A temporary stereocentre approach for the asymmetric synthesis of chiral cyclopropane-carboxaldehydes

Article abstract of DOI:10.1039/b908600e

A novel way of combining chiral auxiliaries and substrate directable reactions is described that employs a three-step sequence of aldol/cyclopropanation/retro-aldol reactions for the asymmetric synthesis of enantiopure cyclopropane-carboxaldehydes. In the first step, reaction of the boron enolate of (S)-N-propionyl-5,5-dimethyl-oxazolidin-2-one with a series of α,β-unsaturated aldehydes affords their corresponding syn-aldol products in high de. In the second step, directed cyclopropanation of the alkene functionalities of these syn-aldols occurs under the stereodirecting effect of their 'temporary'β-hydroxyl stereocentres to give a series of cyclopropyl-aldols in high de. Finally, retro-aldol cleavage of the lithium alkoxide of these cyclopropyl-aldols results in destruction of their temporary β-hydroxy stereocentres to afford the parent chiral auxiliary and chiral cyclopropane-carboxaldehydes in >95% ee. The potential of this methodology has been demonstrated for the asymmetric synthesis of the cyclopropane containing natural product cascarillic acid in good yield.

Full text of DOI:10.1039/b908600e

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PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
A temporary stereocentre approach for the asymmetric synthesis of chiral
cyclopropane-carboxaldehydes†
Matt Cheeseman, Iwan R. Davies, Phil Axe, Andrew L. Johnson and Steven D. Bull*
Received 1st May 2009, Accepted 27th May 2009
First published as an Advance Article on the web 8th July 2009
DOI: 10.1039/b908600e
A novel way of combining chiral auxiliaries and substrate directable reactions is described that employs
a three-step sequence of aldol/cyclopropanation/retro-aldol reactions for the asymmetric synthesis of
enantiopure cyclopropane-carboxaldehydes. In the first step, reaction of the boron enolate of
(S)-N-propionyl-5,5-dimethyl-oxazolidin-2-one with a series of a,b-unsaturated aldehydes affords their
corresponding syn-aldol products in high de. In the second step, directed cyclopropanation of the
alkene functionalities of these syn-aldols occurs under the stereodirecting effect of their ‘temporary’
b-hydroxyl stereocentres to give a series of cyclopropyl-aldols in high de. Finally, retro-aldol cleavage of
the lithium alkoxide of these cyclopropyl-aldols results in destruction of their temporary b-hydroxy
stereocentres to afford the parent chiral auxiliary and chiral cyclopropane-carboxaldehydes in >95% ee.
The potential of this methodology has been demonstrated for the asymmetric synthesis of the
cyclopropane containing natural product cascarillic acid in good yield.
genation, aldol, Mannich and conjugate addition reactions for
stereocontrol.21
Introduction
Chiral aldehydes containing a-stereocentres are widely employed
as versatile chiral building blocks1 for the asymmetric synthesis
of complex natural products2 and drug like molecules,3 which
has resulted in a wide range of methodology being devel-
oped for their asymmetric synthesis. They may be prepared
directly via reduction of chiral amides,4 Weinreb amides,5 N-acyl-
5,5-dimethyl-oxazolidin-2-ones,6 N-acyl-thiazolidine-2-thiones,7
N-acyl-sultams,8 thioesters,9 and oxazolines,10 although the yield
of chiral aldehyde produced may be low due to compet-
ing over-reduction to its corresponding alcohol. Enantiopure
a-substituted aldehydes may also be prepared via oxidation of
their corresponding chiral primary alcohols,11 although care must
be taken to ensure that racemisation of their a-stereocentres does
not occur.12 Alternative oxidative protocols based on the cleavage
of chiral diols,13 or ozonolysis of chiral alkenes/hydrazones
have also been widely reported.14 A wide range of asymmetric
methodologies have also been developed that do not employ
oxidative or reductive steps to generate the aldehyde functionality,
including strategies based on the hydroformylation of alkenes,15
rearrangement reactions,16 conjugate addition reactions,17 cy-
cloaddition reactions,18,19 as well as approaches that rely on the
kinetic resolution of racemic substrates.20 There has also recently
been great progress in the development of efficient organocatalytic
approaches that employ transient iminium/enamine intermediates
for the asymmetric synthesis of chiral a-substituted aldehydes.
These include protocols that employ asymmetric a-halogenation,
a-sulfenylation, epoxidation, cyclopropanation, transfer hydro-
A number of chiral auxiliary based approaches have also
been reported that rely on derivatisation of an achiral aldehyde
with a chiral auxiliary to reversibly afford chiral oxathiane,22
oxazolidine,23 imidazolidine,24 acetal,25 or a-acetoxy-sulfone
equivalents.26 These chiral aldehyde equivalents are then stereose-
lectively transformed into new chiral intermediates that contain
new a-stereogenic centres in high de, with diastereoselectivity
being controlled by the presence of the chiral auxiliary fragment.
Subsequent cleavage of the chiral auxiliary fragment then affords
a chiral aldehyde containing an a-stereogenic centre in high
ee. We are interested in developing new ways of combining
chiral auxiliaries and substrate directable reactions for asymmetric
synthesis, and now report on the development of novel ‘tempo-
rary stereocentre’ methodology that enables chiral cyclopropane-
carboxaldehydes to be prepared in high ee. Part of this research
has been communicated previously.27
Results and discussion
We were interested in developing new methodology for the asym-
metric synthesis of chiral cyclopropane-carboxaldehydes using a
novel ‘temporary stereocentre’ approach for stereocontrol that
would employ the stereodirecting ability of a chiral auxiliary
fragment to create remote stereocentres in high de (Scheme 1).28
In this ‘temporary stereocentre’ approach it was envisaged that
an N-acyl-oxazolidin-2-one 1 would react as a chiral auxiliary
with an a,b-unsaturated aldehyde 2 to afford syn-aldol 3 in high
de (Step 1). Secondly, stereoselective cyclopropanation of the
alkene functionality of syn-aldol 3 would then occur under the
stereodirecting effect29 of its b-hydroxyl functionality to afford
cyclopropyl-aldol 4 with good levels of diastereocontrol (Step 2).
Finally, retro-aldol fragmentation of cyclopropyl-aldol 4 would
occur to afford the desired chiral cyclopropane-carboxaldehyde 5
Department of Chemistry, University of Bath, Bath, UK BA2 7AY. E-mail:
s.d.bull@bath.ac.uk
† Electronic supplementary information (ESI) available: Additional exper-
imental procedures and characterisation data. CCDC reference number
257652. For ESI and crystallographic data in CIF or other electronic
format see DOI: 10.1039/b908600e
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Scheme 1 Three-step protocol for the asymmetric synthesis of chiral cyclopropane-carboxaldehydes 5.
and chiral auxiliary 1 that could be recycled as required (Step 3).30
The overall outcome of this three-step protocol would therefore
be the stereoselective transformation of achiral a,b-unsaturated
aldehyde 2 into enantiopure cyclopropane-carboxaldehyde 5, us-
ing reversible formation of the temporary b-hydroxyl stereocentre
of syn-aldol 3 to control the diastereofacial selectivity of its
cyclopropanation reaction (Scheme 1).
There was well established precedent that reaction of (Z)-boron
enolates of N-propionyl-oxazolidin-2-ones 1 with a,b-unsaturated
aldehydes 2 should afford b-vinyl-syn-aldols 3 in high de.31
Furthermore, it was known that stereoselective cyclopropanation
of the alkene functionalities of syn-aldols 3 using coordinated
zinc carbenoid species should occur under the stereodirecting
effect of their b-hydroxyl functionalities to afford cyclopropyl-
aldols 4 in high de.32 Whilst we could find no previous reports of
b-hydroxy-N-acyl-oxazolidin-2-ones undergoing retro-aldol reac-
tions, Bartroli and co-workers had previously described that the
lithium alkoxide of ketol 633 underwent clean retro-ketol cleavage
to afford N-propionyl-oxazolidin-2-one 7 and a-chloroketone 8 in
good yield (Scheme 2).
2,4-dione alkoxide 10,36 that equilibrates to a 1,3-oxazinane-
2,4-dione enolate 11 which eliminates carbon dioxide in situ to
afford (E)-a,b-unsaturated amide 12 in 66% de and 92% yield
(Scheme 3).37
In order to prevent this unwanted rearrangement/cyclisation
pathway from occurring it was decided to employ N-propionyl-
5,5-dimethyl-oxazolidinone 1 as a chiral auxiliary for asymmet-
ric synthesis. These ‘SuperQuat’ 5,5-dimethyl-oxazolidin-2-ones38
were originally developed by Davies and coworkers to address
endocyclic cleavage problems that occur when sterically hindered
N-acyl-oxazolidin-2-ones are treated with hard nucleophiles,39
with their gem-5,5-dimethyl substituents blocking intermolecular
attack of nucleophiles at their oxazolidin-2-one carbonyls.40 We
reasoned that the presence of the gem-5,5-dimethyl substituents of
SuperQuat derived alkoxide 14 would also block intramolecular
attack of its b-alkoxide at its oxazolidin-2-one carbonyl, which
would result in the rearrangement/elimination pathway being
disfavoured, thus allowing the desired retro-aldol cleavage reaction
to proceed. In order to test this hypothesis, syn-aldol 13 was treated
with 1.1 equivalents of LHMDS in toluene at 0 ◦C, which resulted
in formation of a lithium alkoxide 14 that underwent clean retro-
aldol cleavage to afford the parent auxiliary 1 (59%), decanal (52%)
and oxazolidine-2-one 16 (27%).41 In this reaction, it is likely that
lithium alkoxide 14 first undergoes a retro-aldol reaction to afford
decanal and lithium enolate 15 which may be protonated on work-
up to afford N-propionyl-oxazolidin-2-one 1, or decompose via
elimination of a ketene equivalent to afford the lithium anion of
oxazolidin-2-one 16 (Scheme 4).38a
However, although this precedent appeared promising, we
were aware that alkoxides of Evans’ derived N-acyl-oxazolidin-
2-one-syn-aldols did not undergo retro-aldol cleavage, instead
undergoing alternative rearrangement/elimination reactions to
afford trisubstituted (E)-a,b-unsaturated amides in >95% de.34,35
For example, treatment of syn-aldol 9 with LHMDS in toluene at
0 ◦C affords a b-alkoxide that undergoes intramolecular attack at
its oxazolidin-2-one carbonyl to afford an unstable oxazinane-
Scheme 2 Retro-ketol reaction of the lithium alkoxide of ketol 6.
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Scheme 3 Rearrangement/elimination mechanism of potassium alkoxides of (rac)-aldol 9 to afford (E)-a,b-unsaturated amide 12 in high de.
Scheme 4 Retro-aldol reaction of b-hydroxy-N-acyl-5,5-dimethyl-oxazolidin-2-one 13.
Having established conditions that resulted in lithium alkoxides
small J(2,3) coupling constants of <5.0 Hz, in comparison with
the larger J(2,3) coupling constant of >7.0 Hz expected for their
corresponding anti-aldol diastereoisomers.47
of aldol 13 undergoing clean retro-aldol cleavage our attention
then turned towards using N-propionyl-5,5-dimethyl-oxazolidin-
2-one (S)-1 as a chiral auxiliary for the asymmetric synthesis of a
series of chiral cyclopropane-carboxaldehydes 5a-i (see Scheme 1).
It was then necessary to identify conditions that would enable
the alkene functionalities of syn-aldols 3a-h to be cyclopropanated
in high de. It was found that treatment of syn-aldols 3a-h with
Et2Zn and CH2I2 in CH2Cl2 at a temperature between -10
and 0 ◦C resulted in highly diastereoselective cyclopropanation
reactions occurring to afford cyclopropyl-aldols 4a-h in >95%
de and 89–99% yield (Table 2).41 Cyclopropanation of allylic
alcohols under modified Furukawa conditions are known to be
syn-selective due to minimisation of A1,3 strain in the transition
state,48 and as a consequence the configuration of the cyclopropane
rings of cyclopropyl-aldols 4a-h were assigned accordingly.49
The configuration of nitrophenyl-syn-aldol 4d was subsequently
confirmed by X-ray crystallographic analysis, that revealed the all
syn-configuration of the stereocentres contained within its N-acyl
side-chain (Fig. 1). The stereochemical outcome of these cyclo-
propanation reactions is therefore consistent with the hydroxyl
i
Therefore, treatment of (S)-1 with 9-BBN-OTf and Pr2NEt in
CH2Cl2 at 0 ◦C, followed by cooling to -78 ◦C and addition of
the appropriate (E)-a,b-unsaturated aldehyde 2a-g, gave a range
of syn-aldol products 3a-g in >95% de and 76–87% isolated
yields (Table 1).42 (Z)-syn-Aldol 3h was prepared in an alter-
native manner because (Z)-a,b-unsaturated aldehydes are more
difficult to prepare, and likely to isomerise to their corresponding
(E)-isomers under the Lewis acidic conditions used in these
aldol reactions.43 Therefore, reaction of the (Z)-boron enolate of
N-propionyl-5,5-dimethyl-oxazolidin-2-one (S)-1 with oct-2-yn-al
gave an alkyne-aldol 17,44 which was hydrogenated with Lindlar’s
catalyst to give (Z)-syn-aldol 3h in >95% de and an overall 60%
yield (Scheme 5).45 The syn-configuration of aldols 3a-h were
assigned from literature precedent,46 and confirmed from their
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Table 1 Asymmetric synthesis of (E)-syn-aldols 3a-g
aldol-ester 21 that contains a single b-hydroxyl stereocentre. Ester
21 was prepared in three steps via reaction of the (Z)-boron enolate
of a-chloro-propionyl-oxazolidin-2-one 18 with crotonaldehyde
to afford syn-aldol 19 in 83% yield that was a-dechlorinated via
treatment with zinc and ammonium chloride in methanol to afford
syn-aldol 20 in 74% yield,50 which was then cleaved via treatment
with sodium methoxide in 71% yield. Subsequent cyclopropana-
tion of aldol-ester 21 afforded cyclopropyl-aldol 22 in >95% de
and 95% yield, thus confirming the dominant stereodirecting effect
of the b-hydroxyl functionality of aldols 3a-h in controlling the
diastereoselectivity of these type of cyclopropanation reactions
(Scheme 6).
To complete our new three-step synthesis of chiral
cyclopropane-carboxaldehydes it was then necessary to de-
velop conditions that would facilitate retro-aldol cleavage of
b-cyclopropyl-syn-aldols 4a-h to afford (S)-1 and their corre-
sponding cyclopropane-carboxaldehydes 5a-h.51 Screening a range
of conditions revealed that the success or failure of these retro-
aldol reactions was highly dependent on the temperature at which
the cleavage reaction was performed. For example, deprotonation
of syn-aldol 4a with LHMDS in toluene at -20 ◦C for 4 hours
resulted in recovery of large quantities of unreacted syn-aldol 4a
with <10% of any retro-aldol cleavage products. Alternatively,
carrying out the retro-aldol cleavage reaction at 20 ◦C resulted
in complete consumption of syn-aldol 4a to afford its parent
5,5-dimethyl-oxazolidin-2-one 16, with <10% of the desired
cyclopropane-carboxaldehyde 5a being formed. Nevertheless, it
was subsequently found that treatment of cyclopropane aldol 4a
with LHMDS in the non-coordinating solvent toluene at an opti-
mal temperature range of between 0–10 ◦C resulted in retro-aldol
reaction to afford the desired cyclopropane-carboxaldehyde 5a in
>95% de and an acceptable 75% isolated yield. These conditions
were then employed to cleave all of the cyclopropyl-syn-aldols 4b-e
and 4h, to give a range of cyclopropane-carboxaldehydes (S,S)-
5b-e and (1S,2R)-5h in >95% de and 55–73% isolated yields after
purification by chromatography.52
syn-Aldols Yield
Entry Aldehydes 2a-g
R
R1 de (%)a 3a-g
(%)
1
2
3
4
5
6
7
2a
2b
2c
2d
2e
2f
Ph
H
H
H
H
H
H
95
95
95
95
95
95
3a
3b
3c
3d
3e
3f
80
81
77
87
85
76
76
Me(CH2)6-
p-MeOC6H4-
o-NO2C6H4-
2-Furyl-
Me
2g
Me
Me 95
3g
a Diastereoisomeric excess of each syn-aldol reaction determined from
examination of the 1H-NMR spectra of their crude reaction products.
Table 2 Asymmetric synthesis of cyclopropyl-aldols 4a-h
syn-Aldols
Entry 3a-h
Cyclopropyl-
aldols 4a-h
Yield
dea (%) (%)
R
R1
1
2
3
4
5
6
7
8
3a
3b
3c
3d
3e
3f
Ph
H
H
4a
4b
4c
4d
4e
4f
95
95
95
95
95
95
95
95
95
89
90
90
92
99
95
96
Me(CH2)6-
p-MeOC6H4- H
o-NO2C6H4-
2-Furyl-
Me
Me
H
H
H
Me
3g
3h
4g
H
n-C5H11 4h
a Diastereoisomeric excess determined from examination of the crude
300 MHz 1H NMR spectra.
Close examination of the 1H NMR spectra of the crude reaction
products of these retro-aldol reactions revealed that equimolar
amounts (55–75% yield) of the cyclopropane-carboxaldehydes
5a-e and 5h and N-propionyl-oxazolidin-2-one (S)-1 had been
formed in each case, as well as varying amounts of the parent
5,5-dimethyl-oxazolidin-2-one 16 (15–30%) (Table 3). Indeed, it
was apparent that the yields of cyclopropane-carboxaldehyde 5a-
e and 5h obtained were inversely proportional to the amount
of 5,5-dimethyl-oxazolidin-2-one 16 formed, with any decom-
position of enolate 15 being accompanied by a proportional
loss in yield of the corresponding cyclopropane-carboxaldehyde
5a-e/5h. Unfortunately, despite repeated efforts, we were un-
able to isolate/identify any other products formed in these
retro-aldol reactions that might explain the loss in yield of
groups of syn-aldols 4a-h coordinating to a zinc-carbenoid species
which is then delivered to one face of their alkene functionalities
in a syn-selective manner that minimizes A1,3 allylic strain in the
transition state.4
We wished to confirm that the high diastereoselectivities ob-
served in these cyclopropanation reactions of syn-aldols 3a-h was
due to the stereodirecting effect of their b-hydroxyl ‘temporary
stereocentres’ and that the oxazolidin-2-one and a-methyl stereo-
centres were not contributing towards diastereocontrol. Therefore,
it was decided to determine what level of diastereocontrol would
be observed for cyclopropanation of the alkene functionality of
Scheme 5 Asymmetric synthesis of (Z)-syn-b-vinyl-aldol 3h.
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Fig. 1 X-Ray crystal structure of o-nitrophenyl-a-methyl-b-cyclopropyl syn-aldol 4d with selected hydrogen atoms omitted for clarity.
Scheme 6 Highly diastereoselective cyclopropanation reaction of syn-aldol 21.
cyclopropane-carboxaldehydes 5a-e/5h. However, examination of
the 1H NMR spectra of the crude reaction products also revealed
that no epimerisation of the a-stereocentres of the cyclopropane-
carboxaldehydes 5a-e/5h had occurred in these retro-aldol re-
actions. This included cis-cyclopropane-carboxaldehyde (1S,2R)-
5h that was potentially susceptible to epimerisation to its more
thermodynamically stable trans-(R,R)-diastereoisomer under ba-
sic conditions.53 Therefore, since simultaneous scrambling of
their b-stereocentres was unlikely to have occurred, it was con-
cluded that all of the cyclopropane-carboxaldehydes 5a-e and
5h had been formed in >95% ee. The absolute configurations
and high enantiomeric excesses of cyclopropane-carboxaldehydes
(S,S)-5a and (S,S)-5b were subsequently confirmed by compar-
ison of their specific rotations with those previously reported
for their corresponding (R,R)-5a and (S,S)-5b enantiomers
(see Table 3).54,55
Attempts to prepare cyclopropane-carboxaldehydes 5f and
5g using these standard retro-aldol cleavage conditions proved
unsuccessful because their inherent volatility meant that they were
lost during removal of solvent in vacuo as part of the reaction
work-up. To solve this isolation problem, an alternative protocol
was devised in which a solution of one equivalent of LHMDS in
toluene-d8 was added to a solution of cyclopropyl-aldols 4f and
4g in toluene-d8 at 10 ◦C. Each reaction was then quenched with
˚
5 drops of ammonium chloride solution, dried over 3 A molecular
sieves, filtered, and the crude reaction mixtures distilled under at-
mospheric pressure to afford pure cyclopropane-carboxaldehydes
(S,S)-5f and (S)-5g as solutions in toluene-d8 (Scheme 7). The 51%
and 61% yields of the respective cyclopropane-carboxaldehydes
(S,S)-5f (>95% de) and (S)-5g were then calculated by addition of
a known amount of 2,5-dimethylfuran57 as an internal standard
to each toluene-d8 distillate, which enabled their concentration to
be accurately determined by comparison of the relative intensities
of their respective integrals in their 1H NMR spectra.
The enantiomeric excess of dimethyl cyclopropane-carboxal-
dehyde (S)-5g was determined using (S,S)-N,N¢-dimethyl-1,2-
diphenylethane-1,2-diamine 23 as a chiral derivatisation agent
for imidazolidine formation (Scheme 8).58 Examination of the
crude 1H-NMR spectrum of this derivatisation reaction revealed
a single set of resonances corresponding to the formation of a
single imidazolidine diastereoisomer 24, and as a consequence the
enantiomeric excess of cyclopropane-carboxaldehyde (S)-5g was
assigned as >95% ee.59
Asymmetric synthesis of cascarillic acid
Cascarillic acid (1S,2R)-25 is a cyclopropane containing natural
product that is a major component of cascarilla essential oil that
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Table 3 Retro-aldol reactions to afford enantiopure cyclopropane-carboxaldehydes 5a-e and 5h
Cyclopropyl-aldols
4a-e and 4h
Cyclopropane–carboxaldehydes 5a-e
and 5h
25
Entry
1
Temp. (◦C)
0
de (%)a
95
Yield (%)
75
[a]D
4a
4b
4c
+392 (Lit(R,R) = -324)54
+45 (Lit(S,S) = +41)55
+228
2
3
0
5
95
95
73
63
4
4d
10
95
55
+110
5
6
4e
4h
0
0
95
95
71
61
+320
-1056
a Determined by examination of the crude 300 MHz 1H-NMR spectra.
Scheme 7 Retro-aldol protocol for the formation of volatile cyclopropane-carboxaldehydes 5f and 5g.
has been used for many years in the treatment of colds and
bronchitis.60 It contains a trans-cyclopropane ring in its fatty acid
side-chain, whose configuration has been shown to be (3S,4R) via
total synthesis from meso-cis-1,2-dihydroxymethylcyclopropane in
eleven steps.61 It was proposed that our ‘temporary stereocentre’
methodology might prove useful for the efficient preparation
of cascarillic acid (1S,2R)-25 in fewer steps, using a synthetic
strategy whereby cyclopropane-carboxaldehyde (R,R)-5i would
be transformed into the natural product using an oxidative one-
carbon homologation reaction (Fig. 2).62
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Fig. 2 Retrosynthetic analysis of cascarillic acid (1S,2R)-25.
stability of lithium enolates of N-acyl-oxazolidin-2-ones were
known to be highly dependent on the temperature at which they
are generated, with elevated temperatures (>0 ◦C) resulting in
rapid rates of decomposition to afford their parent oxazolidin-2-
one 16.38a,63 Therefore, we proposed that retro-aldol cleavage of
the lithium alkoxide of a-isopropyl-cyclopropyl-aldol 28 might
proceed at a faster rate than for the lithium alkoxide of a-methyl-
cyclopropyl-aldol 4i, because its more sterically demanding
a-isopropyl substituent would result in increased relief of steric
strain that should result in its retro-aldol reaction proceeding
at lower temperature. This would result in the enolate of
N-isovaleroyl-5,5-dimethyl-oxazolidin-2-one 26 being generated
at a lower temperature, resulting in less decomposition and a better
yield of cyclopropane-carboxaldehyde (R,R)-5i being obtained.
Therefore, the boron enolate of N-isovaleroyl-oxazolidin-2-one
(R)-26 was reacted with (E)-non-2-enal under our standard syn-
aldol conditions to afford a-isopropyl-cyclopropyl-aldol 27 in
>95% de and 81% yield, followed by cyclopropanation under our
standard conditions to afford a-isopropyl-aldol 28 in >95% de
and 94% yield. Deprotonation of a-isopropyl-cyclopropyl-aldol
28 with a range of different bases (NaHMDS or KHMDS), at
different temperatures (-78 to 0 ◦C), revealed that optimum retro-
aldol conditions were achieved when a-isopropyl-cyclopropyl-
aldol 28 was treated with 1.1 equivalents of KHMDS in THF at
-40 ◦C. These conditions resulted in formation of cyclopropane-
carboxaldehyde (R,R)-5i in a much improved 85% yield, with
<5% of the parent oxazolidin-2-one (R)-16 being formed from
Scheme 8 Determination of the enantiomeric excess of cyclopropane–
carboxaldehyde 5g.
Therefore, N-propionyloxazolidin-2-one auxiliary (R)-1 was
reacted with (E)-non-2-enal using our standard boron enolate
syn-aldol conditions to afford b-vinyl-syn-aldol 3i in >95% de
and 82% isolated yield, followed by treatment with diethylzinc
and diiodomethane in CH2Cl2 at -10 ◦C to give cyclopropyl-
aldol 4i in >95% de and 93% isolated yield. Cyclopropyl-aldol
4i was then treated with LHMDS in toluene at 0 ◦C to afford
the key cyclopropane-carboxaldehyde (R,R)-5i in a disappointing
55% yield after chromatographic purification (Scheme 9). Analysis
1
of the H NMR spectra of the crude reaction product of this
retro-aldol reaction revealed that oxazolidin-2-one (R)-16 had
also been formed in 35% yield that we had shown was always
accompanied by a proportional loss in yield of its respective
cyclopropane-carboxaldehyde (vide supra). Consequently, it was
decided to redesign the structure of the chiral auxiliary used for
synthesis, with the aim of obtaining a better yield of cyclopropane-
carboxaldehyde (R,R)-5i in the retro-aldol cleavage step. The
Scheme 9 Three-step asymmetric synthesis of cyclopropane-carboxaldehyde 5i.
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Scheme 10 Asymmetric synthesis of cascarillic acid (1S,2R)-25.
the competing enolate decomposition pathway (Scheme 9).64
Experimental
This compares with treatment of the corresponding a-methyl-
◦
All reactions were carried out under nitrogen or argon using
standard vacuum line techniques and glassware that was flame
dried and cooled under nitrogen. THF and toluene were distilled
from sodium/benzophenone ketyl, whilst CH2Cl2 was distilled
from CaH2 under nitrogen. All other reagents were used as
supplied without further purification. Flash chromatography was
performed on silica gel (Kieselgel 60). Thin layer chromatography
was performed on Merck aluminium sheets coated with 0.2 mm
silica gel 60 F254. Plates were visualised either by UV light
(254 nm), iodine, ammonium molybdate (7% solution in ethanol)
or potassium permanganate (1% in 2% aqueous acetic acid, con-
taining 7% potassium carbonate). Infrared spectra were recorded
as thin films or KBr discs using a Perkin-Elmer PARAGON
1000 FT-IR spectrometer, with selected peaks reported in cm-1.
1H and 13C NMR spectra were recorded on a Bruker AM-300
spectrometer. Chemical shifts are reported in parts per million
(ppm) and referenced to the residual solvent peak, with coupling
constants (J) measured in Hertz (Hz). Low resolution mass spectra
(m/z) were recorded on either a Finnigan MAT 8340 instrument
or a Finnigan MAT 900 XLT instrument. Major peaks are listed
with intensities quoted as percentages of the base peak. Accurate
mass measurements were recorded on a Finnigan MAT 900 XLT
instrument. Optical rotations were recorded on an Optical Activity
Ltd AA-10 automatic polarimeter in spectroscopic grade solvents
(Aldrich) with concentrations (c) given in g per 100 mL, solvent
and temperature as recorded. Melting points were recorded on a
Bu¨chi 535 melting point apparatus and are uncorrected. Single
crystal X-ray diffraction data were collected on a NoniusKappa
CCD machine. Structural determination and refinement were
achieved using the SHELZ suite of programmes; drawings were
produced using ORTEX. Crystal data for cyclopropyl-aldol 4d:
cyclopropyl-aldol 4i with KHMDS in THF at -40 C which re-
sulted in <5% retro-aldol cleavage occurring, thus demonstrating
that the rate of retro-aldol cleavage of this class of syn-aldol is
highly dependent on the steric demand of its a-substituent.
With the desired cyclopropane-carboxaldehyde (R,R)-5i in
hand, we then carried out a two-step oxidative one-carbon
homologation protocol to afford cascarillic acid (1S,2R)-25.60
Therefore, nucleophilic addition of the lithium anion of (1,3-
dithian-2-yl)trimethylsilane 29 to cyclopropane-carboxaldehyde
(R,R)-5i resulted in formation of ketene-1,3-dithioacetal (R,R)-
30 in >95% de and 93% yield. Attempts to directly hydrolyse
the ketene-1,3-dithioacetal functionality of (R,R)-30 under acidic
hydrolysis conditions resulted in formation of a stable thioester 31.
However, sequential exposure of ketene-1,3-dithioacetal (R,R)-30
to acidic (p-TsOH in THF/H2O) and basic (KOH in acetone/H2O)
hydrolytic conditions resulted in formation of cascarillic acid 25 in
>95% de and 78% yield (Scheme 10). The magnitude and negative
sign obtained for the specific rotation of our synthetic sample of
25
cascarillic acid 25 ([a]D = -11, c 0.41, CHCl3) compared well with
the previously reported value for the (1S,2R)-enantiomer of the
25
natural product ([a]D = -10.5, c 0.55, CHCl3).60a
Conclusion
In conclusion, a novel three-step aldol/cyclopropanation/retro-
aldol reaction sequence has been developed for the direct asym-
metric synthesis of enantiopure cyclopropane-carboxaldehydes
under non-oxidative/non-reductive conditions that we have used
for the efficient asymmetric synthesis of the cyclopropane contain-
ing natural product cascarillic acid. This methodology demon-
strates the potential of employing a chiral auxiliary to reversibly
generate temporary stereocentres that can act as stereodirecting
groups to control the facial selectivity of substrate-directable
reactions.65 We anticipate that this new strategy will prove
applicable to combinations of other types of chiral auxiliary
and substrate-directable reactions,66 thus enabling its potential for
asymmetric synthesis to be realized in other reaction scenarios.
C25H28N2O6, M = 452.49, orthorhombic, a = 7.6700(1), b =
3
˚
˚
14.8370(3), c = 20.5190(3) A, V = 2335.06(7) A , T = 150(2)
K, space group P212121, Z = 4, m(Mo-Ka) = 0.092 mm-1, 43530
measured reflections, 5310 unique (Rint = 0.1280) which were used
in these calculations. GOF on F2 = 1.028, R1 = 0.0382, wR2 =
0.0792, [I > 2s(I)], R1 = 0.0568, wR2 = 0.0862 (for all data).
CCDC = 257652.
3544 | Org. Biomol. Chem., 2009, 7, 3537–3548
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General procedure A for the synthesis of N-acyl-oxazolidin-2-ones
by addition of saturated aqueous sodium hydrogencarbonate
solution (10 mL) to dissolve the resulting white precipitate. The
reaction mixture was then extracted with CH2Cl2 (3 ¥ 10 mL),
washed with brine (10 mL), dried (MgSO4) and the solvent
removed under reduced pressure to give a crude product that was
purified by chromatography.
n-BuLi (1.01 equivalents, 2.5 M solution in hexane) was added
to a solution of the parent oxazolidin-2-one (1 equivalent) in
dry THF at -78 ◦C under nitrogen, and stirred for 30 minutes.
The appropriate acid chloride (1.1 equivalents) was then added
dropwise to the stirred solution over a period of 5 minutes and
the reaction mixture stirred for a further 2 hours, during which
time the reaction was allowed to warm to 0 ◦C. The reaction
was quenched via addition of aqueous saturated ammonium
chloride solution (5 mL), extracted with ethyl acetate (10 mL)
and CH2Cl2 (3 ¥ 20 mL), dried (MgSO4), and solvent removed
under reduced pressure to give a crude product that was purified
by chromatography or crystallisation.
(S)-4-Benzyl-3-((E)-(2S,3R)-3-hydroxy-2-methyl-5-phenyl-pent-4-
enoyl)-5,5-dimethyl-oxazolidin-2-one 3a
9-BBN-OTf (1.7 mmol) was added to a solution of oxazolidin-
2-one 1 (400 mg, 1.53 mmol) in CH2Cl2 (20 mL) followed by
addition of diisopropylethylamine (237 mg, 1.83 mmol) and
(E)-cinnamaldehyde 2a (221 mg, 1.68 mmol) according to general
protocol B to afford a crude product that was purified by chro-
matography to afford the title compound 3a (481 mg, 1.23 mmol)
General procedure B for the synthesis of syn-aldols
as a white solid in 80% yield; M.p. 148–150 ◦C (Et2O); [a]D
=
25
1
9-BBN-OTf (1.1 equivalents, 0.5 M solution in hexane) was
added dropwise to a stirred solution of an N-acyl-oxazolidin-2-
one (1 equivalent) in dry CH2Cl2 at 0 ◦C under nitrogen. After
30 minutes, diisopropylethylamine (1.2 equivalents) was added
dropwise and the resulting solution stirred for a further 30 minutes
at 0 ◦C. The solutionwas then cooled to -78◦C and the appropriate
aldehyde (1.1 equivalents) added dropwise, before allowing the
reaction mixture to warm to room temperature overnight. The
reaction was quenched by addition of Na2PO4/NaH2PO4 buffer
solution (pH 7, 10 mL), then stirred for 10 minutes before addition
of a 2:1 methanol-hydrogen peroxide solution (30%, 10 mL),
followed by stirring for a further 2 hours. The reaction mixture was
then extracted with CH2Cl2 (3 ¥ 20 mL), washed with saturated
sodium hydrogen carbonate solution (10 mL), brine (10 mL), dried
(MgSO4), and the solvent removed under reduced pressure to
afford a crude product that was purified by chromatography or
recrystallisation.
+4.0 (c 1.07, CH2Cl2); H NMR (300 MHz, CDCl3): d = 7.36–
=
7.13 (10H, m, ArH), 6.59 (1H, dd, J = 16.0, 1.5 Hz, CH CHPh),
6.12 (1H, dd, J = 16.0, 6.0 Hz, CH=CHPh), 4.54 (1H, m, CHOH),
4.47 (1H, dd, J = 9.0, 5.0 Hz, CHN), 3.94 (1H, qd, J = 7.0, 4.0 Hz,
COCH), 3.00 (1H, dd, J = 14.0, 5.0 Hz, CHAHBPh), 2.84 (1H,
dd, J = 14.0, 9.0 Hz, CHACHBPh), 2.74 (1H, broad s, OH), 1.32
(3H, s, C(CH3)), 1.30 (3H, s, C(CH3)), 1.13 (3H, d, J = 7.0 Hz,
CHCH3); 13C NMR (75 MHz, CDCl3): d = 175.7, 152.9, 138.1,
135.1, 129.3, 129.2, 129.1, 128.7, 127.7, 127.3, 126.7, 126.3, 82.7,
73.0, 63.8, 43.7, 35.3, 28.3, 22.5, 12.3; IR (KBr, cm-1): 3517 (broad
=
=
OH), 1778 (C Oox), 1698 (C O); HRMS (ES+): m/z calculated
for C24H27NO4: [M + NH4]+ requires 411.2278; found 411.2273.
(S)-4-Benzyl-3-[(2S,3R)-3-hydroxy-2-methyl-3-((1S,2S)-2-phenyl-
cyclopropyl)-propionyl]-5,5-dimethyl-oxazolidin-2-one 4a
Diethylzinc (1.9 mmol) and diiodomethane (510 mg, 1.9 mmol)
were added to syn-aldol 3a (150 mg, 0.38 mmol) in CH2Cl2 (5 mL)
according to general protocol C to afford a crude product that
was purified by chromatography to afford the title compound 4a
General procedure C for the asymmetric synthesis of chiral
cyclopropyl-aldols
25
(146 mg, 0.36 mmol) as a yellow oil in 95% yield; [a]D = +58
1
Diethyl zinc (5 equivalents, 1.0 M solution in hexane) was added
to a stirred solution of syn-aldol (1 equivalent) in dry CH2Cl2 at
-10 ◦C, followed by addition of diiodomethane (5 equivalents) in
one portion under nitrogen in the absence of light. The solution
(c 2.30, CH2Cl2); H NMR (300 MHz, CDCl3): d = 7.28–6.93
(10H, m, ArH), 4.35 (1H, dd, J = 9.0, 5.0 Hz, CHN), 3.97 (1H,
qd, J = 7.0, 4.5 Hz, COCH), 3.37 (1H, m, CHOH), 3.00 (1H,
dd, J = 14.5, 5.0 Hz, CHAHBPh), 2.78 (1H, dd, J = 14.5, 9.0 Hz,
CHACHBPh), 2.54 (1H, broad s, OH), 1.84 (1H, app. dt, J =
9.0, 5.0 Hz, cyclopropyl-CHAr), 1.25 (3H, s, C(CH3)), 1.23 (1H,
obs. m, cyclopropyl-CH), 1.18 (3H, d, J = 7.0 Hz, CHCH3), 1.04
(3H, s, C(CH3)), 1.00 (1H, app. dt, J = 8.5, 5.5 Hz, cyclopropyl-
CHAHB), 0.89 (1H, app. dt, J = 8.5, 5.5 Hz, cyclopropyl-CHAHB);
13C NMR (75 MHz, CDCl3): d = 176.8, 152.8, 142.7, 137.2, 129.5,
129.1, 128.8, 127.3, 126.2, 126.1, 82.6, 75.9, 63.8, 43.8, 35.7, 28.5,
27.0, 22.6, 21.7, 14.4, 12.9; IR (film, cm-1): 3447 (broad OH),
◦
was then warmed to 0 C over a period of 2 hours before being
quenched with saturated sodium sulfite solution (5 mL) and stirred
for 10 minutes. Hydrochloric acid (1.0 M solution in water)
was then added to dissolve the resultant white precipitate and
the crude product extracted with CH2Cl2 (3 ¥ 10 mL), washed
with brine (10 mL), dried (MgSO4), and solvent removed under
reduced pressure to afford a crude product that was purified by
chromatography or recrystallisation.
=
=
1772 (C Oox), 1685 (C O); HRMS (ES+): m/z calculated for
C25H29NO4: [M + NH4]+ requires 425.2435; found 425.2439.
General procedure D for the synthesis of non-volatile
cyclopropane-carboxaldehydes
(S,S)-2-Phenylcyclopropane-carboxaldehyde 5a54
LHMDS (1.1 equivalents, 1.0 M solution in THF) was added to a
stirred solution of a cyclopropyl-aldol (1 equivalent) in dry toluene
(10 mL) under nitrogen, at a temperature between 0 ◦C and 10 ◦C,
and the reaction mixture stirred at this temperature for 2 hours.
The reaction mixture was then quenched via dropwise addition of
saturated aqueous ammonium chloride solution (5 mL), followed
LHMDS (0.33 mmol) was added to a solution of cyclopropyl-
aldol 4a (125 mg, 0.31 mmol) in toluene (5 mL) at 0 ◦C according
to general protocol D to afford a crude reaction product that was
purified by chromatography (to remove oxazolidin-2-ones 1 and
16) to afford the title compound 5a (34 mg, 0.23 mmol) as a yellow
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oil in 75% yield; [a]D = +392 (c 1.44, CHCl3) ([Lit]54 [a]D = -324
25
25
(R)-4-Benzyl-3-{(R)-2-[(S)-((1R,2R)-2-hexyl-cyclopropyl)-
1
for (R,R)-5a, c 0.33, CHCl3); H NMR (300 MHz, CDCl3): d =
hydroxy-methyl]-3-methyl-butyryl}-5,5-dimethyl-oxazolidin-
9.33 (1H, d, J = 5.0 Hz, CHO), 7.34–7.09 (5H, m, ArH), 2.63
(1H, ddd, J = 11.0, 7.0, 5.0 Hz, CHAr), 2.18 (1H, m, OHCCH),
1.74 (1H, app. dt, J = 10.0, 5.0 Hz, cyclopropyl-CHAHB), 1.54
(1H, ddd, J = 10.0, 7.0, 5.0 Hz, cyclopropyl-CHAHB); 13C NMR
2-one 28
Diethylzinc (7.2 mmol) and diiodomethane (1.92 g, 7.2 mmol)
were added to syn-aldol 27 (620 mg, 1.44 mmol) in CH2Cl2 (10 mL)
according to general protocol C to afford a crude reaction product
that was purified by chromatography to afford the title compound
(75 MHz, CDCl3): d = 200.2, 139.4, 129.0, 127.3, 126.7, 34.2,
-1
=
27.0, 16.9; IR (film, cm ): 1699 (C O); HRMS (ES+): m/z
25
28 (602 mg, 1.36 mmol) as a yellow oil in 94% yield; [a]D = -21 (c
calculated for C10H10O: [M + NH4]+ requires 164.1070; found
0.62, MeOH); 1H NMR (300 MHz, CDCl3): d = 7.34–7.18 (5H, m,
Ph), 4.56 (1H, dd, J = 10.0, 3.5 Hz, CHN), 4.22 (1H, dd, J = 8.5,
6.0 Hz, COCH), 3.39 (1H, dd, J = 8.5, 6.0 Hz, CHOH), 3.23 (1H,
dd, J = 14.5, 3.5 Hz, CHAHBPh), 2.86 (1H, dd, J = 14.5, 10.0 Hz,
CHACHBPh), 2.31 (1H, m, CH(CH3)2), 1.85 (1H, broad s, OH),
1.44–1.20 (10H m, (CH2)5), 1.34 (3H, s, C(CH3)), 1.33 (3H, s,
C(CH3)), 1.02 (3H, d, J = 7.0 Hz, CHCH3), 1.00 (1H, obs. m,
cyclopropyl-CH), 0.93 (3H, d, J = 7.0 Hz, CHCH3), 0.88 (3H, t,
J = 7.0 Hz, alkyl-CH3), 0.76 (1H, m, cyclopropyl-CH), 0.43 (1H,
app. dt, J = 8.5, 5.0 Hz, cyclopropyl-CHAHB), 0.28 (1H, app. dt, J =
8.5 Hz, 5.0 Hz, cyclopropyl-CHAHB); 13C NMR (75 MHz, CDCl3):
d = 175.1, 153.7, 137.5, 129.4, 129.1, 127.2, 82.2, 75.5, 64.4, 54.5,
164.1069.
(S,S)-2-Methylcyclopropane-carboxaldehyde 5f67
LHMDS (0.33 mmol) was added to a stirred solution of
cyclopropyl-aldol 4f (100 mg, 0.29 mmol) in dry toluene-d8 (5 mL)
at 10 ◦C under nitrogen over a period of 2 hours. The reaction
mixture was then worked up via dropwise addition of saturated
aqueous ammonium chloride solution (5 drops), and the mixture
allowed to warm to room temperature over a period of thirty
˚
minutes. The reaction mixture was dried (3 A molecular sieves),
filtered, and the filtrate washed with toluene-d8 (1 mL), before the
resultant mixture was distilled at atmospheric pressure (120 ◦C) to
give the title compound 5f as a solution in toluene-d8 in 51% yield.
35.8, 34.2, 32.3, 29.6, 29.5, 28.8, 28.6, 23.1, 22.8, 22.2, 21.4, 21.1,
-1
=
18.8, 14.5, 9.6; IR (film, cm ): 3516 (broad O-H), 1778 (C Oox),
=
1693 (C O); HRMS (ES+): m/z calculated for C27H41NO4: [M +
[a]D = +54 (c 0.71, toluene-d8); 1H NMR (300 MHz, toluene-d8):
25
NH4]+ requires 461.3374; found 461.3370.
d = 8.67 (1H, d, J = 5.0 Hz, CHO), 1.11 (1H, app. sextet, J = 4.5 Hz,
OHCCH), 0.98–0.87 (2H, m, cyclopropyl-CH) and cyclopropyl-
CHAHB), 0.80 (1H, m, cyclopropyl-CHAHB), 0.67 (3H, d, J =
6.0 Hz, CH3); 13C NMR (75 MHz, toluene-d8): d = 197.3, 29.9,
15.8, 14.8, 14.0. The yield of 5f was calculated by adding a known
amount of 2,5-dimethylfuran (0.2 mmol) to the solution of 5f
(((R,R)-2-Hexylcyclopropyl)methylene)-1,3-dithiane 30
n-BuLi (1.1 mmol) was added to a stirred solution of (1,3-dithian-
2-◦yl)trimethylsilane 29 (224 mg, 1.17 mmol) in dry THF (5 mL) at
0 C under nitrogen and the reaction mixture stirred for 1 hour.
The reaction mixture was then cooled to -30 ◦C and a solution of
cyclopropane-carboxaldehyde (R,R)-5i (140 mg, 0.9 mmol) in dry
THF (2 mL) added, before allowing the reaction mixture to warm
to room temperature over 2 hours. The reaction was then quenched
with aqueous saturated ammonium chloride solution (2 mL),
extracted with ether (3 ¥ 10 mL), sodium hydrogen carbonate
solution (10 mL), dried (MgSO4), and the solvent removed under
reduced pressure to give a crude product that was purified by
chromatography to afford the title compound 30 as a colorless oil
1
in toluene-d8, which allowed H NMR spectroscopic analysis to
be used to determine the concentration of 5f via comparison of
the relative intensity of its integrals with the integrals of 2,5-
dimethylfuran.57
(R)-4-Benzyl-3-((E)-(2R,3S)-3-hydroxy-2-isopropyl-undec-4-
enoyl)-5,5-dimethyl-oxazolidin-2-one 27
9-BBN-OTf (3.30 mmol) was added to a solution of oxazolidin-
2-one 26 (891 mg, 3.08 mmol) in CH2Cl2 (50 mL) followed
by addition of diisopropylethylamine (477 mg, 3.70 mmol) and
(E)-non-2-enal 2d (474 mg, 3.39 mmol) according to general
protocol B to afford a crude product that was purified by chro-
matography to afford the title compound 27 (1.07 g, 2.47 mmol)
as a yellow oil in 81% yield; [a]D = +22 (c 0.85, CH2Cl2); H
NMR (300 MHz, CDCl3): d = 7.27–7.11 (5H, m, ArH), 5.71–5.54
(2H, m, CH=CH), 4.53 (1H, dd, J = 10.0, 4.0 Hz, CHN), 4.36
(1H, app. t, J = 7.0 Hz, CHOH), 4.09 (1H, dd, J = 9.0, 7.0 Hz,
OHCCH), 3.09 (1H, dd, J = 14.5, 4.0 Hz, CHAHBPh), 2.81 (1H,
dd, J = 14.5, 10.0 Hz, CHAHBPh), 2.04–1.88 (4H, obs. m, OH,
(215 mg, 0.84 mmol) in 93% yield; [a]D = -20 (c 0.30, CH2Cl2); 1H
25
NMR (300 MHz, CDCl3): d = 5.42 (1H, d, J = 10.0 Hz, CH=C),
2.91 (4H, m, S(CH2)2, 2.22–2.13 (2H, m, SCH2CH2), 1.58 (1H,
m, cyclopropyl-CH), 1.41–1.20 (10H, m, (CH2)5), 0.88 (3H, t, J =
7.0 Hz, CH3), 0.79 (1H, m, cyclopropyl-CH), 0.65–0.56 (2H, m,
cyclopropyl-CH2); 13C NMR (75 MHz, CDCl3): d = 140.4, 121.6,
25
1
34.1, 32.3, 31.3, 30.5, 29.7, 29.5, 26.0, 23.1, 22.2, 20.3, 15.2, 14.5;
-1
=
IR (film, cm ): 1678 (C C), (C-S); HRMS (ES+): m/z calculated
for C14H24S2: [M + H]+ requires 257.1392; found 257.1393.
2-((1S,2R)-2-Hexylcyclopropyl)acetic acid (cascarillic acid) 2560
=
CH CHCH2 and (CH3)2CH), 1.35–1.12 (8H, m, (CH2)4), 1.24
(6H, app. s, C(CH3)2), 0.90 (3H, d, J = 7.0 Hz, CHCH3), 0.82 (3H,
obs. d, J = 7.0 Hz, CHCH3), 0.80 (3H, obs. t, J = 7.0 Hz, alkyl-
CH3); 13C NMR (75 MHz, CDCl3): d = 174.7, 153.9, 137.4, 135.8,
129.5, 129.1, 128.9, 127.2, 82.4, 73.8, 64.3, 54.1, 35.9, 32.7, 32.1,
29.5, 29.3, 28.7, 28.6, 23.0, 22.6, 21.0, 20.4, 14.5; IR (film, cm-1):
3501 (broad OH), 1778 (C Oox), 1693 (C O); HRMS (ES+): m/z
calculated for C26H39NO4: [M + NH4]+ requires 447.3217; found
447.3213.
para-TsOH (5 mg) was added to a solution of dithiane 30 (150 mg,
0.60 mmol) in THF/water (8 : 1) (5 mL) and the reaction
mixture heated at 75 ◦C for six hours, before cooling and removal
of the solvent under reduced pressure. The resulting residue
was then dissolved in acetone/water (8 : 1) (5 mL), potassium
hydroxide (150 mg) added, and the reaction mixture heated at
85 ◦C for two hours, before cooling to room temperature. The
reaction mixture was cautiously acidified via dropwise addition
=
=
3546 | Org. Biomol. Chem., 2009, 7, 3537–3548
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of concentrated hydrochloric acid and the resulting solution was
extracted ethyl acetate (3 ¥ 5 mL), dried (MgSO4) and solvent
removed under reduced pressure to give a crude product that was
purified by chromatography to afford the title compound 25 as
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25
a colorless oil (86 mg, 47 mmol) in 78% yield; [a]D = -11 (c
0.41, CHCl3), ([Lit]60a [a]D = -10.5, c 0.55, CHCl3); H NMR
(300 MHz, CDCl3): d = 2.26 (2H, app. d, J = 7.0 Hz, CH2CO2H),
1.41–1.18 (10H, m, (CH2)5), 0.88 (3H, t, J = 7.0 Hz, CH3), 0.77
(1H, m, cyclopropyl-CH), 0.56 (1H, m, cyclopropyl-CH), 0.33
(2H, m, cyclopropyl-CH2); 13C NMR (75 MHz, CDCl3): d =
25
1
176.6, 37.5, 32.8, 30.9, 28.3, 28.1, 21.6, 17.7, 13.1, 13.0, 10.6;
-1
=
IR (film, cm ): 1711 (C O); HRMS (EI): m/z calculated for
C11H20O2: [M]+ requires 184.1458; found 184.1458.
Acknowledgements
We would like to thank the EPSRC and the University of Bath for
funding and the mass spectrometry service at Swansea, University
of Wales for their assistance.
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