporated films. Optical rotations were
recorded on an Optical Activity Ltd. AA-100 polarimeter and
[α]D values (all reported at 21 ЊC) are given in units of 10Ϫ1 deg
cm2 gϪ1; concentration c in units of g 100 mlϪ1. Mass spectra
were recorded on a Kratos Concept or a Fisson VG Trio 2000.
Chemical ionisation (CI) was performed using NH3. Micro-
analysis was obtained from the microanalytical section of the
University of Manchester’s Chemistry Department. Melting
points were obtained on a Kofler block and are uncorrected.
Thin layer chromatography (TLC) was carried out using Poly-
gram G/UV254 pre-coated plastic plates. Flash column chrom-
atography was carried out using the solvent system indicated
and Silica Gel 60 230–400 mesh. Gas/liquid chromatography
(GC) was carried out using a chiral column; CP-Chirasil
DEXCB column (25 m × 0.32 mm, 0.28 µ) controlled by a
Shimadzu Chromatopac R4AX unit. All solvents and reagents
requiring purification were done so using standard laboratory
techniques according to methods published in ref. 15. Tetra-
hydrofuran (THF) was dried and distilled from sodium metal
using benzophenone as indicator, under an atmosphere of
nitrogen. Dichloromethane (DCM) was distilled over calcium
hydride. Petroleum ether (boiling range 40–60 ЊC) was distilled
prior to use. Ammonia was distilled from sodium metal and
ferric chloride. Where mentioned, isoprene was added to metal
ammonia reductions dropwise until the blue colour of the
reaction was dispersed.
Scheme 7
be hydrolysed to give some carboxylic acid under mild (2 M
(aq.) HCl) conditions, TLC analysis showed that this acid
began to convert into the lactones 28 and 29 during the course
of the reaction. It was decided, therefore, to convert 20 directly
into the two lactones by reaction with strong acid. Gratifyingly,
the two diastereoisomers were isolated in 72 and 22% yields. We
were able to separate the two isomers by chromatography on
silica but we could not assign the relative configuration at C-8
(which is on the lactone ring; the relative stereochemistry
shown at C-8 in Scheme 7 is arbitrary). Analysis of the two
lactones by GC (on a chiral support) showed that each was of
94% ee which is similar to the diastereoisomeric excess of the
starting material. The mechanism of acid-catalysed lactonis-
ation of the intermediate acid seems unremarkable involving
protonation of the alkene and cyclisation of the carboxylic
acid. It is not clear whether the two lactones are themselves
interconverting under the reaction conditions. The five mem-
bered lactone structure of 28 and 29 was indicated by IR (C᎐O
᎐
at 1769 cmϪ1) and the presence of a methyl doublet (δ 1.41 ppm,
J 6) in the 1H NMR spectrum.
The configuration of the acids produced in Scheme 6 was
determined from an X-ray crystal structure of amide 30. This
was prepared by coupling acid (Ϫ)-13 (94% ee, using CDI) to
(R)-(ϩ)-α-methylbenzylamine, Scheme 8. The details of this
Scheme 8
X-ray have been reported elsewhere.5 This structure reveals the
configuration at C-2 of the tetrahydrofuran ring.
(2ЈS)-[2Ј-(Hydroxymethyl)-2Ј,3Ј,4Ј,5Ј-tetrahydro-1ЈH-pyrrol-1Ј-
yl](3-methyl-2-furyl)methanone 8
The structure shown in Scheme 8 can be used to assign
stereochemistry to most of the compounds described in this
paper. Knowing the configuration at C-2 of 30 means that we
know the configuration of acid (Ϫ)-13 from which it came. We
can then work out the configuration of amide 16, assuming that
the configuration at C-2 does not change during hydrolysis of
the amide, which seems reasonable. We can also assume that the
configuration at C-2 is the same for acids 25–27 (and therefore
for amides 17–21). The basis of this second assumption is that
the enolate D (Fig. 3) will react with all electrophiles from the
same face. This is sensible with the carbon electrophiles used
and is only really debatable with a proton electrophile (which
may protonate on oxygen and rearrange). Of course, knowing
the configuration of (Ϫ)-13 means that the stereochemistry of
(ϩ)-13, Scheme 3 is also secure.
To conclude, we have investigated a range of chiral auxil-
iaries for the Birch reduction of 2-furoic acid derivatives. Bis-
(methoxymethyl)pyrrolidine is the auxiliary of choice as long
as a substituent is present at C-3 of the heterocycle. Using this
protocol we prepared dihydrofurans with a range of substitu-
ents at the C-2 position and with excellent levels of diastereo-
selectivity. A model is presented which explains the sense of
diastereoselectivity observed in such reductive alkylations.
Moreover, the chiral auxiliary could be readily removed by
treatment with acid to give carboxylic acid derivatives with
very high enantiomeric excess. The use of this methodology
3-Methyl-2-furoic acid 7 (0.5 g, 3.8 mmol) was stirred in THF
(25 ml) at RT and carbonyldiimidazole (0.707 g, 8.7 mmol)
was added. The reaction was stirred for 30 min and then
(S)-prolinol (0.39 ml, 3.8 mmol) was added in one portion.
After stirring overnight at RT the THF was removed under
reduced pressure and the residue dissolved in dichloromethane
(50 ml). The organics were washed with 2 M (aq.) HCl (20 ml)
and brine (20 ml) before being dried (MgSO4). Evaporation
under reduced pressure gave a brown oil which was purified by
chromatography on a silica column, eluting with 30% ethyl
acetate–petrol, to afford 8 as a colourless oil (734 mg, 89%)
(Found Mϩ, 209.1052. C11H15NO3 requires Mϩ, 209.1052); νmax
(film)/cmϪ1 3400, 2957, 2929, 2878, 1609, 1494; δH (300 MHz,
CDCl3) 7.37 (1H, d, J 1.6), 6.34 (1H, d, J 1.4), 5.31 (1H, br s,
OH), 4.44–4.41 (1H, m), 3.98–3.67 (4H, m), 2.35 (3H, s), 2.14–
1.79 (4H, m); δC (75 MHz, CDCl3) 162.0, 143.0, 142.4, 129.5,
115.0, 67.2, 61.9, 49.2, 27.8, 25.0, 11.8; m/z (CIϩ) 210 (M ϩ 1,
100%), 109 (M Ϫ 100, 10%); [α]D Ϫ66.5 (c 0.01 in CHCl3).
(2ЈS)-[2Ј-(Methoxymethyl)-2Ј,3Ј,4Ј,5Ј-tetrahydro-1ЈH-pyrrol-1Ј-
yl](3-methyl-2-furyl)methanone 9
A solution of the amide 8 (1.5 g, 7.2 mmol) in THF (50 ml) was
added to sodium hydride (373 mg, 9.3 mmol) at 0 ЊC under N2.
After 1 hour at 0 ЊC, methyl iodide (1.4 ml, 21.5 mmol) was
J. Chem. Soc., Perkin Trans. 1, 2000, 3724–3731
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added and the reaction heated at reflux overnight. The THF
was then removed under reduced pressure and the residue dis-
solved in dichloromethane (100 ml). The organics were washed
with 2 M (aq.) HCl (20 ml), and brine (20 ml), and dried
(MgSO4). Evaporation under reduced pressure gave the crude
product as a brown oil (1.4 g, 87%). Purification by flash
chromatography gave 9 as an orange oil (1.2 g, 75%) (Found
M ϩ Hϩ, 224.1283. C12H18NO3 requires M ϩ Hϩ, 224.1287);
νmax (film)/cmϪ1 2974, 2927, 2885, 1611, 1494; δH (300 MHz,
CDCl3) 7.30 (1H, s), 6.29 (1H, s), 4.58–4.38 (1H, br s), 3.93–
3.12 (7H, m), 2.32 (3H, s), 2.11–1.78 (4H, m); δC (75 MHz,
CDCl3) 159.9, 143.2, 141.9, 128.5, 114.8, 72.4, 59.0, 57.1, 48.4,
27.0, 24.8, 11.7; m/z (CIϩ) 224 (M ϩ 1, 100%), 178 (M Ϫ 45,
10%); [α]D Ϫ97.0 (c 0.01 in CHCl3).
dryness under reduced pressure to give a yellow oil. Column
purification, eluting with 50% ethyl acetate–petrol, afforded 12
as a mixture of diastereoisomers as a colourless oil (210 mg,
56%). Data for major diastereoisomer shown (Found M ϩ Hϩ,
226.1442. C12H19NO3 requires M ϩ Hϩ, 226.1443); νmax/cmϪ1
3433 (br, O–H), 2974, 2854, 1609 (C᎐O); δ (300 MHz, CDCl )
᎐
H
3
5.61 (1H, br s), 4.82 (1H, m), 4.74–4.44 (2H, m), 4.39 (1H, m),
3.99–3.38 (4H, m), 2.02–1.79 (4H, m), 1.81 (3H, br s), 1.53 (3H,
s); δC (75 MHz, CDCl ) 173.1 (C᎐O), 139.3, 120.8, 93.0, 73.4,
᎐
3
67.7, 62.4, 46.9, 27.2, 25.2, 23.0, 12.0; m/z (CI) 226 (M ϩ Hϩ,
100%).
(2R)-2,3-Dimethyl-2,5-dihydrofuran-2-carboxylic acid 13
Compound 12 (200 mg, 0.89 mmol) was heated at reflux in
2 M (aq.) hydrochloric acid (3 ml) for 1.5 h. The reaction
mixture was extracted into ethyl acetate (4 × 30 ml) and the
combined organics dried (MgSO4) and evaporated to dryness
under reduced pressure. The crude product was purified by
column chromatography, eluting with 30% ethyl acetate–
petrol containing 5% acetic acid to give 13 as a yellow oil
(53 mg, 42%) (Found C, 59.06; H, 7.30%; C7H10O3 requires
C, 59.14; H, 7.09%. Found M ϩ NH4ϩ, 160.0977. C7H10O3
requires M ϩ NH4ϩ, 160.0973); νmax/cmϪ1 3400 (br, OH), 1744
(2RS,2ЈS)-[2Ј-(Methoxymethyl)-2Ј,3Ј,4Ј,5Ј-tetrahydro-1ЈH-
pyrrol-1Ј-yl](2,3-dimethyl-2,5-dihydrofuran-2-yl)methanone 10
Compound 9 (500 mg, 2.2 mmol) was stirred in THF (10 ml)
and ammonia (120 ml) at Ϫ78 ЊC. Sodium (144 mg, 6.2 mmol)
was added to the reaction and stirred for 1 h, during which time
the reaction became blue. Isoprene was then added followed by
methyl iodide (948 µl, 6.6 mmol) and the reaction mixture
became colourless. Ammonium chloride (0.5 g) was added,
and the ammonia then allowed to evaporate. The residual
tetrahydrofuran was removed under reduced pressure and
the crude product was purified by column chromatography,
eluting with 50% ethyl acetate–petrol, affording 10 as a mixture
of diastereoisomers (55:45) as a colourless oil (375 mg, 70%).
Data for the mixture are shown (Found M ϩ Hϩ, 240.1599.
C13H22NO3 requires M ϩ Hϩ, 240.1600); νmax (film)/cmϪ1 2976,
2930, 2889, 2879, 1626; δH (300 MHz, CDCl3) 5.41 (1H, s),
4.59–4.31 (2H, m), 4.09–4.27 (1H, m), 3.69–3.06 (4H, m),
3.21, 3.18 (s, 3H), 1.85–1.51 (4H, m), 1.50 (3H, br s), 1.34, 1.33
(3H, s); δC (75 MHz, CDCl3) 173.1, 140.5, 139.5, 121.2, 93.3,
73.9, 72.5, 72.2, 59.4, 59.3, 58.6, 58.5, 46.9, 26.9, 26.8, 25.4,
23.4, 12.6, 12.4; m/z (CIϩ) 240 (M ϩ 1, 100%), 97 (M Ϫ 142,
10%).
(C᎐O); δ (300 MHz, CDCl ) 9.6 (1H, br), 5.52 (1H, br s), 4.69–
᎐
H
3
4.58 (2H, m), 1.79–1.77 (3H, br s), 1.48 (3H, s); δC (75 MHz,
CDCl3) 174.3, 137.6, 121.7, 91.1, 74.3, 22.3 and 11.9; m/z (CI)
160 (Mϩ ϩ NH4ϩ, 100%), 97 (Mϩ Ϫ CO2H); [α]D ϩ63.5 (c 0.15
in EtOH).
(2ЈS,5ЈS)-[2Ј,5Ј-Bis(methoxymethyl)-2Ј,3Ј,4Ј,5Ј-tetrahydro-1ЈH-
pyrrol-1Ј-yl](3-methyl-2-furyl)methanone 15
Thionyl chloride (12 ml, excess) was added to 3-methyl-2-furoic
acid (2.39 g, 19.0 mmol) and the resulting dark mixture refluxed
for 3–4 h. Excess thionyl chloride was then removed under
reduced pressure, azeotroping with toluene. To the brown liquid
was added dichloromethane (10 ml), and this solution was then
added dropwise to a stirring mixture of (S,S)-bis(methoxy-
methyl)pyrrolidine (3.32 g, 21.0 mmol), 2 M (aq.) sodium
hydroxide (40 ml, 80 mmol) and dichloromethane (40 ml) at
0 ЊC. The mixture was allowed to warm to room temperature
and stirred overnight. The dichloromethane was then removed
under reduced pressure, and the residue extracted into ethyl
acetate (4 × 75 ml). The combined organics were then dried
(MgSO4) and evaporated to dryness under reduced pressure to
yield a brown oil. The crude product was purified by column
chromatography, eluting with 25% ethyl acetate–petrol to give
15 as a pale yellow oil (4.6 g, 91%) (Found Mϩ, 267.1478,
(2ЈS)-{2Ј-[(Benzyloxy)methyl]-2Ј,3Ј,4Ј,5Ј-tetrahydro-1ЈH-
pyrrol-1Ј-yl}(3-methyl-2-furyl)methanone 11
A solution of amide 8 (1.85 g, 8.8 mmol) in THF (35 ml)
was added to a suspension of washed sodium hydride (60%
dispersion, 708 mg, 17.7 mmol) in THF (5 ml) at 0 ЊC. After 1 h
at 0 ЊC, benzyl bromide (1.2 ml, 10.1 mmol) and tetra-n-
butylammonium iodide (20 mg) were added, and the reaction
then stirred overnight at room temperature. The suspension was
filtered, the residue washed with THF and the solvent was
removed under reduced pressure to give the crude product.
Column purification, eluting with 30% ethyl acetate–petrol
afforded 11 as a colourless oil (2.6 g, 98%) (Found M ϩ Hϩ,
300.1598. C18H21NO3 requires M ϩ Hϩ, 300.1600); νmax/cmϪ1
C14H21NO4 requires Mϩ, 267.1471); νmax/cmϪ1 1617 (C᎐O);
᎐
δH (300 MHz, CDCl3) 7.25 (1H, d, J 1.5), 6.25 (1H, d, J 1.5),
4.74–4.64 (1H, m), 4.48–4.37 (1H, m), 3.48 (1H, dd, J 9.0 and
3.0), 3.35–3.23 (1H, m), 3.26 (3H, s), 3.12 (3H, s), 3.04–2.88
(2H, m), 2.25 (3H, s), 2.20–1.79 (4H, m); δC (75 MHz, CDCl3)
2965, 2874, 1617 (C᎐O); δ (200 MHz, CDCl3) 7.38–7.22 (6H,
᎐
H
m), 6.30 (1H, d, J 1.5), 4.61–4.43 (m, 3H), 3.96–3.45 (m, 4H),
2.35 (3H, s) and 2.17–1.80 (4H, m); δC (75 MHz, CDCl3) 159.8,
143.4, 141.8, 139.5, 129.6, 128.2, 127.4, 114.8, 73.1, 70.2, 57.2,
48.5, 27.0, 24.8, 11.7; m/z (CI) 300 (M ϩ Hϩ, 100%); [α]D Ϫ154.6
(c 0.57 in CH2Cl3).
159.5 (C᎐O), 142.9, 141.5, 128.5, 114.8, 73.7, 71.8, 58.9, 58.8,
᎐
57.4, 57.0, 27.3, 23.9, 11.5; m/z (CI) 268 (M ϩ Hϩ, 100%); [α]D
Ϫ123.8 (c 0.64 in EtOH).
(2S,2ЈS,5ЈS)-[2Ј,5Ј-Bis(methoxymethyl)-2Ј,3Ј,4Ј,5Ј-tetrahydro-
1ЈH-pyrrol-1Ј-yl](2,3-dimethyl-2,5-dihydrofuran-2-yl)methanone
16
(2R,2ЈS)-(2,3-Dimethyl-2,5-dihydrofuran-2-yl)[2Ј-(hydroxy-
methyl)-2Ј,3Ј,4Ј,5Ј-tetrahydro-1ЈH-pyrrol-1Ј-yl]methanone 12
A solution of 15 (1.0 g, 3.7 mmol) in THF (15 ml) was added to
ammonia (200 ml) at Ϫ78 ЊC under N2. Freshly cut sodium (258
mg, 11.2 mmol) was then added, and the mixture stirred at
Ϫ78 ЊC for 30 min, during which time the solution became blue.
Isoprene was then added to disperse the blue colour, followed
immediately by methyl iodide (700 µl, 11 mmol), which resulted
in the yellow solution becoming colourless. After stirring for
a further 40 min, the reaction was quenched by the addition
of solid ammonium chloride (0.5 g) and the stoppers removed
Compound 11 (500 mg, 1.7 mmol) was stirred in THF (10 ml)
and ammonia (120 ml) at Ϫ78 ЊC. Lithium (58 mg, 8.4 mmol)
was added to the reaction and stirred for 1 h, during which time
the reaction became blue. Isoprene was then added followed
by methyl iodide (474 µl, 3.3 mmol) and the reaction mix-
ture became colourless. Ammonium chloride (0.5 g) was added,
and the ammonia then allowed to evaporate. The residue
was extracted into ethyl acetate (4 × 50 ml) and evaporated to
3728
J. Chem. Soc., Perkin Trans. 1, 2000, 3724–3731

View Article Online
from the reaction flask to allow evaporation of ammonia. The
residual tetrahydrofuran was removed under reduced pressure
and the crude product was purified by column chromatography,
eluting with 25% ethyl acetate–petrol, to afford 16 as a yellow
oil (1.04 g, 98%) (Found M ϩ Hϩ, 284.1853. C15H25NO4
requires M ϩ Hϩ, 284.1862); νmax/cmϪ1 1621 (C᎐O); δ (300
MHz, CDCl3) 5.48–5.45 (1H, m), 4.67 (1H, m), 4.57–4.53 (2H,
m), 4.23 (1H, m), 3.45 (1H, dd, J 9.0 and 3.0), 3.30–3.09 (2H,
m), 3.27 (3H, s), 3.21 (3H, s), 2.97 (1H, t, J 9.0), 2.12–1.74 (7H,
(2S,2ЈS,5ЈS)-[2Ј,5Ј-Bis(methoxymethyl)-2Ј,3Ј,4Ј,5Ј-tetrahydro-
1ЈH-pyrrol-1Ј-yl](2-ethyl-3-methyl-2,5-dihydrofuran-2-yl)-
methanone 19
Sodium (50 mg, 2.1 mmol) was added to a solution of 15 (240
mg, 0.9 mmol) in THF (10 ml) and ammonia (100 ml) at
Ϫ78 ЊC and stirred for 25 min during which time the reaction
turned blue. The colour was dispersed with isoprene followed
by ethyl iodide (217 µl, 0.27 mmol) and after 30 min stirring
at Ϫ78 ЊC the reaction was quenched with saturated (aq.)
ammonium chloride (2 ml) and the ammonia allowed to evap-
orate. The residue was extracted with ethyl acetate (4 × 50 ml)
and the combined organics dried (MgSO4) and evaporated to
dryness under reduced pressure to give the crude product as
an orange oil. Column purification, eluting with 25% ethyl
acetate–petrol, afforded 19 as a clear oil (197 mg, 74%) (Found
M ϩ Hϩ, 298.2015, C16H27NO4 requires M ϩ Hϩ, 298.2018);
᎐
H
m), 1.44 (3H, s); δ (75 MHz, CDCl ) 172.1 (C᎐O), 140.9, 120.3,
᎐
C
3
93.3, 74.0, 73.0, 71.3, 58.7, 58.6, 57.9, 57.6, 27.3, 25.9, 23.3,
12.7; m/z (CI) 284 (M ϩ Hϩ, 100%); [α]D Ϫ107.1 (c 2.0 in
EtOH).
(2S,2ЈS,5ЈS)-[2Ј,5Ј-Bis(methoxymethyl)-2Ј,3Ј,4Ј,5Ј-tetrahydro-
1ЈH-pyrrol-1Ј-yl](2-benzyl-3-methyl-2,5-dihydrofuran-2-yl)-
methanone 17
νmax/cmϪ1 1619 (C᎐O); δ (300 MHz, CDCl ) 5.50 (1H, dd, J 3.0
᎐
H
3
To a solution of 15 (200 mg, 0.75 mmol) in THF (8 ml) and
ammonia (120 ml) at Ϫ78 ЊC was added sodium (52 mg, 2.3
mmol). The reaction was stirred for 25 min during which time
the reaction mixture turned blue. Isoprene was then added until
the blue colour was dispersed, followed by addition of benzyl
bromide (257 µl, 2.3 mmol). After 1 min the reaction mixture
became colourless and after a further 10 min stirring, the
reaction was quenched by the addition of saturated (aq.)
ammonium chloride solution (1 ml). The ammonia was then
allowed to evaporate, and the resulting residue was extracted
into ethyl acetate (4 × 50 ml). The combined organics were
dried (MgSO4) and evaporated under reduced pressure to give a
brown oil. The crude material was purified by column chrom-
atography, eluting with 30% ethyl acetate–petrol to give 17
as a yellow oil (153 mg, 57%) (Found M ϩ Hϩ, 360.2171.
C21H29NO4 requires M ϩ Hϩ, 360.2175); νmax/cmϪ1 2922, 1618
and 1.5), 4.76 (1H, m), 4.60–4.58 (2H, m), 4.30 (1H, m), 3.49
(1H, dd, J 9.0 and 3.0), 3.30 (3H, s), 3.26 (3H, s), 3.24–3.12 (2H,
m), 3.00 (1H, t, J 9.0), 2.10–1.68 (9H, m), 0.82 (3H, t, J 7.5);
δ (75 MHz, CDCl ) 171.8 (C᎐O), 139.3, 121.1, 96.5, 74.2, 73.8,
᎐
C
3
71.4, 60.2, 58.7, 58.0, 57.6, 27.3, 23.2, 14.0, 12.9, 7.5; m/z (CI)
298 (M ϩ Hϩ, 100%); [α]D Ϫ146.2 (c 1.2 in EtOH).
(2S,2ЈS,5ЈS)-[2Ј,5Ј-Bis(methoxymethyl)-2Ј,3Ј,4Ј,5Ј-tetrahydro-
1ЈH-pyrrol-1Ј-yl](2-allyl-3-methyl-2,5-dihydrofuran-2-yl)-
methanone 20
A solution of 15 (500 mg, 1.9 mmol) in THF (8 ml) was added
to ammonia (80 ml) at Ϫ78 ЊC. To this was added sodium (130
mg, 5.6 mmol), and the reaction stirred for 40 min. Isoprene
was then added to the blue solution until the colour changed to
yellow, followed by the immediate addition of allyl bromide
(485 µl, 5.6 mmol). The solution then became pink, but after
10 min the yellow colour returned. After 1 h stirring at Ϫ78 ЊC,
the reaction was quenched by the addition of saturated (aq.)
ammonium chloride (2 ml) and the ammonia allowed to evap-
orate, and the residue extracted into ethyl acetate (4 × 75 ml).
The combined organics were dried (MgSO4) and evaporated to
dryness under reduced pressure to yield the crude product as a
yellow oil. The crude product was purified by column chrom-
atography (25% ethyl acetate–petrol) to give 20 as a pale yellow
oil (358 mg, 62%) (Found M ϩ Hϩ, 310.2018. C17H27NO4
requires M ϩ Hϩ, 310.2018); νmax/cmϪ1 3062, 2976, 2854 and
(C᎐O); δH (300 MHz, CDCl3) 7.37–7.15 (5H, m), 5.50 (1H, m),
᎐
4.69 (1H, m), 4.51 (1H, m), 4.31–4.24 (2H, m), 3.34–3.20 (10H,
m), 3.15 (1H, dd, J 8.5, 3.5), 2.85 (1H, t, J 8.5), 1.89–1.77 (7H,
m); δC (75 MHz, CDCl ) 170.1 (C᎐O), 139.2, 136.7, 130.8,
᎐
3
127.4, 126.2, 122.1, 96.5, 74.2, 73.6, 71.1, 58.7, 58.6, 58.0, 57.5,
44.3, 27.1, 22.9, 13.2; m/z (CI) 360 (M ϩ Hϩ, 100%), 268
(M Ϫ 91), 173 (M Ϫ 186); [α]D Ϫ132.5 (c 1.5, in EtOH).
(2S,2ЈS,5ЈS)-[2Ј,5Ј-Bis(methoxymethyl)-2Ј,3Ј,4Ј,5Ј-tetrahydro-
1ЈH-pyrrol-1Ј-yl](2-isobutyl-3-methyl-2,5-dihydrofuran-2-yl)-
methanone 18
1619 (C᎐O); δ (300 MHz, CDCl ) 5.77–5.66 (1H, m), 5.58 (1H,
᎐
H
3
A solution of 15 (115 mg, 0.43 mmol) in THF (5 ml) and
ammonia (50 ml) was stirred at Ϫ78 ЊC. Freshly cut sodium (30
mg, 1.3 mmol) was then added, and the mixture stirred at
Ϫ78 ЊC for 30 min, during which time the solution turned from
yellow to blue. Isoprene was then added to disperse the blue
colour, followed immediately by isobutyl iodide (250 µl, 2.15
mmol). After stirring for 4 h, the pale yellow reaction mixture
was quenched by the addition of saturated (aq.) ammonium
chloride solution (1 ml) and the ammonia was allowed to evap-
orate. The residue was extracted with ethyl acetate (4 × 25 ml),
and the combined organics washed with brine, then dried
(MgSO4) and evaporated to dryness under reduced pressure to
yield a brown oil. The crude product was purified by column
chromatography, eluting with 25% ethyl acetate–petrol, to
afford 18 as a yellow oil (95 mg, 68%) (Found M ϩ Hϩ,
326.2336. C18H31NO4 requires M ϩ Hϩ, 326.2331); νmax/cmϪ1
m), 5.13–5.02 (2H, m), 4.76 (1H, m), 4.60–4.59 (2H, m), 4.31
(1H, m), 3.48 (1H, dd, J 9.0 and 3.0), 3.31 (3H, s), 3.25 (3H, s),
3.31–3.13 (2H, m), 3.00 (1H, t, J 9.0), 2.78 (1H, dd, J 14.0 and
7.0), 2.53 (1H, dd, J 14.0 and 7.0), 2.05–1.70 (7H, m); δC (75
MHz, CDCl ) 171.0 (C᎐O), 139.1, 132.9, 121.4, 118.1, 95.8,
᎐
3
74.1, 73.9, 71.4, 58.7, 58.1, 57.6, 43.3, 27.3, 23.2, 12.8; m/z (CI)
310 (M ϩ Hϩ, 100%); [α]D Ϫ156.3 (c 0.53 in EtOH).
(2S,2ЈS,5ЈS)-[2Ј,5Ј-Bis(methoxymethyl)-2Ј,3Ј,4Ј,5Ј-tetrahydro-
1ЈH-pyrrol-1Ј-yl](3-methyl-2,5-dihydrofuran-2-yl)methanone 21
To a solution of 15 (500 mg, 1.9 mmol) in THF (8 ml) and
ammonia (100 ml) at Ϫ78 ЊC, was added sodium (130 mg, 5.6
mmol). This mixture was stirred for 20 min to allow dissolution
of the metal, then isoprene was added to disperse the blue
colour, followed by immediate addition of saturated (aq.)
ammonium chloride solution (2 ml). The colourless solution
was allowed to warm to room temperature with evaporation of
the ammonia, then the residue was extracted into ethyl acetate
(4 × 75 ml). The combined organics were dried (MgSO4) and
evaporated to dryness under reduced pressure to give the crude
product as a yellow oil. The crude product was purified by
column chromatography, eluting with 25% ethyl acetate–petrol,
to afford two compounds as colourless oils, 21 (298 mg, 60%)
and its diastereoisomer (29 mg, 5%). Compound 21 (Found
1619 (C᎐O); δ (300 MHz, CDCl ) 5.47 (1H, dd, J 3.0 and 1.5),
᎐
H
3
4.75 (1H, m), 4.52 (2H, m), 4.25 (1H, m), 3.45 (1H, dd, J 9.0
and 3.0), 3.25 (3H, s), 3.20 (3H, s), 3.27–3.17 (1H, m), 3.10 (1H,
dd, J 8.5 and 2.5), 2.94 (1H, t, J 9.0), 2.02 (1H, dd, J 14.0 and
5.5), 2.05–1.75 (7H, m), 1.69–1.58 (1H, m), 1.42 (1H, dd, J 14.0
and 7.0), 0.87 (3H, d, J 6.5), 0.83 (3H, d, J 6.5); δC (75 MHz,
CDCl ) 171.8 (C᎐O), 140.8, 120.7, 96.9, 74.1, 73.2, 71.3, 58.6,
᎐
3
58.6, 58.0, 57.7, 46.8, 27.3, 24.5, 24.2, 23.7, 23.2, 13.1; m/z (CI)
326 (M ϩ Hϩ, 100%); [α]D Ϫ131.6 (c 1.02 in EtOH).
J. Chem. Soc., Perkin Trans. 1, 2000, 3724–3731
3729

View Article Online
M ϩ Hϩ, 270.1702. C14H23NO4 requires M ϩ Hϩ, 270.1705);
νmax/cmϪ1 2971, 2858, 1655 (C᎐O); δ (360 MHz, CDCl3) 5.61
(1H, br s), 5.29–5.22 (1H, m), 4.83–4.75 (1H, m), 4.63–4.55
(1H, m), 4.18 (1H, m), 4.10 (1H, m), 3.43–3.34 (3H, m), 3.27
(3H, s), 3.22 (3H, s), 3.16 (1H, t, J 9.0), 2.12–1.80 (4H, m), 1.66
mixture was extracted immediately with ethyl acetate (4 × 50
ml), and the combined organics were dried (MgSO4) and
evaporated to dryness under reduced pressure, to give the
title compound as a brown oil (400 mg, 86%); [α]D Ϫ79.1
(c 0.21 in EtOH). Other spectroscopic data were as reported
above.
᎐
H
(3H, s); δC (75 MHz, CDCl ) 170.3 (C᎐O), 135.0, 123.2, 86.1,
᎐
3
76.8, 74.2, 71.5, 59.2, 58.8, 57.5, 57.2, 27.5, 25.0, 11.9; m/z (CI)
270 (M ϩ Hϩ, 100%); [α]D Ϫ155.4 (c 5.4 in EtOH).
(2S)-2-Benzyl-3-methyl-2,5-dihydrofuran-2-carboxylic acid 25
Minor diastereoisomer 21 (Found M ϩ Hϩ, 270.1700.
C14H23NO4 requires M ϩ Hϩ, 270.1705); νmax/cmϪ1 2071, 1656
Compound 17 (62 mg, 0.17 mmol) was heated at reflux in 2 M
(aq.) hydrochloric acid (2 ml, 4 mmol) for 10 h. The reaction
mixture was extracted into ethyl acetate (4 × 15 ml) and the
combined organics were dried (MgSO4), and evaporated to
dryness under reduced pressure to give the crude product as a
brown oil. Column purification, eluting with 20% ethyl acetate–
petrol containing 5% acetic acid, afforded 25 as an orange oil
(30 mg, 80%) (Found MϩϩH2O, 236.1045. C13H14O3 requires
MϩϩH2O, 236.1048); νmax/cmϪ1 3250–3100 (br, OH), 3031,
2920, 1728; δH (250 MHz, CDCl3) 7.31–7.19 (5H, m), 5.52 (1H,
dd, J 3.0 and 1.5), 4.67–4.58 (1H, m), 4.43–4.32 (1H, m), 3.29
(1H, d, J 14.0), 3.07 (1H, d, J 14.0), 1.96–1.90 (3H, m); δC (75
(C᎐O); δ (250 MHz, CDCl3) 5.60–5.58 (1H, m), 5.28–5.22
᎐
H
(1H, m), 4.70–4.60 (2H, m), 4.28–4.10 (2H, m), 3.56 (1H, dd,
J 9.5 and 3.0), 3.38–3.16 (3H, m), 3.27 (3H, s), 3.26 (3H, s),
2.15–1.70 (7H, m); δC (75 MHz, CDCl ) 169.7 (C᎐O), 135.1,
᎐
3
122.8, 87.2, 75.7, 75.1, 70.9, 59.0, 58.8, 57.2, 56.8, 27.1, 24.9,
12.7; m/z (CI) 270 (M ϩ Hϩ, 100%).
(2ЈS,5ЈS)-[2Ј,5Ј-Bis(methoxymethyl)-2Ј,3Ј,4Ј,5Ј-tetrahydro-1ЈH-
pyrrol-1Ј-yl](2-furyl)methanone 23
Furoyl chloride 22 (309 µl, 3.1 mmol) was added dropwise to a
stirring mixture of (S,S)-bis(methoxymethyl)pyrrolidine (500
mg, 3.1 mmol) in 3 M aq. sodium hydroxide (5 ml) and dichlo-
romethane (5 ml) at 0 ЊC. The reaction was stirred overnight at
room temperature, and dichloromethane was then removed
under reduced pressure. The residue was extracted into ethyl
acetate (4 × 50 ml) and the combined organic layers dried
(MgSO4) and evaporated to dryness under reduced pressure to
give 23 as a cream solid (784 mg, 99%). Mp 41–43 ЊC (Found C,
61.56; H, 7.79; N, 5.58%. C13H19NO4 requires C, 61.64; H, 7.56;
N, 5.53%; Found M ϩ Hϩ, 254.1389. C13H19NO4 requires
M ϩ Hϩ, 254.1392); νmax/cmϪ1 2978, 1617 (C᎐O); δ (300 MHz,
MHz, CDCl ) 173.0 (C᎐O), 135.7, 135.1, 130.2, 128.0, 126.8,
᎐
3
123.2, 94.4, 74.8, 40.9, 12.4; m/z (CI) 236 (M ϩ H2Oϩ, 100%),
173 (M Ϫ CO2H).
(2S)-2-Ethyl-3-methyl-2,5-dihydrofuran-2-carboxylic acid 26
Compound 19 (82 mg, 0.28 mmol) was refluxed in 6 M (aq.)
hydrochloric acid (1 ml) for 4 h. The reaction mixture was
extracted into ethyl acetate (4 × 30 ml) and the combined
organics were dried (MgSO4) and evaporated to dryness under
reduced pressure to give a brown oil. Column purification, elut-
ing with 30% ethyl acetate–petrol containing 5% acetic acid,
afforded 26 as a yellow oil (32 mg, 74%) (Found Mϩ Ϫ CO2H,
111.0808. C8H12O3 requires Mϩ Ϫ CO2H, 111.0810); νmax/cmϪ1
᎐
H
CDCl3) 7.51 (1H, dd, J 3.4 and 1.8), 7.15 (1H, dd, J 3.4 and
0.8), 6.51 (1H, dd, J 3.4 and 1.8), 4.78–4.67 (1H, m), 4.48–4.36
(1H, m), 3.56–3.48 (1H, m), 3.35 (1H, t, J 8.0), 3.28 (3H, s), 3.19
(3H, s), 3.14–3.08 (2H, m), 2.22–1.83 (4H, m); δC (75 MHz,
3400 (br, OH), 1720 (C᎐O); δ (300 MHz, CDCl ) 5.56 (1H, m),
᎐
H
3
4.73–4.52 (2H, m), 1.98–1.66 (5H, m), 0.82 (3H, t, J 7.5); δC (75
CDCl ) 158.1 (C᎐O), 148.7, 143.6, 116.6, 111.5, 73.9, 71.7, 59.0,
᎐
3
58.9, 57.8, 57.3, 27.4, 24.1; m/z (CI) 254 (M ϩ Hϩ, 100%); [α]D
Ϫ103.8 (c 0.45 in CH2Cl2).
3
MHz, CDCl ) 173.9 (C᎐O), 135.8, 122.5, 94.6, 74.8, 28.0, 12.1,
᎐
7.3; m/z (CI) 111 (M Ϫ CO2H, 100%); [α]D Ϫ127.3 (c 0.59 in
EtOH).
(2SR,2ЈS,5ЈS)-[2Ј,5Ј-Bis(methoxymethyl)-2Ј,3Ј,4Ј,5Ј-tetra-
hydro-1ЈH-pyrrol-1Ј-yl](2-methyl-2,5-dihydrofuran-2-yl)-
methanone 24
(2S)-2-Isobutyl-3-methyl-2,5-dihydrofuran-2-carboxylic acid 27
Compound 18 (280 mg, 0.86 mmol) was refluxed in 6 M (aq.)
hydrochloric acid (3 ml) for 6 h. The reaction mixture was
extracted into ethyl acetate (4 × 50 ml), the combined organics
were dried (MgSO4), and evaporated to dryness under reduced
pressure to yield a brown oil. Column purification, eluting with
30% ethyl acetate–petrol containing 5% acetic acid, afforded
27 as a yellow oil (105 mg, 68%) (Found M ϩ NH4ϩ, 202.1440,
C10H16O3 requires M ϩ NH4ϩ, 202.1443); νmax/cmϪ1 3300, (br,
OH), 1710 (C᎐O); δ (250 MHz, CDCl3) 5.54 (1H, d, J 1.5),
To a solution of 23 (500 mg, 1.98 mmol) in THF (8 ml) and
ammonia (120 ml) at Ϫ78 ЊC was added sodium (136 mg, 5.9
mmol). The reaction was stirred for 30 min during which time
the reaction turned blue. Isoprene was then added until the
blue colour was dispersed, followed by addition of methyl
iodide (370 µl, 5.9 mmol). After 30 min the reaction mixture was
colourless and was quenched by the addition of saturated
(aq.) ammonium chloride solution (1 ml). Ammonia was then
allowed to evaporate, and the resulting residue was extracted
into ethyl acetate (4 × 50 ml). The combined organics were
dried (MgSO4) and evaporated under reduced pressure to give a
brown oil. The crude material was purified by column chrom-
atography, eluting with 20% ethyl acetate–petrol to give 24
(59:41 mixture of diastereoisomers) as a yellow oil (239 mg,
45%) (Found M ϩ Hϩ, 270.1701. C14H23NO4 requires M ϩ Hϩ,
270.1705); νmax/cmϪ1 2976, 2856, 1621 (C᎐O); δ (300 MHz,
᎐
H
4.70–4.53 (2H, m), 1.75 (3H, d, J 2.0), 1.90–1.57 (3H, m), 0.86
(6H, t, J 6.5); δ (75 MHz, CDCl ) 175.3 (C᎐O), 137.0, 122.3,
᎐
C
3
ϩ
93.9, 74.3, 43.0, 24.3, 23.9, 23.3, 12.2; m/z (CI) 202 (M ϩ NH4
100%); [α]D Ϫ53.1 (c 0.10 in EtOH).
,
(5S,8SR)-4,8–Dimethyl-1,7-dioxaspiro[4.4]non-3-en-6-one
28/29
᎐
H
Compound 20 (60 mg, 0.19 mmol) was heated at reflux in 6 M
(aq.) hydrochloric acid for 24 h, followed by a further 48 h at
room temperature. The acidic solution was extracted into ethyl
acetate (4 × 20 ml) and the combined organics were dried
(MgSO4). Evaporation under reduced pressure afforded the
two lactones as a brown oil. Column purification, eluting with
20% ethyl acetate–petrol afforded the two diastereoisomers
(28: 23 mg, 72%) and (29: 7 mg, 22%). Compound 28 (Found
M ϩ NH4ϩ, 186.1132. C9H12O3 requires M ϩ NH4ϩ, 186.1130);
CDCl3) 6.07–5.80 (2H, m), 4.74–4.11 (4H, m), 3.57–2.98 (10H,
m), 2.07–1.71 (4H, m), 1.50, 1.43 (3H, s); δC (75 MHz, CDCl3)
173.2, 172.8 (C᎐O), 133.5, 132.8, 125.3, 125.1, 93.3, 93.2, 75.4
᎐
75.2, 74.7, 74.5, 71.4, 71.1, 58.8, 58.6, 58.6, 58.6, 58.1, 57.6,
57.6, 57.4, 27.3, 27.1, 27.0, 26.0, 23.6, 23.3; m/z (CI) 270
(M ϩ Hϩ,100%).
(2S)-2,3-Dimethyl-2,5-dihydrofuran-2-carboxylic acid 13
Aqueous hydrochloric acid (2 M, 10 ml) was added to 16 (927
mg, 3.3 mmol) and the reaction heated at reflux for 6 h. The
νmax/cmϪ1 1769 (C᎐O); δ (360 MHz, CDCl ) 5.70 (1H, d, J 1.5),
᎐
H
3
4.77–4.71 (1H, m), 4.61–4.51 (2H, m), 2.51 (1H, dd, J 13.5 and
3730
J. Chem. Soc., Perkin Trans. 1, 2000, 3724–3731

View Article Online
7.0), 1.99 (1H, dd, J 13.5 and 7.0), 1.71–1.70 (3H, m), 1.41 (3H,
References
d, J 6.0); δ (90.5 MHz, CDCl ) 175.9 (C᎐O), 134.8, 125.0, 92.1,
᎐
C
3
1 For reviews see: T. J. Donohoe, R. Garg and C. A. Stevenson,
Tetrahedron: Asymmetry, 1996, 7, 317; T. J. Donohoe, P. M. Guyo
and A. Raoof, Targets in Heterocyclic Systems, Italian Society of
Chemistry, 1999, 3, pp. 117–145.
2 For reviews of the Birch reduction see: L. N. Mander, in
Comprehensive Organic Synthesis, ed. B. M. Trost and I. Fleming,
Pergamon, New York, 1991, vol. 8; P. W. Rabideau and Z. Marcinow,
Org. React., 1992, 42, 1; P. W. Rabideau, Tetrahedron, 1989, 45, 1579.
3 T. J. Donohoe and P. M. Guyo, J. Org. Chem., 1996, 61, 7664;
T. J. Donohoe, P. M. Guyo, R. L. Beddoes and M. Helliwell,
J. Chem. Soc., Perkin Trans. 1, 1998, 667; T. J. Donohoe, R. R. Harji
and R. P. C. Cousins, Tetrahedron Lett., 2000, 41, 1331.
4 T. J. Donohoe, unpublished results.
75.6, 73.9, 40.1, 22.1, 11.6; m/z (CI) 186 (M ϩ NH4ϩ, 100%);
[α]D Ϫ46.7 (c 0.70 in EtOH).
ϩ
Compound 29 (Found M ϩ NH4
, 186.1137. C9H12O3
requires M ϩ NH4ϩ, 186.1130); νmax/cmϪ1 1771 (C᎐O); δ (360
᎐
H
MHz, CDCl3) 5.85 (1H, dd, J 3.0 and 1.5), 4.81–4.60 (3H, m),
2.33 (1H, dd, J 14.0 and 5.5), 1.95 (1H, dd, J 14.0 and 9.5),
1.75–1.73 (3H, m), 1.45 (3H, d, J 6.0); δC (90.5 MHz, CDCl3)
174.4 (C᎐O), 133.4, 125.6, 92.5, 75.0, 74.8, 40.2, 20.7, 11.5; m/z
᎐
(CI) 186 (M ϩ NH4ϩ, 100%).
(2S,1ЈR)-N-(1Ј-Phenylethyl)-2,3-dimethyl-2,5-dihydrofuran-2-
5 T. Kinoshita and T. Miwa, Carbohydr. Res., 1973, 28, 175;
T. Kinoshita, K. Miyano and T. Miwa, Bull. Chem. Soc. Jpn., 1975,
48, 1865; J. Slobbe, Aust. J. Chem., 1976, 29, 2553; T. Kinoshita and
T. Miwa, Bull. Chem. Soc. Jpn., 1978, 51, 223: see also reference 8.
6 For recent references see: A. G. Schultz, T. J. Guzi, E. Larsson,
R. Rahm, K. Thakkar and J. M. Bidlack, J. Org. Chem., 1998, 63,
7795; A. G. Schultz, M. A. Holoboski and M. S. Smyth, J. Am.
Chem. Soc., 1996, 118, 6210 and references therein.
carboxamide 30
To a solution of (–)-13 (100 mg, 0.70 mmol) in THF (5 ml) was
added CDI (125 mg, 0.78 mmol) and the mixture stirred for 1 h
at room temperature. (R)-(ϩ)-α-Methylbenzylamine (100 µl,
0.78 mmol) was then added and the reaction stirred overnight
at room temperature. THF was then removed under reduced
pressure, and the residue dissolved in ether (30 ml), and washed
successively with 2 M (aq.) hydrochloric acid (5 ml), saturated
aq. sodium bicarbonate solution (5 ml) and brine (5 ml). The
solution was dried (MgSO4) and evaporated under reduced
pressure to give the crude product as a brown oil. Column puri-
fication, eluting with 30% ethyl acetate–petrol, afforded 30 as a
yellow solid (116 mg, 52%), which was further purified by
recrystallisation from dichloromethane–pentane to give colour-
less crystals. Mp 210–211 ЊC (Found C, 73.18; H, 8.03; N,
5.58%. C15H19NO2 requires C, 73.31; H, 7.79; N, 5.88%. Found
Mϩ, 245.1407. C15H19NO2 requires Mϩ, 245.1416); νmax/cmϪ1
7 T. J. Donohoe, M. Helliwell, C. A. Stevenson and T. Ladduwahetty,
Tetrahedron Lett., 1998, 39, 3071.
8 I. M. Coggiola, Nature (London), 1963, 200, 954; T. Kinoshita and
T. Miwa, J. Chem. Soc., Chem. Commun., 1974, 181; T. Masamune,
M. Ono and H. Matsue, Bull. Chem. Soc. Jpn., 1975, 48, 491; A. J.
Birch and J. Slobbe, Tetrahedron Lett., 1975, 627; A. J. Birch and
J. Slobbe, Tetrahedron Lett., 1976, 2079; J. E. Semple, P. C. Wang,
Z. Lysenko and M. M. Joullie, J. Am. Chem. Soc., 1980, 102, 7505;
Y. Ohta, M. Onoshima, M. Tamura, R. Tanaka, Y. Morimoto,
K. Yoshihara and T. Kinoshita, J. Heterocycl. Chem., 1998, 35, 461.
9 T. Kinoshita, D. Ichinari and J. Sinya, J. Heterocycl. Chem., 1996,
33, 1313.
10 See: I. Fleming, Frontier Orbitals and Organic Chemical Reactions,
Wiley, New York, 1976, p. 45.
2971, 2926, 1667 (C᎐O); δ (360 MHz, CDCl3) 7.26–7.14 (5H,
᎐
H
m), 5.38 (1H, m), 4.98 (1H, quintet, J 7.0), 4.59–4.85 (2H, m),
1.76–1.74 (3H, m), 1.43–1.41 (6H, m); δC (100 MHz, CDCl3)
11 A. G. Shultz, M. Macielag, P. Sundaraman, A. G. Taveras and
M. Welch, J. Am. Chem. Soc., 1988, 110, 7828.
12 Both enantiomers of this amine can also be prepared on a large
scale, see: Y. Yamamoto, J. Hoshino, Y. Fujimoto, J. Ohmoto and
S. Sawada, Synthesis, 1993, 298.
13 W. Bauer, T. Laube and D. Seebach, Chem. Ber., 1985, 118, 764;
T, Laube, J. D. Dunitz and D. Seebach, Helv. Chim. Acta, 1985, 68,
1373.
14 For examples see: T. J. Donohoe, C. A. Stevenson, M. Helliwell,
R. Irshad and T. Ladduwahetty, Tetrahedron: Asymmetry, 1999, 10,
1315; T. J. Donohoe, J.-B. Guillermin, C. Frampton and D. S.
Walters, Chem. Commun., 2000, 465.
172.0 (C᎐O), 143.4, 140.0, 128.8, 127.0, 125.9, 119.9, 91.9, 73.8,
᎐
48.0, 22.8, 22.0, 12.3; m/z (CI) 246 (M ϩ Hϩ, 100%); [α]D
Ϫ131.56 (c 1.0 in EtOH).
Acknowledgements
We wish to thank Merck Sharp and Dohme and the EPSRC for
funding this project. AstraZeneca Pharmaceuticals (Strategic
Research Fund) and Pfizer are also thanked for unrestricted
financial support.
15 D. D. Perrin, W. L. F. Armarego and D. R. Perrin, Purification of
Laboratory Chemicals, Pergamon Press, Oxford, 1966.
J. Chem. Soc., Perkin Trans. 1, 2000, 3724–3731
3731