Stereoselective synthesis of (E)-trisubstituted α,β-unsaturated amides and acids

Article abstract of DOI:10.1039/b503633j

Potassium alkoxides of N-acyl-oxazolidin-2-one-syn-aldols undergo stereoselective elimination reactions to afford a range of trisubstituted (E)-αβ-unsaturated amides in >95% de, that may be subsequently converted into their corresponding (E)-αβ-unsaturated acids or (E)-αβ-unsaturated oxazolines in good yield. syn-Aldols derived from αβ-unsaturated aldehydes gave their corresponding trisubstituted (E)-αβ-unsaturated-amides with poorer levels of diastereocontrol, whilst there was a similar loss in (E)-selectivity during elimination of syn-aldols derived from chiral aldehydes. These elimination reactions proceed via rearrangement of the potassium alkoxide of the syn-aldol to a 1,3-oxazinane-2,4-dione enolate intermediate that subsequently eliminates carbon dioxide to afford a trisubstituted (E)-αβ-unsaturated amide. The (E)-selectivity observed during the ElcB-type elimination step has been rationalised using a simple conformational model that employs a chair-like transition state to explain the observed stereocontrol. The Royal Society of Chemistry 2005.

Full text of DOI:10.1039/b503633j

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A R T I C L E
Stereoselective synthesis of (E)-trisubstituted a,b-unsaturated
amides and acids
Fred J. P. Feuillet,a Matt Cheeseman,a Mary F. Mahonb and Steven D. Bull*a
a Department of Chemistry, University of Bath, UK BA2 7AY
b Bath Chemical Crystallography, Department of Chemistry, University of Bath, UK BA2 7AY.
E-mail: s.d.bull@bath.ac.uk
Received 11th March 2005, Accepted 25th May 2005
First published as an Advance Article on the web 30th June 2005
Potassium alkoxides of N-acyl-oxazolidin-2-one-syn-aldols undergo stereoselective elimination reactions to afford a
range of trisubstituted (E)-a,b-unsaturated amides in >95% de, that may be subsequently converted into their
corresponding (E)-a,b-unsaturated acids or (E)-a,b-unsaturated oxazolines in good yield. syn-Aldols derived from
a,b-unsaturated aldehydes gave their corresponding trisubstituted (E)-a,b-unsaturated-amides with poorer levels of
diastereocontrol, whilst there was a similar loss in (E)-selectivity during elimination of syn-aldols derived from chiral
aldehydes. These elimination reactions proceed via rearrangement of the potassium alkoxide of the syn-aldol to a
1,3-oxazinane-2,4-dione enolate intermediate that subsequently eliminates carbon dioxide to afford a trisubstituted
(E)-a,b-unsaturated amide. The (E)-selectivity observed during the E1cB-type elimination step has been rationalised
using a simple conformational model that employs a chair-like transition state to explain the observed stereocontrol.
followed by base-catalysed elimination to afford trisubstituted
Introduction
(E)-a,b-unsaturated esters in good de.13 Only a few reports on the
(E)-2,3-Trisubstituted-a,b-unsaturated carboxylic acid deriva-
tives are versatile synthetic fragments for natural product
use of stereoselective versions of the Perkin reaction have been
described, although Verkade et al. have described a potentially
synthesis,1 that also function as useful substrates for a wide range
useful ‘one-pot’ protocol that employs a pro-azaphosphatrane
of asymmetric methodology.2 They are most often prepared
using highly stereoselective Wittig reactions, where reaction of
an a-substituted-ester-ylid with an aldehyde affords the desired
base for the dehydrative aldol-condensation of an ester with an
aldehyde to afford trisubstituted (E)-a,b-unsaturated esters in
high de.14
trisubstituted (E)-a,b-unsaturated ester in excellent yield.3 Simi-
Natural products that contain trisubstituted (E)-a,b-
lar excellent levels of stereocontrol are also observed for Horner–
unsaturated-amide fragments also occur widely in nature,15
Wadsworth–Emmons reactions, where anions of a-substituted-
phosphonate esters also react with aldehydes in a highly (E)-
whilst they have often been employed as structural motifs for
the preparation of medicinally active compounds.16 A number of
selective manner.4 Whilst less widely used in natural product
different synthetic routes is available for their stereoselective syn-
synthesis, numerous other strategies have been developed for
thesis, including direct amide formation from their correspond-
their stereoselective synthesis, including hydrocarboxylation of
ing (E)-acids17 or (E)-esters,18 Horner–Wadsworth–Emmons
alkynes,5 addition of carbanions to Baylis–Hillman adducts,6
methodology,19 aldol dehydration,20 SmI2 mediated elimination
cross-metathesis approaches,7 and the rearrangement of lithium
of a-chloro-b-hydroxy-amides or a,b-epoxy-amides,21 or rear-
ynolates.8
rangement of lithium ynolates.22 The development of versatile
A wide range of aldol methodology is now available for the
stereoselective synthesis of syn- or anti-a-alkyl-b-hydroxy-acid
derivatives, and as a consequence, a number of elimination
protocols has been developed for their stereoselective conversion
protocols for their synthesis is therefore of great interest to
the synthetic community. Consequently, we now report herein
that potassium alkoxides of N-acyl-oxazolidin-2-one-syn-aldols
undergo stereoselective elimination reactions to afford a highly
into trisubstituted (E)-a,b-unsaturated acid derivatives. For
practical route to trisubstituted (E)-a,b-unsaturated amides
example, Ohmizu et al. have shown that treatment of anti-
with good levels of stereocontrol. Part of this work has been
a-alkyl-b-hydroxy-esters with EDCI and CuCl2 in toluene at
communicated previously.23
80 ◦C results in syn-elimination to afford trisubstituted (E)-
a,b-unsaturated esters, whilst treatment of the corresponding
syn-a-alkyl-b-hydroxy-esters gave the alternative trisubstituted
Results and discussion
(Z)-a,b-unsaturated ester in high de.9 Alternatively, treatment
of a-alkyl-b-hydroxy-esters with excess triphenylphosphine and
diethyl azodicarboxylate results in an anti-selective elimination
reaction, with syn-a-alkyl-b-hydroxy-esters affording trisubsti-
tuted (E)-a,b-unsaturated esters, whilst anti-a-alkyl-b-hydroxy-
esters gave their corresponding (Z)-isomers.10 Bartoli et al.
have reported that treatment of diastereoisomeric mixtures
of syn-/anti-a-alkyl-b-hydroxy esters with CeCl3 and NaI in
refluxing acetonitrile gave trisubstituted (E)-esters in high
de.11 Similarly, Concello´n et al. have described similar good
levels of (E)-selectivity when samarium iodide is employed
for the reductive elimination of mixtures of syn-/anti-a-halo-
b-hydroxy-acid derivatives.12 Mixtures of syn-/anti-a-alkyl-b-
hydroxy-esters may also be dehydrated via step-wise protocols
involving conversion to their corresponding tosylates/mesylates,
We have recently reported a novel aldol/cyclopropanation/
retro-aldol strategy for the asymmetric synthesis of chiral
cyclopropane carboxaldehydes in high de.24 The success of
this methodology required the development of conditions that
would result in b-hydroxy-N-acyl-oxazolidin-2-ones undergoing
a clean retro-aldol reaction to afford their respective N-acyl-
oxazolidin-2-one and aldehyde fragments. In order to establish
optimal conditions for this type of retro-aldol reaction, it
was decided to employ a series of racemic b-hydroxy-N-acyl-
oxazolidin-2-ones 3a–j as simple model substrates to probe
the steric and electronic requirements of this fragmentation
pathway. Consequently, a series of four N-acyl-oxazolidin-2-
ones 2a–d were prepared in 62–74% yield via treatment of
oxazolidin-2-one 1 in THF with 1.1 equivalents of n-BuLi at
2 9 7 6
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 9 7 6 – 2 9 8 9
T h i s j o u r n a l i s
T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 5
©

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Table 1 Yields of syn-aldols 3a–j
Aldol
R
R1
de (%)
Yield (%)a
3a
3b
3c
3d
3e
3f
iPr
Me
Me
Bn
iPr
iPr
iPr
Ph
iPr
Me
Cyclohexyl
Ph
Et
Me(CH2)6–
Et
Ph
>95
>95
>95
>95
>95
>95
>95
>95
>95
>95
58
69
31
74
48
50
60
37
72
88
3g
3h
3i
pMeOC6H4–
Et
=
(E)–MeCH CH–
=
3j
(E)–PhCH CH–
a Yields of syn-aldol products obtained in <70% were a result of
unreacted N-acyl-oxazolidin-2-one 2a–d being recovered at the end of
the aldol reaction.
−78 ◦C, followed by addition of the appropriate acid chloride.
After screening a range of boron sources and conditions, it was
found that treatment of N-acyl-oxazolidin-2-ones 2a–d with 9-
Fig. 1 One of the two molecules which comprise the asymmetric unit
in the crystal structure of (E)-4a. Ellipsoids are depicted at the 30%
probability level.
i
BBN triflate (in hexanes) and Pr2NEt in CH2Cl2, followed by
addition of the appropriate aldehyde at −78 ◦C, resulted in the
formation of the desired syn-aldol products 3a–j.25 Examination
of the 1H NMR spectrum of each crude reaction product
revealed the presence of desired syn-aldols 3a–j in >95% de,
which were purified to homogeneity by chromatography in poor
to unoptimised 31–88% yields (Scheme 1, Table 1). The relative
configuration of each of the racemic aldol products 3a–j was
assigned as syn- by analogy with literature precedent for the
reaction of (Z)-boron-enolates of N-acyl-oxazolidin-2-ones in
these types of aldol reactions.26 This stereochemical assignment
unremarkable, with crystal packing occurring via intermolecular
hydrogen bonding between the primary hydroxyl groups of
adjacent (E)-amide molecules.
In order to determine whether this elimination reaction
was general in scope, the remaining series of syn-aldols 3b–
g wa◦s treated with 1.5 equivalents of KHMDS in THF at
−78 C for 2 hours, after which time the reaction was worked
up with saturated NH4Cl(aq). Examination of the crude 1H
NMR spectrum of each crude reaction product revealed that
trisubstituted (E)-a,b-unsaturated amides 4b–g had been formed
in >90% de in each case, which were subsequently obtained
in 67–99% yield after chromatographic purification (Scheme 3,
Table 2). The structure of each (E)-a,b-unsaturated amide
4b–g followed from comparison of their spectroscopic data
with that of (E)-amide 4a, whilst the alkene geometry of (E)-
amides 4a–c was confirmed via acidic hydrolysis to their known
(E)-acids 26a–c (vide infra). It is noteworthy that this simple
elimination methodology appeared general in scope with linear
and branched R substituents being tolerated at the a-position of
syn-aldols 3a–g, and with aliphatic and aromatic (neutral and
electron rich) R1-substituents being tolerated at their b-position
(Scheme 1, Table 1). Attempts to carry out these elimination
reactions at 0 ◦C resulted in the desired (E)-amides 4 being
produced in inferior de; for example, treatment of syn-aldol 3b
1
was subsequently confirmed for syn-aldol 3b whose H NMR
spectrum was identical to the data previously reported for this
diastereoisomer (J(2,3) = 3.0 Hz), whilst being clearly different
1
from the H NMR spectrum of its corresponding anti-aldol
diastereoisomer (J(2,3) = 8.5 Hz).27
Scheme
1
Reagents and conditions: (i) n-BuLi, THF, −78 ◦C,
RCH2COCl; (ii) 9-BBN-OTf, Pr2NEt, CH2Cl2, 0 to −78 ◦C, R1CHO,
i
◦
CH2Cl2.
with KHMDS in THF at 0 C resulted in (E)-amide 4b being
produced in only 80% de.
Attempts to establish anionic conditions that would result
in syn-aldol 3a undergoing a retro-aldol reaction under anionic
conditions were unsuccessful, since treatment of syn-aldol 3a
with 1.5 equivalents of KHMDS in THF at −78 ◦C over a period
of 2 hours resulted in an unexpected stereoselective elimination
reaction to afford the trisubstituted a,b-unsaturated amide (E)-
4a in 94% de, and in 77% isolated yield (Scheme 2). The geometry
of the alkene functionality of (E)-4a was confirmed via X-ray
crystallographic analysis that clearly revealed the cis-orientation
of the a-iso-propyl group and the b-cyclohexane group (Fig. 1).
Other aspects of the X-ray crystal structure of (E)-4a were
Scheme 3 Reagents and conditions: (i) KHMDS, THF, −78 ◦C.
Table 2 Yields for synthesis of (E)-amides 4b–g
Amide
R
R1
de (%)
Yield (%)
4b
4c
4d
4e
4f
Me
Me
Bn
iPr
iPr
iPr
Ph
Et
>95
>95
92
>95
92
91
67
91
99
90
88
Me(CH2)6–
Et
Ph
4g
pMeOC6H4–
90
Scheme 2 Reagents and conditions: (i) KHMDS, THF, −78 ◦C.
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 9 7 6 – 2 9 8 9
2 9 7 7

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Further investigations revealed that elimination of syn-aldol
3h containing an a-phenyl group under these conditions, gave
a mixture of the desired (E)-amide 4h (>95% de) and N-
phenylacetyl-oxazolidin-2-one 2d in a 2 : 1 ratio, which was
purified by chromatography to afford (E)-4h in 47% yield.
Presumably, N-phenylacetyl-oxazolidin-2-one 2d arises from a
competing retro-aldol reaction as originally conceived, where the
potassium alkoxide of syn-aldol 3h had fragmented to afford (E)-
4h and propionaldehyde (not isolated). It is likely that the retro-
aldol reaction of the alkoxide of syn-aldol 4h is more favoured
than for the other syn-aldols 4a–g investigated in this study,
because the enolate of N-phenylacetyloxazolidin-2-one 2d is
stabilised by the presence of its a-phenyl substituent (Scheme 4).
Treatment of syn-aldols 3i and 3j with KHMDS in CH2Cl2 at
−78 ◦C afforded (2E,4E)-a,b,c,d-unsaturated amides 4i and 4j in
a stereoselective manner, however they were both formed with
poorer levels of stereocontrol. Thus, treatment of syn-aldol 3i
with KHMDS at −78 ◦C resulted in (2E,4E)-a,b,c,d-unsaturated
amide 4i, and its geometric isomer (2Z,4E)-a,b,c,d-unsaturated
amide 5, in a 4 : 1 ratio, and in a combined 93% yield (Scheme 5).
Attempted chromatographic purification of these geometric
isomers over silica gel was unsuccessful, however (2E,4E)-4i and
(2Z,4E)-5 could be partially separated via chromatography over
silica gel doped with silver nitrate.28 The presence of the (2Z)-
alkene geometry of (2Z,4E)-5 was confirmed from examination
In order to demonstrate that this elimination methodology
was applicable to the stereoselective synthesis of trisubstituted-
(E)-amides of potential use as building blocks for natural
product synthesis, we next explored its use for the preparation
of three trisubstituted (E)-a,b-unsaturated amides 10a–c derived
from chiral aldehydes (Scheme 6). Reaction of the (Z)-boron
enolate of N-propionyl-oxazolidin-2-one 2a with perillaldehyde
(R)-7 (90% pure) resulted in a 1 : 1 mixture of syn-aldol
diastereoisomers 8a/9a in 64% yield.30 Treatment of this mixture
of syn-aldols 8a/9a with KHMDS in THF at −78 ◦C resulted in
a clean elimination reaction to afford a,b,c,d-unsaturated amide
(E,E,R)-10a in 50% de, which was purified to homogeneity via
chromatography in 51% yield. Since elimination of syn-aldols
derived from a,b-unsaturated aldehydes had been shown to
afford (E,E)-unsaturated-amides in inferior de, we next reacted
the (Z)-boron enolate of 2a with citronellal (S)-11 (96% pure)
to afford an inseparable 1 : 1 mixture of diastereoisomeric syn-
aldols 8b/9b in 93% yield. This mixture was subsequently treated
with KHMDS in THF at −78 ◦C to afford (E,S)-amide 10b in
60% de, that was purified to homogeneity via chromatography
in 55% yield. The moderate diastereocontrol observed in this
elimination reaction was somewhat surprising, since elimination
of the related syn-aldol 3d, which also contained a long alkyl
chain at its b-position, gave its corresponding (E)-amide 4d in
92% de. Finally, reaction of the (Z)-boron enolate of 2a with
1.1 equivalents of D-glyceraldehyde acetonide (R)-12 afforded
a 2 : 1 mixture of syn-aldol diastereoisomers 8c/9c that were
co-isolated in 58% yield after chromatography over silica.31 The
2 : 1 mixture of syn-aldols 8c/9c produced in this reaction is
likely to result from attack of the boron-enolate of 2a at the
carbonyl of (R)-12 occurring under substrate control, where
formation of the major aldol diastereoisomer (stereochemistry
not determined) is favoured by the stereodirecting effect of
the a-stereogenic centre of aldehyde (R)-12. Generation of the
potassium alkoxides of syn-aldols 8c/9c via treatment of this
mixture with KHMDS in THF at −78 ◦C, resulted in the
formation of (E,S)-amide 10c in 80% de, which was purified
to homogeneity via chromatography in 42% isolated yield.32
1
of its H NMR spectrum which revealed a coupling constant
of J(4,5) = 15.0 Hz, that was similar in value to that observed
for (2E,4E)-4i of J(4,5) = 13.0 Hz. Similarly, treatment of syn-
aldol 3j with KHMDS in THF at −78 ◦C also gave a 4 :
1 mixture of (2E,4E)-4j and (2Z,4E)-6 in a combined 97%
yield (Scheme 5).29 Fractional recrystallisation of this mixture of
geometric isomers from ethyl acetate afforded the major amide
(2E,4E)-4j in 64% isolated yield, whose alkene geometry was
confirmed via hydrolysis to its known parent (2E,4E)-acid 27
(vide infra). Therefore, it appears that elimination of syn-aldols
derived from a,b-unsaturated aldehydes under these conditions
occurs with intrinsically poorer levels of stereocontrol than for
the other syn-aldols 3a–g investigated in this study.
Scheme 4 Reagents and conditions: (i) KHMDS, THF, −78 ◦C.
Scheme 5 Reagents and conditions: (i) KHMDS, THF, −78 ◦C.
2 9 7 8
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 9 7 6 – 2 9 8 9

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Scheme 6 Reagents and conditions: (i) 2a, 9-BBN-OTf, iPr2NEt, CH2Cl2, 0 to −78 ◦C; (ii) KHMDS, THF, −78 ◦C.
Therefore, whilst the potassium alkoxides of syn-aldols 8a–
c/9a–c derived from chiral aldehydes eliminated to afford their
desired trisubstituted a,b-unsaturated amides (E)-10a–c, it is
clear that these reactions had proceeded with inferior levels of
(E)-stereocontrol to those previously observed for the simpler
syn-aldols 4a–g.
ment to afford 1,3-oxazinane-2,4-diones,34 and as a consequence
syn-1,3-oxazinane-2,4-dione 16 was prepared in 97% yield via
treatment of syn-aldol 3b with 10 mol% of Et2Zn in CH2Cl2 at
room temperature. Subsequent treatment of syn-1,3-oxazinane-
2,4-dione 16 with KHMDS in THF at −78 ◦C gave amide
(E)-4b in an identical >95% de to that previously observed
for elimination of the potassium alkoxide of syn-aldol 3b
(Scheme 7).35 This observation therefore provides good evidence
that the potassium alkoxide of 1,3-oxazinane-2,4-diones 13, and
their corresponding enolates 14, are key intermediates in these
stereoselective elimination reactions (Fig. 2).
We next confirmed that the loss in stereoselectivity observed
during elimination of the potassium alkoxides of syn-aldol 3i was
occurring during elimination of carbon dioxide from the enolate
of syn-1,3-oxazinane-2,4-dione intermediate 17. Thus, treatment
of syn-aldol 3i with 10 mol% Et2Zn in CH2Cl2 resulted in a zinc
alkoxide that cleanly rearranged to afford its syn-1,3-oxazinane-
2,4-dione 17 in >95% de with no loss of stereochemical integrity
at either its a- or b-stereocentres. syn-1,3-Oxazinane-2,4-dione
17 was treated with KHMDS in THF at −78 ◦C under
conditions used previously for the direct elimination of syn-aldol
3i, to afford an identical 4 : 1 ratio of (2E,4E)-a,b-unsaturated
amide 4i and (2Z,4E)-a,b-unsaturated amide 5 in an excellent
88% yield (Scheme 8). Therefore, it appears that the loss of
stereocontrol observed for syn-aldol 3i occurs exclusively during
elimination of carbon dioxide from the enolate derived from
syn-1,3-oxazinane-2,4-dione intermediate 17.
Mechanism of the stereoselective elimination reaction of
syn-aldols
It is well known that sterically unhindered N-acyloxazolidin-2-
ones can undergo endocyclic ring cleavage via either inter- or in-
tramolecular attack of alkoxide nucleophiles at their oxazolidin-
2-one carbonyl groups.33 Consequently, it was proposed that
the high diastereoselectivities observed for the elimination of
syn-aldols 3 could be explained by a novel intramolecular
cyclisation/E1cB-type elimination mechanism as shown in
Fig. 2. In this mechanism, deprotonation of syn-aldol 11 would
result in potassium alkoxide 12, that would then undergo
intramolecular attack at the oxazolidin-2-one carbonyl resulting
in O–O carbonyl migration to afford 1,3-oxazinane-2,4-dione
alkoxide intermediate 13. Subsequent anion equilibration of
alkoxide 13 would then give 1,3-oxazinane-2,4-dione enolate 14
that would then undergo stereoselective elimination of carbon
dioxide to afford the trisubstituted secondary amide (E)-15 in
high de (Fig. 2).
In order to provide evidence for this mechanism, it was
proposed that treatment of 1,3-oxazinane-2,4-dione 16 with
KHMDS in THF at −78 ◦C should result in stereoselective
elimination to afford trisubstituted amide (E)-4b in an identical
de to that observed for elimination of its parent syn-aldol 3b.
We have reported previously that zinc alkoxides of a-alkyl-
b-hydroxy-N-acyl-oxazolidin-2-ones undergo clean rearrange-
Finally, we explored the elimination of the corresponding anti-
aldol 18 which was prepared via treatment of 2a with MgCl2,
TMSCl, Et3N and benzaldehyde in EtOAc in an unoptimised
33% yield, according to Evans’ recently published procedure.36
Treatment of anti-aldol 18 with KHMDS in THF at −78 ◦C
afforded amide (E)-4b in >95% de, a value identical to that
Fig. 2 Intramolecular cyclisation/E1cB-elimination mechanism for the stereoselective elimination of syn-aldol 11.
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 9 7 6 – 2 9 8 9
2 9 7 9

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Scheme 7 Reagents and conditions: (i) Et2Zn, THF, rt; (ii) KHMDS, THF, −78 ◦C.
Scheme 8 Reagents and conditions: (i) 10 mol% Et2Zn, THF, rt; (ii) KHMDS, THF, −78 ◦C.
Fig. 3 Simple conformational model to explain (E)-selectivity in elimination reaction.
observed previously for elimination of the corresponding syn-
aldol 3b under the same conditions (Scheme 9). Furthermore,
treatment of anti-aldol 18 with Et2Zn in CH2Cl2 resulted in
rearrangement to afford the corresponding anti-1,3-oxazinane-
2,4-dione 19 in >95% de, which on treatment with KHMDS
in THF at −78 ◦C also afforded amide (E)-4b in >95% de
(Scheme 9). These observations are therefore clearly consistent
with the key elimination step of both anti-aldol 18 and syn-
aldol 3b occurring via an E1cB-type mechanism, in which a
common enolate intermediate 20 eliminates CO2 to afford the
a,b-unsaturated amide (E)-4b in high de (Scheme 9).
conformational model that compares the relative energies of
transition state intermediates 22 and 24 (Fig. 3). In the case
of transition state 22 that leads to (E)-amide 21, concerted
elimination of carbon dioxide from a cyclic ring system requires
overlap of an equatorial C5-carbanion with the o*-orbital of the
C6–O bond, which can only occur from a chair conformer in
which the C5–R group occupies an axial position, and the C6–
R1 group occupies an equatorial position. This compares with
transition state 24 that leads to (Z)-amide 25, where a similar
orbital alignment results in a chair conformer in which both the
C5–R group and C6–R1 substituents both occupy axial positions.
Since transition state 22 contains only one axial substituent, it
is likely to be lower in energy than transition state 24 which
contains two axial substituents, and as a consequence formation
of (E)-amide 21 is favoured. Whilst this ‘carbanion’ model
Whilst it is likely that the key E1cB-type elimination reac-
tions of the 1,3-oxazinane-2,4-dione enolate 23 occur via a
concerted reaction mechanism, the observed (E)-selectivity in
these elimination reactions may be rationalised using a simple
Scheme 9 Reagents and conditions: (i) MgCl2, TMSCl, Et3N, PhCHO, EtOAc; (ii) KHMDS, THF, −78 ◦C; (iii) 10 mol% Et2Zn, THF, rt.
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 9 7 6 – 2 9 8 9
2 9 8 0

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is clearly an over-simplification of the concerted elimination
processes that are likely to be occurring in these elimination
reactions, similar electronic and steric considerations are likely
to be operating to maximise orbital overlap in the transition
state that preferentially leads to the formation of (E)-amides in
these reactions. However, it is also clear from the poorer levels
of stereocontrol (50–80% de) observed for the elimination of
syn-aldols derived from a,b-unsaturated aldehydes and chiral
aldehydes, that subtle changes in the conformation and/or
electron density of the transition states of these E1CB-type
reactions can result in significant losses in (E)-selectivity.
Synthesis of (E)-a,b-unsaturated carboxylic acids and
(E)-a,b-unsaturated oxazolines
Scheme 11 Reagents and conditions: (i) SOCl2, CH2Cl2, 0 ◦C.
(E)-a,b-unsaturated oxazolines in good yield. Alkoxides of syn-
aldols derived from a,b-unsaturated aldehydes were eliminated
to afford their corresponding trisubstituted (E)-a,b-unsaturated-
amides in an inferior 80% de, whilst there was also a similar
loss in (E)-selectivity during elimination of more complex syn-
aldols derived from chiral aldehydes. These elimination reactions
proceed via rearrangement of their syn-aldol alkoxide to a
1,3-oxazinane-2,4-dione enolate intermediate that subsequently
eliminates carbon dioxide to afford a trisubstituted (E)-a,b-
unsaturated amide. The (E)-selectivity observed during the
critical E1cB-type elimination step of this reaction has been
rationalised using a simple conformational model that employs
chair-like transition states to explain the observed stereocontrol.
Having shown that this elimination methodology afforded an
excellent general route to (E)-trisubstituted a,b-unsaturated
amides, their conversion to other carboxylic acid derivatives
was explored in order to demonstrate the synthetic versatility
of this methodology. Five representative (E)-a,b-unsaturated
amides 4a–d and 4j were refluxed in 6 M HCl(aq) for 5 hours to
afford their corresponding (E)-a,b-unsaturated acids 26a–d and
27 respectively in 77–99% isolated yield (Scheme 10, Table 3).37
Importantly, examination of the 1H NMR spectra of the crude
reaction products of these hydrolysis reactions revealed that all
of the a,b-unsaturated acids had been produced as single isomers
with no evidence of any alkene migration having occurred under
the strong acid conditions used for hydrolysis. The structures
of a,b-unsaturated acids (E)-26b and (E)-26c were confirmed
via comparison with commercially available samples of (E)-2-
methylpentenoic acid and (E)-2-methyl-3-phenylpropenoic acid
respectively, whilst spectroscopic data for (E)-26a and (E)-27
were identical to previous literature reports.38,39
Experimental
General experimental
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 was distilled from
sodium/benzophenone ketyl, whilst CH2Cl2 was distilled from
CaH2 under nitrogen. All other reagents were used as supplied
without further purification. Flash column chromatography was
performed on silica gel (Kieselgel 60). TLC 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, containing 7%
potassium carbonate). Infra red 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 are referenced to the residual solvent peak,
with coupling constants (J) measured in Hertz. 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, using a path length of 10 cm, in spectroscopic
grade solvents (Aldrich), with concentrations (c) given in g
per 100 cm3, solvent and temperature as recorded. Melting
points were recorded on a Bu¨chi 535 melting point apparatus
and are uncorrected. Elemental analyses were performed using
an Exeter Analytical Inc CE-440 Elemental analyser. Single
crystal X-ray diffraction data were collected on a Nonius Kappa
CCD machine. Structural determination and refinement were
achieved using the SHELZ suite of programmes; drawings were
produced using ORTEX.
Scheme 10 Reagents and conditions: (i) 6 M HCl(aq)
Table 3 Yields for synthesis of (E)-acids 26a–d and 27
.
Acid
R
R1
de (%)
Yield (%)
26a
26b
26c
26d
27
iPr
Me
Me
Bn
Cyclohexyl
Ph
Et
>95
>95
>95
>95
>95
99
95
91
95
77
Me(CH2)6–
=
Me
(E)–PhCH CH–
The synthetic potential of this methodology was further
demonstrated via cyclisation of the N-hydroxyamide fragment
of (E)-amides 4b or 4c to afford their corresponding trisubsti-
tuted (E)-a,b-unsaturated oxazolines (E)-28 and (E)-29. Thus,
addition of thionyl chloride (5 eq.) in a dropwise fashion to an
ice-cold solution of a,b-unsaturated amides 4b and 4c in CH2Cl2,
resulted in the desired oxazolines (E)-28 and (E)-29 in 97% and
88% yield respectively (Scheme 11). It should be noted that these
types of (E)-a,b-unsaturated oxazolines are useful synthetic
intermediates that are easily converted into their corresponding
(E)-a,b-unsaturated acids, alcohols and aldehydes using known
literature procedures.40
Conclusion
In conclusion, we have demonstrated that potassium alkoxides
of N-acyl-oxazolidin-2-one derived-syn-aldols undergo stereos-
elective elimination reactions to afford a range of trisubstituted
(E)-a,b-unsaturated amides in excellent de, that could be easily
converted into their corresponding (E)-a,b-unsaturated acids or
General procedure A: preparation of N-acyl-oxazolidin-2-ones
A solution of n-butyllithium in hexanes (1.1 eq.) was added
dropwise via syringe to a stirred solution of oxazolidin-2-one
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 9 7 6 – 2 9 8 9
2 9 8 1

View Article Online
◦
1 (1 eq.) in THF at −78 C under a nitrogen atmosphere and
chloride (5.16 g, 63.2 mmol) in THF (250 mL), according to
general procedure A, afforded after recrystallisation from hot
ethyl acetate the title compound 2a (5.940 g, 41.54 mmol)
the mixture was allowed to stir for 15 minutes. The appropriate
acid chloride (1.1 eq.) was then added at −78 ◦C. The reaction
was stirred at this temperature for 2 hours and allowed to warm
to room temperature over a 1 hour period. Saturated NH4Cl(aq)
was added and the reaction extracted with CH2Cl2 (× 3). The
combined organic extracts were washed with NaHCO3(aq), dried
(MgSO4), and concentrated in vacuo to afford the desired N-acyl
oxazolidin-2-one.
◦
in 72% yield as a white crystalline solid, mp 77–79 C (lit,33
80–81 ◦C); mmax (KBr disc)/cm−1 1773 (C O)ox, 1700 (C O);
dH(300 MHz, CDCl3) 1.17 (3H, t, J 7.5, CH2CH3), 2.94 (2H, q,
J 7.5, CH2CH3), 4.02 (2H, app t, J 8.0, CH2N), 4.42 (2H, app t,
J 8.0, CH2O); dC(CDCl3) 8.7, 29.1, 42.9, 62.4, 154.0, 174.6; m/z
=
=
•
•
(EI+ ) 143 (49, M+ ), 57 (100%, CH3CH2CO+); HRMS (FAB+)
C6H9NO3 [MH+] requires 143.0577; found 143.0574.
General procedure B: preparation of
N-acyl-oxazolidin-2-one-syn-aldols
3-(3-Methylbutanoyl)-1,3-oxazolidin-2-one 2b41. Reaction of
oxazolidin-2-one 1 (9.905 g, 113.85 mmol) with a 2.5 M solution
of n-butyllithium in hexanes (50.10 mL, 125.23 mmol) and iso-
valeryl chloride (21.50 mL, 125.23 mmol) in THF (500 mL),
according to general procedure A, afforded after purification
through silica gel chromatography (40% ethyl acetate–petrol)
the title compound 2b (14.408 g, 84.26 mmol) in 74% yield as
A 0.5 M solution of 9-BBN-OTf in hexanes (1.2 eq.) was added
via syringe to a stirred solution of N-acyloxazolidin-2-one (1
◦
eq.) in CH2Cl2 at 0 C and allowed to stir at this temperature
for 5 minutes. N,N-diisopropylethylamine (1.4 eq.) was added,
the reaction was stirred for 25 minutes at 0 C before cooling
◦
to −78 ◦C. An aldehyde (1.1 eq.) was then added, the reaction
was stirred for 2 hours and allowed to warm to 0 ◦C for 30
minutes. pH 7.0 phosphate buffer was added, allowed to stir for
5 min and a 2 : 1 solution of methanol–hydrogen peroxide added
dropwise. The reaction was extracted with CH2Cl2 (× 3) and the
combined organic extracts were washed with NaHCO3(aq), brine,
dried (MgSO4) and concentrated in vacuo to afford the desired
syn-aldol.
a colourless oil, mmax (neat)/cm−1 1779 (C O)ox, 1699 (C O);
dH(300 MHz, CDCl3) 0.99 (6H, d, J 7.0, CH(CH3)2), 2.18 (1H,
=
=
i
m, J 7.0, CH(CH3)2), 2.81 (2H, d, J 7.0, CH2 Pr), 4.03 (2H,
app t, J 8.0, CH2N), 4.42 (2H, app t, J 8.0, CH2O); dC(CDCl3)
22.8, 25.3, 42.9, 43.9, 62.3, 153.9, 173.2; m/z (CI+, iso-butane)
172 (85, MH+), 129 (82, MH+–CH(CH3)2), 85 (100%); HRMS
(FAB+) C8H14NO3 [MH+] requires 172.0974; found 172.0974.
3-(3-Phenylpropanoyl)-1,3-oxazolidin-2-one 2c42. Reaction
of oxazolidin-2-one 1 (1.496 g, 17.20 mmol) with a 2.5 M
solution of n-butyllithium in hexanes (7.60 mL, 18.91 mmol)
and phenylpropionyl chloride (2.80 mL, 18.91 mmol) in THF
(90 mL), according to general procedure A, afforded after pu-
rification through silica gel chromatography (20% ethyl acetate–
petrol) the title compound 2c (2.765 g, 12.63 mmol) in 73% yield
as a white solid, mp 100–101 ◦C; mmax (KBr disc)/cm−1 3008
General procedure C: preparation of trisubstituted
(E)-a,b-unsaturated amides
A 0.5 M solution of KHMDS in toluene (1.5 eq.) was added
dropwise to a stirred solution of syn-aldol (1 eq.) in THF at
−78 ◦C under nitrogen, and the reaction was stirred at −78 ◦C
for two hours. Saturated NH4Cl(aq) was added and the reaction
was extracted with CH2Cl2 (× 3). The combined organic extracts
were washed with brine, dried (MgSO4), and concentrated in
vacuo to afford the desired (E)-a,b-unsaturated amide.
=
=
(C–H)ar, 1765 (C O)ox, 1692 (C O); dH(300 MHz, CDCl3) 2.91
(2H, t, J 7.5, CH2CH2Ph), 3.17 (2H, t, J 7.5, CH2CH2Ph), 3.90
(2H, app t, J 8.0, CH2N), 4.29 (2H, app t, J 8.0, CH2O), 7.09–
7.24 (5H, m, Ar–H); dC(CDCl3) 30.6, 37.2, 42.9, 62.5, 126.6,
•
•
General procedure D: preparation of 1,3-oxazinane-2,4-diones
128.8, 128.9, 140.9, 153.9, 172.9; m/z (EI+ ) 219 (55, M+ ), 132
(27, PhCH2CH2CO+), 104 (100), 88 (87, M+ –PhCH2CH2CO•);
•
A 1.0 M solution of Et2Zn in toluene (0.1 eq.) was added
dropwise to a stirred solution of syn-aldol (1 eq.) in CH2Cl2
at room temperature, and the reaction was stirred for 2 hours.
Saturated NH4Cl(aq) was added and the reaction was extracted
with CH2Cl2 (× 3). The combined organic extracts were washed
with brine, dried (MgSO4), and concentrated in vacuo to afford
the desired syn-1,3-oxazinane-2,4-dione.
HRMS (ES+) C12H17N2O3 [MNH4 ] requires 237.1234; found
+
237.1237.
3-(2-Phenylacetyl)-1,3-oxazolidin-2-one 2d43. Reaction of
oxazolidin-2-one 1 (9.90 g, 113.79 mmol) with a 1.6 M solution
of n-butyllithium in hexanes (78.20 mL, 125.17 mmol) and
phenyl acetyl chloride (21.50 mL, 125.17 mmol) in THF
(500 mL), according to general procedure A, afforded after
purification through silica gel chromatography (20% ethyl
acetate–petrol) the title compound 2d (14.404 g, 70.26 mmol)
General procedure E: preparation of trisubstituted
(E)-a,b-unsaturated acids
◦
in 62% yield as a white solid, mp 61–63 C (lit,43 64–65 ◦C);
An (E)-a,b-unsaturated amide was refluxed in 6.0 M HCl for
five hours. The reaction mixture was allowed to cool to room
temperature, saturated with sodium chloride, and extracted with
ethyl acetate (5 × 10 ml). The combined organic layers were dried
over magnesium sulfate and the solvent was removed in vacuo
to afford the desired (E)-a,b-unsaturated carboxylic acid.
mmax (KBr disc)/cm−1 3010 (C–H)ar, 1773 (C O)ox, 1696 (C O);
dH(300 MHz, CDCl3) 3.92 (2H, app t, J 8.0, CH2N), 4.25 (2H, s,
CH2Ph), 4.29 (2H, app t, J 8.0, CH2O), 7.26–7.31 (5H, m,
Ar–H); dC(CDCl3) 43.2, 47.8, 63.2, 128.1, 129.4, 130.0, 131.6,
154.7, 172.3; m/z (EI•+) 205 (30, M•+), 118 (100), 91 (60%,
=
=
PhCH2 ); HRMS (ES+) C11H11NO3 [MH+] requires 205.0739;
+
found 205.0742.
General procedure F: preparation of trisubstituted
(E)-a,b-oxazolines
syn-3-{2-[Cyclohexyl(hydroxy)methyl]-3-methylbutanoyl}-
1,3-oxazolidin-2-one 3a. Reaction of 3-(3-methylbutanoyl)-
1,3-oxazolidin-2-one 2b (1.500 g, 8.77 mmol) with a 0.5 M
solution of 9-BBN-OTf in hexanes (21.11 mL, 10.53 mmol),
N,N-diisopropylethylamine (1.99 mL, 11.40 mmol) and
cyclocarboxaldehyde (1.17 mL, 9.65 mmol) in CH2Cl2 (40 mL),
according to general procedure B, afforded after purification
through silica gel chromatography (gradient, 10–20% ethyl
acetate–petrol) the title compound syn-3a (1.451 g, 5.11 mmol)
in 58% yield as a white solid, mp 131–133 ◦C; mmax (KBr
Thionyl chloride (5 eq.) was added dropwise to a stirred solution
of a,b-unsaturated amide (1 eq.) in CH2Cl2 in an ice bath, and
the reaction mixture was stirred for 2 hours at this temperature.
A 5.0 M solution of NaOH (3 mL) was added dropwise and
the reaction was extracted with CH2Cl2 (× 3). The combined
organic extracts were washed with brine, dried (MgSO4), and
concentrated in vacuo to afford the desired (E)-a,b-unsaturated
oxazoline.
3-Propionyl-1,3-oxazolidin-2-one 2a33. Reaction of oxazolidin-
2-one 1 (5.0 g, 57.47 mmol) with a 2.5 M solution of n-
butyllithium in hexanes (25.30 mL, 63.2 mmol) and propionyl
disc)/cm−1 3510 (s, OH), 1773 (C O)ox, 1676 (C O);
dH(300 MHz, CDCl3) 1.02 (3H, d, J 7.0, CH(CH3)2), 1.03
(3H, d, J 7.0, CH(CH3)2), 1.12–1.27 (4H, m, Cy–H), 1.61–1.67
=
=
2 9 8 2
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 9 7 6 – 2 9 8 9

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(2H, m, Cy–H), 1.73–1.77 (2H, m, Cy–H), 1.83–1.91 (2H, m,
Cy–H), 2.04–2.10 (1H, m, Cy–H), 2.31 (1H, m, J 7.0, 5.0,
CH(CH3)2), 3.72–3.78 (1H, m, CHOH), 4.04 (2H, app t, J 8.0,
CH2N), 4.22 (1H, dd, J 7.0, 5.0, CHiPr), 4.41 (2H, app t, J 8.0,
CH2O); dC(CDCl3) 19.6, 21.5, 26.7, 27.4, 28.2, 30.6, 41.7, 43.0,
49.3, 61.9, 76.0, 153.7, 175.6; m/z (FAB+) 284 (97, MH+), 266
(100%, M+–OH); HRMS (FAB+) C15H26NO4 [MH+] requires
284.1862; found 284.1868.
2b (0.965 mg, 5.85 mmol) with a 0.5 M solution of 9-BBN-OTf
in CH2Cl2 (14.0 mL, 7.02 mmol), N,N-diisopropylethylamine
(1.43 mL, 8.19 mmol) and propionaldehyde (0.47 mL,
6.44 mmol) in CH2Cl2 (30 mL), according to general procedure
B, afforded after purification through silica gel chromatography
(gradient, 25–40% ethyl acetate–petrol) the title compound
syn-3e (0.644 g, 2.81 mmol) in 48% yield as a white solid,
mp 60–62 ◦C; mmax(KBr disc)/cm−1 3463 (br, OH), 1752
=
=
(C O)ox, 1696 (C O); dH(300 MHz, CDCl3) 0.85 (3H, d, J 7.0,
CH(CH3)2), 0.90 (3H, d, J 7.0, CH(CH3)2), 0.91 (3H, t, J 7.0,
CH2CH3), 1.35 (1H, ddq, J 14.0, 10.0, 7.0, CHAHBCH3), 1.51
(1H, dqd, J 14.0, 7.0, 2.3, CHAHBCH3), 2.12 (1H, m, J 8.0,
7.0, CH(CH3)2), 2.54 (1H, br s, OH), 3.83 (1H, app t, J 7.0,
CHiPr), 3.91–4.02 (3H, m, CH2N, CHOH), 4.30–4.37 (2H, m,
CH2O); dC(CDCl3) 9.7, 19.2, 19.9, 24.4, 27.0, 41.8, 53.1, 60.8,
72.1, 153.3, 173.6; m/z (CI+, iso-butane) 230 (5, MH+), 212
(8, M+–OH), 171 (34%, M+–CH3CH2CHOH); HRMS (FAB+)
C11H20NO4 [MH+] requires 230.1392; found 230.1394.
syn-3-(3-Hydroxy-2-methyl-3-phenylpropanoyl)-1,3-oxazolidin-
2-one 3b27. Reaction of 3-propionyl-1,3-oxazolidin-2-one 2a
(0.545 g, 3.81 mmol) with a 0.5 M solution of 9-BBN-OTf in
hexanes (9.14 mL, 4.57 mmol), N,N-diisopropylethylamine
(0.86 mL, 4.95 mmol) and benzaldehyde (0.43 mL, 4.19 mmol)
in CH2Cl2 (20 mL), according to general procedure B, afforded
after purification through silica gel chromatography (gradient,
20–30% ethyl acetate–petrol) the title compound syn-3b
(0.653 g, 2.62 mmol) in 69% yi◦eld as a white crystalline solid,
◦
mp 102–104 C (lit,27 105–106 C); mmax (KBr disc)/cm−1 3561
=
=
(s, OH), 1766 (C O)ox, 1682 (C O); dH(300 MHz, CDCl3) 1.15
(3H, d, J 7.0, CH3), 3.07 (1H, d, J 3.0, OH), 3.95–4.07 (2H,
m, CH2N), 4.12 (1H, qd, J 7.0, 3.0, CHCH3), 4.31–4.45 (2H,
m, CH2O), 5.13 (1H, app t, J 3.0, CHOH), 7.24–7.43 (5H, m,
Ar–H); dC(CDCl3) 10.8, 43.0, 44.6, 62.4, 73.9, 126.4, 127.9,
syn-3-{2-[Hydroxy(phenyl)methyl]-3-methylbutanoyl}-1,3-
oxazolidin-2-one 3f. Reaction of 3-(3-methylbutanoyl)-1,3-
oxazolidin-2-one 2b (0.993 g, 5.81 mmol) with a 0.5 M solution
of 9-BBN-OTf in hexanes (11.7 mL, 5.85 mmol), N,N-
diisopropylethylamine (1.40 mL, 8.19 mmol) and benzaldehyde
(0.65 mL, 6.43 mmol) in CH2Cl2 (30 mL), according to
general procedure B, afforded after purification through
silica gel chromatography (25% ethyl acetate–petrol) the title
compound syn-3f (0.811 g, 2.93 mmol) in 50% yield as a white
solid, mp 93–95 ◦C; mmax(KBr disc)/cm−1 3450 (s, OH), 1751
128.6, 141.6, 153.5, 177.2; m/z (CI+, NH3) 267 (41, MNH4 ),
+
250 (10, MH+), 232 (38, M+–OH), 206 (22, MH+–CO2), 161
(100%); HRMS (FAB+) C13H16NO4 [MH+] requires 250.1079;
found 250.1081.
syn-3-(3-Hydroxy-2-methylpentanoyl)-1,3-oxazolidin-2-one
3c. Reaction of 3-propionyl-1,3-oxazolidin-2-one 2a (0.991 g,
6.93 mmol) with a 1.0 M solution of 9-BBN-OTf in CH2Cl2
(8.39 mL, 8.39 mmol), N,N-diisopropylethylamine (1.70 mL,
9.79 mmol) and propionaldehyde (0.56 mL, 7.69 mmol) in
CH2Cl2 (35 mL), according to general procedure B, afforded
after purification through silica gel chromatography (gradient,
25–40% ethyl acetate–petrol) the title compound syn-3c
(0.427 g, 2.12 mmol) in 31% yield as a white solid, mp 60–62 ◦C;
C9H15NO4 requires C, 53.7; H, 7.51; N, 6.96%; found C, 53.6;
H, 7.45; N, 6.89%; mmax(KBr disc)/cm−1 3471 (br, OH), 1752
=
=
(C O)ox, 1695 (C O); dH(300 MHz, CDCl3) 1.01 (3H, d, J 7.0,
CH(CH3)2), 1.08 (3H, d, J 7.0, CH(CH3)2), 2.36 (1H, m, J 7.0,
5.5, CH(CH3)2), 2.41 (1H, d, J 3.0, OH), 3.62 (1H, ddd, J 11.0,
9.5, 7.0, CHAHBN), 3.84 (1H, ddd, J 11.0, 9.5, 7.0, CHAHBN),
4.07 (1H, app dt, J 9.0, 8.0, CHAHBO), 4.24 (1H, app dt, J
9.0, 8.0, CHAHBO), 4.48 (1H, dd, J 8.0, 5.5, CHiPr), 5.01 (1H,
dd, J 8.0, 3.0, CHOH), 7.25–7.40 (5H, m, Ar–H); dC(CDCl3)
18.0, 19.8, 27.1, 41.3, 53.0, 60.3, 72.9, 125.6, 126.7, 127.1, 140.9,
+
152.0, 172.7; m/z (CI+, NH3) 295 (8, MNH4 ), 278 (5, MH+),
260 (28, M+–OH), 234 (9, M+-iPr), 105 (100%); HRMS (ES+)
+
C15H23N2O4 [MNH4 ] requires 295.1652; found 295.1653.
=
=
(C O)ox, 1696 (C O); dH(300 MHz, CDCl3) 0.91 (3H, t, J 7.5,
CH2CH3), 1.13 (3H, d, J 7.0, CHCH3), 1.44 (2H, m, CH2CH3),
2.78 (1H, br s, OH), 3.79–3.89 (2H, m, CHOH, CHCH3),
4.01–4.07 (2H, m, CH2N), 4.37 (2H, app t, J 8.5, CH2O);
dC(CDCl3) 8.3, 8.5, 24.8, 39.6, 40.8, 60.1, 71.2, 151.4, 175.6;
m/z (CI+, iso-butane) 202 (100, MH+), 184 (95, M+–OH), 143
(57%, M+–CH3CH2CHOH); HRMS (FAB+) C9H16NO4 [MH+]
requires 202.1079; found 202.1080.
syn-3-{2-[Hydroxy(4-methoxyphenyl)methyl]-3-methylbutanoyl}-
1,3-oxazolidin-2-one 3g. Reaction of 3-(3-methylbutanoyl)-
1,3-oxazolidin-2-one 2b (1.500 g, 8.77 mmol) with a 0.5 M
solution of 9-BBN-OTf in hexanes (21.10 mL, 10.53 mmol),
N,N-diisopropylethylamine (1.99 mL, 11.40 mmol) and
p-anisaldehyde (1.17 mL, 9.65 mmol) in CH2Cl2 (40 mL),
according to general procedure B, afforded after purification
through silica gel chromatography (gradient, 10–20% ethyl
acetate–petrol) the title compound syn-3g (1.592 g, 5.18 mmol)
in 60% yield as a white crystalline solid, mp 117–118 ◦C; mmax
syn-3-(2-Benzyl-3-hydroxydecanoyl)-1,3-oxazolidin-2-one 3d.
Reaction of 3-(3-phenylpropanoyl)-1,3-oxazolidin-2-one 2c
(0.500 g, 2.28 mmol) with a 0.5 M solution of 9-BBN-OTf
in hexanes (5.48 mL, 2.74 mmol), N,N-diisopropylethylamine
(0.56 mL, 3.20 mmol) and octanal (0.39 mL, 2.51 mmol) in
CH2Cl2 (10 mL), according to general procedure B, afforded
after purification through silica gel chromatography (20% ethyl
acetate–petrol) the title compound syn-3d (0.582 g, 1.68 mmol)
in 74% yield as a colourless oil, mmax(neat)/cm−1 3474 (br, OH),
(KBr disc)/cm−1 3449 (s, OH), 1755 (C O)ox, 1691 (C O);
dH(300 MHz, CDCl3) 1.02 (3H, d, J 7.0, CH(CH3)2), 1.08 (3H,
d, J 7.0, CH(CH3)2), 2.24 (1H, d, J 3.5, OH), 2.35 (1H, m, J 7.0,
5.5, CH(CH3)2), 3.65 (1H, ddd, J 11.0, 9.5, 7.0, CHAHBN), 3.79
(3H, s, ArOCH3), 3.86 (1H, ddd, J 11.0, 9.5, 7.0, CHAHBN),
4.12 (1H, app dt, J 9.0, 7.0, CHAHBO), 4.26 (1H, app td, J
9.0, 7.0, CHAHBO), 4.48 (1H, dd, J 8.0, 5.5, CHiPr), 4.97 (1H,
dd, J 8.0, 3.5, CHOH), 6.84 (2H, d, J 8.5, Ar–H), 7.30 (2H,
d, J 8.5, Ar–H); dC(CDCl3) 19.5, 21.3, 28.7, 42.9, 54.5, 55.6,
=
=
=
=
1775 (C O)ox, 1695 (C O); dH(300 MHz, CDCl3) 0.81 (3H, t,
J 7.0, CH3), 1.16–1.28 (8H, m, CH2), 1.44–1.52 (4H, m, CH2),
2.65 (1H, br s, OH), 2.92 (1H, dd, J 13.0, 5.5, CHAHBPh),
2.99 (1H, dd, J 13.0, 10.0, CHAHBPh), 3.62 (1H, ddd, J 10.0,
9.0, 6.0, CHAHBN), 3.73–4.00 (3H, m, CHAHBN, CHOH,
CHAHBO), 4.18 (1H, app dt, J 9.0, 6.0, CHAHBO), 4.33–4.40
(1H, m, CHCH2Ph), 7.11–7.19 (5H, m, Ar–H); dC(CDCl3) 14.5,
23.0, 26.4, 29.6, 29.9, 32.2, 33.5, 34.4, 42.9, 49.5, 62.1, 72.6,
126.8, 128.7, 129.4, 139.3, 153.7, 175.9; m/z (CI+, NH3) 365
•
61.8, 74.0, 114.0, 128.5, 134.6, 153.6, 159.6, 174.2; m/z (EI+ )
•
•
307 (12, M+ ), 171 (28, M+ –ArCHOH•), 149 (100%); HRMS
(FAB+) C16H21NO5 [MH+] requires 307.1420; found 307.1426.
syn-3-(3-Hydroxy-2-phenylpentanoyl)-1,3-oxazolidin-2-one
3h. Reaction of 3-(2-phenylacetyl)-1,3-oxazolidin-2-one 2d
(0.994 g, 4.85 mmol) with a 1.0 M solution of 9-BBN-OTf
in CH2Cl2 (5.86 mL, 5.86 mmol), N,N-diisopropylethylamine
(1.20 mL, 6.83 mmol) and propionaldehyde (0.39 mL,
5.37 mmol) in CH2Cl2 (20 mL), according to general procedure
B, afforded after purification through silica gel chromatography
(11, MNH4 ), 348 (13, MH+), 237.2 (100%); HRMS (ES+)
+
C20H30NO4 [MH+] requires 348.2169; found 348.2171.
syn-3-(3-Hydroxy-2-isopropylpentanoyl)-1,3-oxazolidin-2-one
3e41. Reaction of 3-(3-methylbutanoyl)-1,3-oxazolidin-2-one
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 9 7 6 – 2 9 8 9
2 9 8 3

View Article Online
•
•
•
(25% ethyl acetate–petrol) the title compound syn-3h (0.464 g,
1.76 mmol) in 37% yield as a colourless oil, mmax(neat)/cm−1 3519
(85, M+ –CH3 ), 179 (68%, M+ –HOCH2CH2NH•); HRMS
(FAB+) C14H25NO2 [MH+] requires 239.1885; found 239.1886.
=
=
(br, OH), 1771 (C O)ox, 1694 (C O); dH(300 MHz, CDCl3)
0.99 (3H, t, J 7.5, CH2CH3), 1.35–1.48 (2H, m, CH2CH3), 2.70
(1H, d, J 3.0, OH), 3.92 (1H, ddd, J 11.0, 9.5, 6.5, CHAHBN),
4.06 (1H, ddd, J 11.0, 9.5, 7.0, CHAHBN), 4.11–4.17 (1H, m,
CHOH), 4.29 (1H, app dt, J 9.5, 8.0, CHAHBO), 4.38 (1H, app
dt, J 9.5, 8.0, CHAHBO), 5.04 (1H, d, J 5.5, CHPh), 7.26–7.44
(5H, m, Ar–H); dC(CDCl3) 10.5, 27.6, 42.9, 53.5, 62.0, 74.0,
128.1, 128.7, 130.3, 134.2, 153.0, 174.2; m/z (CI+, NH3) 281 (20,
X-Ray crystal data for 4a
(C14H25NO2): Mr = 239.35, T = 150(2) K, monoclinic, space
˚
group P21/c, a = 17.3540(2), b = 9.79700(10), c = 17.7370(2) A,
◦
b = 104.153(1) , V = 2924.06(7) A , Z = 8, qcalcd = 1.087 Mg m−3,
3
˚
l = 0.071 mm , k = 0.71073 A, hmax = 27.46◦, 43295 measured
−1
˚
reflections, 6676 independent reflections [R(int) = 0.0787], GOF
on F2 = 1.007, R1 = 0.0453, wR2 = 0.1035 (I>2r(I)), R1 =
0.0818, wR2 = 0.1198 (for all data), largest difference peak and
MNH4 ), 264 (19, MH+), 223 (100%); HRMS (ES+) C14H18NO4
+
[MH+] requires 264.1230, found 264.1227.
−3
˚
hole 0.232 and −0.215 e A . Crystal data were collected on a
Nonius Kappa CCD diffractometer. The structure was solved
by direct methods and refined on all F2 data using the SHELX-
97 suite of programs.44 The asymmetric unit was seen to consist
of two molecules, one of which exhibited 55 : 45 positional
disorder in the cyclohexyl carbons. All hydrogen atoms were
included at calculated positions, with the exception of the H1
and H1A (hydroxyl groups), which were located and refined.
The supramolecular array is dominated by extensive hydrogen-
bonding.†
syn-3-[(E)-3-Hydroxy-2-isopropyl-4-hexenoyl]-1,3-oxazolidin-
2-one 3i. Reaction of 3-(3-methylbutanoyl)-1,3-oxazolidin-2-
one 2b (0.965 g, 5.85 mmol) with a 0.5 M solution of 9-BBN-OTf
in hexanes (14.10 mL, 7.02 mmol), N,N-diisopropylethylamine
(1.32 mL, 7.60 mmol) and trans-crotonaldehyde (0.53 mL,
6.44 mmol) in CH2Cl2 (30 mL), according to general procedure
B, afforded after purification through silica gel chromatography
(25% ethyl acetate–petrol) the title compound syn-3i (1.090 g,
4.54 mmol) in 72% yield as a low-melting point white solid,
mmax(nujol)/cm−1 3454 (br, OH), 1770 (C O)ox, 1690 (C O);
dH(300 MHz, CDCl3) 0.92 (3H, d, J 6.5, CH(CH3)2), 0.97
(3H, d, J 6.5, CH(CH3)2), 1.72 (3H, d, J 5.5, CH CHCH3),
=
=
(E)-N-(2-Hydroxyethyl)-2-methyl-3-phenyl-2-propenamide
4b. Reaction of syn-3-(3-hydroxy-2-methyl-3-phenylpropanoyl)-
1,3-oxazolidin-2-one 3b (0.200 g, 0.80 mmol) with a 0.5 M
solution of KHMDS in toluene (2.41 mL, 1.20 mmol) in THF
(4 mL), according to general procedure C, afforded the title
compound (E)-4b (0.143 g, 0.70 mmol) in 91% yield and >95%
de as a white solid, mp 101–103 ◦C; mmax (KBr disc)/cm−1
3284 (br, OH, NH), 1644 (C O), 1620 (C C), 1575 (C O);
dH(300 MHz, CDCl3) 2.04 (3H, d, J 1.0, C C(CH3)), 3.08 (1H,
br s, OH), 3.46–3.51 (2H, m, CH2N), 3.74 (2H, app t, J 5.0,
CH2O), 6.48 (1H, br s, NH), 7.19 (1H, s, C CH), 7.20–7.33
=
1.99–2.11 (1H, m, CH(CH3)2), 2.23 (1H, br s, OH), 4.01–4.10
(3H, m, CH2N, CHiPr), 4.34–4.48 (3H, m, CH2O, CHOH),
=
5.60–5.81 (2H, m, CH CHCH3); dC(CDCl3) 18.2, 20.4, 21.1,
28.6, 43.2, 54.3, 62.0, 73.5, 130.0, 130.5, 154.7, 174.7; m/z
(CI+, iso-butane) 242 (6, MH+), 224.1 (75, M+–OH), 171.0
(64, M+–CHOHCHCHCH3), 156.0 (100%); HRMS (FAB+)
C12H20NO4 [MH+] requires 242.1392; found 242.1393.
=
=
=
=
=
syn-3-[(E)-3-Hydroxy-2-methyl-5-phenyl-4-pentenoyl]-1,3-
oxazolidin-2-one 3j. Reaction of 3-propionyl-1,3-oxazolidin-2-
one 2a (0.500 g, 3.50 mmol) with a 0.5 M solution of 9-BBN-OTf
in hexanes (8.40 mL, 4.20 mmol), N,N-diisopropylethylamine
(0.79 mL, 4.55 mmol) and trans-cinnamaldehyde (0.49 mL,
3.85 mmol) in CH2Cl2 (15 mL), according to general procedure
B, afforded after purification through silica gel chromatography
(gradient, 20–40% EtOAc–petrol) the title compound syn-3j
(0.841 g, 3.06 mmol) in 88% yield as a white crystalline solid,
mp 100–101 ◦C; mmax(KBr disc)/cm−1 3476 (s, OH), 1762
(5H, m, Ar–H); dC(CDCl3) 14.6, 43.3, 62.8, 128.3, 128.7, 129.7,
131.7, 135.0, 136.3, 171.2; m/z (CI+, NH3) 206 (100%, MH+);
HRMS (FAB+) C12H16NO2 [MH+] requires 206.1176, found
206.1177.
(E)-N-(2-Hydroxyethyl)-2-methyl-2-pentenamide 4c. Reac-
tion of syn-3-(3-hydroxy-2-methylpentanoyl)-1,3-oxazolidin-2-
one 3c (0.050 g, 0.25 mmol) with a 0.5 M solution of KHMDS
in toluene (0.75 mL, 0.37 mmol) in THF (3 mL), according
to general procedure C, afforded the title compound (E)-4c
(0.026 g, 0.17 mmol) in 67% yield and >95% de as a white solid
of low melting point (<30 ◦C), mmax(KBr disc)/cm−1 3405 (br,
=
=
(C O)ox, 1683 (C O); dH(300 MHz, CDCl3) 1.17 (3H, d, J
7.0, CH3), 2.97 (1H, d, J 1.0, OH), 3.88–3.99 (3H, m, CH2N,
CHCH3), 4.28–4.34 (2H, m, CH2O), 4.58 (1H, ddd, J 6.0,
=
=
=
OH, NH), 1701 (C O), 1615 (C C), 1538 (C O); dH(300 MHz,
CDCl3) 1.04 (3H, t, J 7.5, CH2CH3), 1.85 (3H, s, CH3), 2.17 (2H,
app pentet, J 7.5, CH2CH3), 2.86 (1H, br s, OH), 3.50 (2H, app
q, J 6.0, 5.0, CH2NH), 3.77 (2H, app t, J 6.0, CH2OH), 6.19
=
4.0, 1.0, CHOH), 6.14 (1H, dd, J 16.0, 6.0, HC CHPh),
6.59 (1H, d, J 16.0, HC CHPh), 7.15–7.34 (5H, m, Ar–H);
=
dC(CDCl3) 11.6, 43.0, 43.5, 62.4, 73.2, 126.9, 128.1, 129.0
•
•
=
(2C), 131.8, 136.9, 153.8, 176.8; m/z (EI+ ) 275 (7, M+ ), 143
(1H, s, NH), 6.38 (1H, t, J 7.5, C CH); dC(CDCl3) 11.5, 12.2,
20.6, 41.7, 61.4, 128.7, 137.5, 169.7; m/z (CI+, NH3) 158 (100%,
MH+); HRMS (ES+) C8H16NO2 [MH+] requires 158.1176; found
158.1179.
(42, M+ –PhCHCHCHOH•), 104.1 (100%); HRMS (ES+)
•
+
C15H21N2O4 [MNH4 ] requires 293.1496; found 293.1495.
(E)-3-Cyclohexyl-N-(2-hydroxyethyl)-2-isopropyl-2-propenamide
4a. Reaction of syn-3-{2-[cyclohexyl(hydroxy)methyl]-3-
methylbutanoyl}-1,3-oxazolidin-2-one 3a (0.100 g, 0.35 mmol)
with a 0.5 M solution of KHMDS in toluene (1.06 mL,
0.53 mmol) in THF (2 mL), according to general procedure C,
gave the title compound (E)-4a (0.075 g, 0.31 mmol) in 94%
de. The crude product was purified for analysis by silica gel
chromatography (gradient, 20–30% ethyl acetate–petrol), to
afford the title compound (E)-4a (0.064 g, 0.27 mmol) in 77%
yield and >95% de as a white solid, mp 84–86 ◦C; mmax(KBr
(E)-2-Benzyl-N-(2-hydroxyethyl)-2-decenamide 4d. Reac-
tion of syn-3-(2-benzyl-3-hydroxydecanoyl)-1,3-oxazolidin-2-
one 3d (0.135 g, 0.39 mmol) with a 0.5 M solution of KHMDS
in toluene (1.17 mL, 0.58 mmol) in THF (3 mL), according to
general procedure C, gave the title compound (E)-4d (0.110 g,
0.36 mmol) in 92% de. The crude product was purified for
analysis by silica gel chromatography (60% ethyl acetate–petrol)
to afford the title compound (E)-4d (0.108 g, 0.36 mmol) in
91% yield and >95% de as a colourless oil, mmax(neat)/cm−1
=
=
=
3342 (br, OH, NH), 1656 (C O), 1620 (C C), 1537 (C O);
dH(300 MHz, CDCl3) 0.88 (3H, t, J 7.0, CH3), 1.23–1.28 (8H,
m, Alk-H), 1.39–1.46 (2H, m, CH2), 2.21 (2H, app q, J 7.5,
disc)/cm−1 3291 (br, OH, NH), 1652 (C O), 1619 (C C), 1541
=
=
=
(C O); dH(300 MHz, CDCl3) 1.01–1.37 (6H, m, Cy-H), 1.18
(6H, d, J 7.0, CH(CH3)2), 1.60–1.78 (4H, m, Cy-H), 2.25–2.39
(1H, m, Cy-H), 2.83 (1H, m, J 7.0, CH(CH3)2), 2.95 (1H, t,
J 4.5, OH), 3.44 (2H, app q, J 5.5, 4.5, CH2NH), 3.74 (2H,
app q, J 5.5, 4.5, CH2OH), 5.59 (1H, d, J 10.0, C CH), 6.08
(1H, br s, NH); dC(CDCl3) 22.1, 26.1, 26.2, 28.6, 33.3, 37.0,
=
CH CCH2), 2.97 (1H, br s, OH), 3.33 (2H, app q, J 5.5, 5.0,
CH2NH), 3.57 (2H, m, CH2OH), 3.69 (2H, s, CH2Ph), 6.17
=
† CCDC reference number 207151. See http://dx.doi.org/10.1039/
b503633j for crystallographic data in CIF or other electronic format.
•
•
42.9, 63.3, 137.9, 142.0, 173.1; m/z (EI+ ) 239 (65, M+ ), 224
2 9 8 4
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 9 7 6 – 2 9 8 9

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=
(1H, br t, J 5.0, NH), 6.54 (1H, t, J 7.5, C CH), 7.16–7.30 (5H,
m, Ar–H); dC(CDCl3) 14.5, 23.0, 28.9, 29.3, 29.5, 29.8, 32.1,
2-one 2d (20%). The crude product was purified by silica gel
chromatography (40% ethyl acetate–petrol) to afford the title
compound (E)-4h (0.078 g, 0.35 mmol) in 47% yield and >95%
de as a colourless oil, mmax (neat)/cm−1 3418 (br, OH, NH), 1657
33.1, 43.1, 62.9, 126.8, 128.5, 129.1, 134.0, 139.0, 139.3, 170.5;
m/z (EI+ ) 303 (10, M+ ), 243 (13, M+ –HOCH2CH2NH•), 91
•
•
•
+
(100%, PhCH2 ); HRMS (ES+) C19H30NO2 [MH+] requires
(C O), 1617 (C C), 1522 (C O); dH(300 MHz, CDCl3) 0.99
(3H, t, J 7.5, CH2CH3), 1.98 (2H, app pentet, J 7.5, CH2CH3),
3.16 (1H, br s, OH), 3.39 (2H, app q, J 5.5, 5.0, CH2NH),
3.66 (2H, app t, J 5.0, CH2OH), 5.79 (1H, br s, NH), 7.03
=
=
=
304.2271; found 304.2275.
(E)-N-(2-Hydroxyethyl)-2-isopropyl-2-pentenamide 4e45. Reac-
tion of syn-3-(3-hydroxy-2-methylpentanoyl)-1,3-oxazolidin-2-
one 3e (0.100 g, 0.44 mmol) with a 0.5 M solution of KHMDS
in toluene (1.30 mL, 0.65 mmol) in THF (3 mL), according
to general procedure C, afforded the title compound (E)-4e
(0.080 g, 0.43 mmol) in 99% yield and >95% de as a colourless
=
(1H, t, J 7.5, C CH), 7.17–7.21 (2H, m, Ar–H), 7.35–7.46
(3H, m, Ar–H); dC(CDCl3) 13.4, 23.1, 43.4, 62.8, 128.6, 129.0,
•
•
130.2, 135.1, 135.8, 143.8, 168.8; m/z (EI+ ) 219 (18, M+ ),
159 (22, M+ –HOCH2CH2NH•), 77 (100%); HRMS (FAB+)
•
C13H18NO2 [MH+] requires 220.1332; found 220.1332.
oil, mmax(neat)/cm−1 3338 (br, OH, NH), 1653 (C O), 1617
=
=
=
(C C), 1534 (C O); dH(300 MHz, CDCl3) 1.03 (3H, t, J 7.5,
CH2CH3), 1.16 (6H, d, J 7.0, CH(CH3)2), 2.14 (2H, app pentet,
J 7.5, CH2CH3), 2.81 (1H, septet, J 7.0, CH(CH3)2), 3.43 (2H,
app q, J 5.5, 4.5, CH2NH), 3.50 (1H, br s, OH), 3.73 (2H,
(2E,4E)-N-(2-Hydroxyethyl)-2-isopropyl-2,4-hexadienamide
4i and (2Z,4E)-N-(2-hydroxyethyl)-2-isopropyl-2,4-hexadienamide
5. Reaction of syn-3-[(E)-3-hydroxy-2-isopropyl-4-hexenoyl]-
1,3-oxazolidin-2-one 3i (0.200 g, 0.83 mmol) with a 0.5 M
solution of KHMDS in toluene (2.50 mL, 1.25 mmol) in
THF (5 mL), according to general procedure C, gave the
title compound (E,E)-4i (0.153 g, 0.78 mmol) in 93% yield
and in 60% de which was purified through silica (pre-coated
with silver nitrate) gel chromatography to afford the title
compound (E,E)-4i (0.016 g, 0.08 mmol) in 10% yield as a
pale oil, dH(300 MHz, CDCl3) 1.20 (6H, d, J 7.0, CH(CH3)2),
=
app t, J 5.0, CH2OH), 5.77 (1H, t, J 7.5, C CH), 6.26 (1H,
br s, NH); dC(CDCl3) 13.2, 20.1, 20.7, 27.2, 41.7, 61.8, 133.0,
142.2, 171.9; m/z (CI+, iso-butane) 186 (88, MH+), 185 (32, M+),
125 (100%, M+–HOCH2CH2NH); HRMS (FAB+) C10H20NO2
[MH+] requires 186.1494, found 186.1495.
(E)-N-(2-Hydroxyethyl)-2-isopropyl-3-phenyl-2-propenamide
4f. Reaction of syn-3-{2-[hydroxy(phenyl)methyl]-3-methyl-
butanoyl}-1,3-oxazolidin-2-one 3f (0.085 g, 0.31 mmol) with a
0.5 M solution of KHMDS in toluene (1.08 mL, 0.54 mmol) in
THF (3 mL), according to general procedure C, afforded title
compound (E)-4f (0.068 g, 0.29 mmol) in 92% de. The crude
product was purified for analysis by silica gel chromatography
(40% ethyl acetate–petrol) to afford the title compound (E)-4f
(0.065 g, 0.22 mmol) in 90% yield and >95% de as a white
solid, mp 101–103 ◦C; mmax (KBr disc)/cm−1 3317 (s, OH, NH),
1641 (C O), 1612 (C C), 1538 (C O); dH(300 MHz, CDCl3)
1.24 (6H, d, J 7.0, CH(CH3)2), 2.95 (1H, br s, OH), 3.07 (1H,
septet, J 7.0, CH(CH3)2), 3.52 (2H, app q, J 5.5, 5.0, CH2NH),
3.79 (2H, app t, J 5.0, CH2OH), 6.33 (1H, br s, NH), 6.79
=
1.83 (3H, dd, J 7.0, 1.5, CH CHCH3), 2.95 (1H, septet,
J 7.0, CH(CH3)2), 3.20 (1H, br s, OH), 3.45 (2H, app dt,
J 5.5, 4.0, CH2NH), 3.74 (2H, app t, J 5.0, CH2OH), 5.89
=
(1H, dq, J 13.0, 7.0, CH CHCH3), 6.21 (1H, br s, NH),
6.33 (1H, br d, J 10.5, CH–CH CHCH3), 6.39 (1H, ddq,
=
=
J 13.0, 10.5, 1.5, CH–CH CHCH3); dC(CDCl3) 19.0, 21.8,
•
28.6, 42.8, 63.0, 126.6, 130.6, 135.2, 141.0, 172.5; m/z (EI+ )
•
•
•
•
197 (23, M+ ), 182 (33, M+ –CH3 ), 169 (38, M+ –CH3CH•),
154 (100, M+ –(CH3)2CH•), 137 (28, M+ –HO(CH2)2NH•),
•
•
=
=
=
109 (43, M+ –HO(CH2)2NHCO•), and its geometric isomer
•
(Z,E)-5 (0.015 g, 0.08 mmol) in 9% yield, dH(300 MHz, CDCl3)
1.08 (6H, d, J 7.0, CH(CH3)2), 1.77 (3H, dd, J 7.0, 1.5,
=
CH CHCH3), 2.64 (1H, septet, J 7.0, CH(CH3)2), 3.00 (1H,
=
(1H, br s, C CH), 7.25–7.39 (5H, m, Ar–H); dC(CDCl3) 21.9,
br s, OH), 3.53 (2H, app dt, J 5.5, 4.5, CH2NH), 3.78 (2H, app
28.5, 42.8, 63.0, 128.0, 128.8, 129.1, 130.1, 136.1, 145.7, 172.4;
=
•
•
•
m/z (EI+ ) 233 (19, M+ ), 173 (48, M+ –HOCH2CH2NH•),
t, J 5.0, CH2OH), 5.79 (1H, dq, J 15.0, 7.0, CHCH CHCH3),
=
•
•
5.99 (1H, d, J 11.0, CH–CH CHCH3), 6.13 (1H, br s, NH),
145(57, M+ –HOCH2CH2NHCO ), 91 (100%, PhCH2 ); HRMS
+
=
6.28 (1H, ddq, J 15.0, 11.0, 1.5, CH–CH CHCH3).
(ES+) C14H20NO2 [MH+] requires 234.1489, found 234.1489.
(2E,4E)-N-(2-Hydroxyethyl)-2-methyl-5-phenyl-2,4-penta-
dienamide 4j. Reaction of syn-3-[(E)-3-hydroxy-2-methyl-
5-phenyl-4-pentenoyl]-1,3-oxazolidin-2-one 4j (0.275 g,
1.00 mmol) with a 0.5 M solution of KHMDS (3.00 mL,
1.50 mmol) in THF (5 mL), according to general procedure
C, gave the title compound (E)-4j (0.223 g, 0.97 mmol) in
97% yield and in 60% de The crude product was purified for
analysis by recrystallisation from hot ethyl acetate, to afford the
title compound (E)-4j (0.147 g, 0.64 mmol) in 64% yield and
>95% de as a white solid, mp 141–142 ◦C; mmax(KBr disc)/cm−1
(E)-N-(2-Hydroxyethyl)-2-isopropyl-3-(4-methoxyphenyl)-2-
propenamide 4g. Reaction of syn-3-{2-[hydroxy(4-meth-
oxyphenyl)methyl]-3-methylbutanoyl}-1,3-oxazolidin-2-one 3g
(0.200 g, 0.65 mmol) with a 1.0 M solution of KHMDS in
toluene (1.95 mL, 0.98 mmol) in THF (4 mL), according to
general procedure C, gave the title compound (E)-4g (0.155 g,
0.59 mmol) in 90% de. The crude product was purified for
analysis by silica gel chromatography (40% ethyl acetate–petrol)
to afford the title compound (E)-4g (0.149 g, 0.57 mmol) in 88%
yield and >95% de as a white solid, mp 91–93 ◦C; mmax (KBr
disc)/cm−1 3279 (s, OH), 3064 (C C)ar, 2834 (C–H)OMe, 1645
=
=
3293 (br, OH), 3250 (br, NH), 1642 (C O), 1585 (C C), 1542
=
=
(C O); dH(300 MHz, CDCl3) 2.08 (3H, s, CH3), 2.87 (1H, t,
=
=
=
=
=
(C O), 1620 (C C), 1606 (C C)ar, 1542 (C O), 1510 (C C)ar;
dH(300 MHz, CDCl3) 1.24 (6H, d, J 7.0, CH(CH3)2), 3.09 (1H,
septet, J 7.0, CH(CH3)2), 3.18 (1H, br s, OH), 3.50 (2H, app dt,
J 5.5, 5.0, CH2NH), 3.75–3.85 (2H, m, CH2OH), 3.82 (3H, s,
J 5.0, OH), 3.55 (2H, app q, J 5.5, 5.0, CH2NH), 3.80 (2H,
app q, J 5.0, 5.0, CH2OH), 6.32 (1H, br s, NH), 6.83 (1H, d, J
15.0, CH–CH CHPh), 7.01 (1H, d, J 11.0, CHCH CHPh),
=
=
=
7.10 (1H, dd, J 15.0, 11.0, CHCH CHPh), 7.28–7.48 (5H, m,
=
ArOCH3), 6.38 (1H, br s, NH), 6.73 (1H, s, C CH), 6.89 (2H,
d, J 9.0, Ar–H), 7.21 (2H, d, J 9.0, Ar–H); dC(CDCl3) 21.9, 28.4,
Ar–H); dC(CDCl3) 13.6, 43.3, 63.1, 124.0, 127.3, 128.9, 129.1,
•
•
129.9, 134.9, 137.0, 138.6, 170.5; m/z (EI+ ) 231 (33, M+ ),
42.8, 55.7, 62.9, 114.2, 128.5, 129.7, 130.5, 144.1, 159.4, 172.6;
171 (80, MH+ –HOCH2CH2NH•), 154 (78, M+ –Ph•), 141
•
•
•
•
•
m/z (EI+ ) 263 (35, M+ ), 203 (26, M+ –HOCH2CH2NH•), 84
(100%); HRMS (FAB+) C15H21NO3 [MH+] requires 263.1521;
found 263.1518.
(47, M+ –PhCH•), 128 (100, M+ –PhCHCH•), 115 (38%, M+ –
PhCHCHCH•); HRMS (FAB+) C14H18NO2 [MH+] requires
232.1332, found 232.1330.
•
•
•
(E)-N-(2-Hydroxyethyl)-2-phenyl-2-pentenamide 4h. Reac-
tion of syn-3-(3-hydroxy-2-phenylpentanoyl)-1,3-oxazolidin-2-
one 3h (0.200 g, 0.76 mmol) with a 0.5 M solution of KHMDS
in toluene (2.24 mL, 1.12 mmol) in THF (2 mL), according
to general procedure C, gave a mixture of the title compound
(E)-4h (80%) in >95% de and the parent N-acyl oxazolidin-
3-{(2R,3R)-3-Hydroxy-3-[(4R)-4-isopropenyl-1-cyclohexen-
1-yl]-2-methylpropanoyl}-1,3-oxazo lid-in-2-one 8a and 3-{(2S,3S)-
3-hydroxy-3-[(4R)-4-isopropenyl-1-cyclohexen-1-yl]-2-methyl-
propanoyl}-1,3-oxazolidin-2-one 9a. Reaction of 3-propionyl-
1,3-oxazolidin-2-one 2a (0.500 g, 3.50 mmol) with a 0.5 M
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 9 7 6 – 2 9 8 9
2 9 8 5

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291 (30%, MNH4 ), 274 (46, MH+), 256 (5, M+–OH), 230 (20,
MH+–CO2), 144 (13, MH+–CHOHR), 105.0 (100%); HRMS
(ES+) C12H20NO6 [MH+] requires 274.1285, found 274.1282.
+
solution of 9-BBN-OTf in hexanes (8.40 mL, 4.20 mmol),
N,N-diisopropylethylamine (0.85 mL, 4.90 mmol) and L-
(−)-perillaldehyde (0.60 mL, 3.85 mmol) in CH2Cl2 (20 mL),
according to general procedure B, afforded after purification
through silica gel chromatography (20% ethyl acetate–petrol)
the title compounds 8a/9a (0.656 g, 2.24 mmol) in 64% yield as
a white solid, as a 1 : 1 mixture of diastereomers, mp 87–88 ◦C;
(E,E)-N-(2-Hydroxyethyl)-3-[(4R)-4-isopropenyl-1-cyclohexen-
1-yl]-2-methyl-2-propenamide 10a. Reaction of the mixture
of aldols 8a/9a (0.100 g, 0.34 mmol) with a 0.5 M solution
of KHMDS in toluene (2.05 mL, 1.02 mmol) in THF (4 mL),
according to general procedure C, gave the title compound
(R,E,E)-10a in 50% de. The crude mixture was purified by
silica gel chromatography (60% ethyl acetate–petrol) to afford
the title compound (R,E,E)-10a (0.043 mg, 0.17 mmol) in 51%
mmax(KBr disc)/cm−1 3495 (s, OH), 1769 (C O)ox, 1691 (C O);
dH(300 MHz, CDCl3) 1.13 (3H, d, J 6.0, CH3, 8a), 1.15 (3H,
d, J 6.0, CH3, 9a), 1.38–1.55 (2H, m, Cy-H), 1.74 (6H, s, 2 ×
=
=
=
CH3C CH2), 1.82–1.88 (2H, m, Cy-H), 1.92–2.06 (4H, m,
Cy-H), 2.11–2.24 (4H, m, Cy-H), 2.76 (1H, s, OH, 8a), 2.78
(1H, s, OH, 9a), 3.75 (1H, m, CHCH3, 8a), 3.96–4.00 (1H, m,
CHCH3, 9a), 4.05 (4H, app t, J 8.0, CH2N), 4.35–4.45 (2H,
m, CHOH), 4.44 (4H, app t, J 8.0, CH2O), 4.70–4.76 (4H, m,
21
isolated yield and >95% de as a white solid, [a]D −72.2 (c 0.90,
CH2Cl2); mp 67–69 ◦C; mmax(KBr disc)/cm−1 3300 (br, NH), 3292
=
=
=
(s, OH), 1634 (C O), 1603 (C C), 1538 (C O); dH(300 MHz,
=
CDCl3) 1.35–1.48 (1H, m, Cy-H), 1.68 (3H, s, CH2 CHCH3),
=
=
CH2 C), 5.80–5.83 (2H, m, CH C); dC(CDCl3) 10.2, 10.9,
21.2, 21.3, 25.7, 26.0, 26.5, 27.7, 27.8, 30.6, 30.9, 40.4, 40.8,
41.2, 41.7, 43.1, 62.4, 68.4, 74.3, 74.6, 109.0, 109.1, 122.4, 123.0,
136.2, 136.7, 149.9, 150.2, 153.6, 177.5, 177.6; m/z (CI+, NH3)
=
1.75–1.84 (1H, m, Cy-H), 1.95 (3H, s, CH CCH3), 2.00–2.11
(2H, m, Cy-H), 2.16–2.24 (3H, m, Cy-H), 3.28 (1H, s, OH), 3.42
(2H, app q, J 5.0, CH2NH), 3.68 (2H, app t, J 5.0, CH2OH),
4.67 (2H, d, J 7.0, C CH2), 5.76 (1H, m, C CHCH2), 6.33
(1H, br s, NH), 6.66 (1H, s, CH3C CH); dC(CDCl3) 14.7,
=
=
311 (9, MNH4 ), 294 (15, MH+), 276 (40, M+–OH), 161 (100),
+
=
144 (39%, MH+–CHOHCy); HRMS (FAB+) C16H24NO4 [MH+]
requires 294.1700; found 294.1695.
21.2, 28.0, 29.4, 31.6, 40.8, 43.3, 62.9, 109.3, 128.5, 131.5,
•
•
134.6, 137.4, 149.7, 171.8; m/z (EI+ ) 249 (16, M+ ), 208
•
•
(11, M+ –CH3CH(CH2)•), 189 (10%, M+ –HOCH2CH2NH•),
121 (55%, Cy+), 91 (100%); HRMS (ES+) C15H24NO2 [MH+]
requires 250.1802, found 250.1802.
3-(2R,3S,5S)-3-Hydroxy-2,5,9-trimethyl-8-decenoyl)-1,3-
oxazolidin-2-one 8b and 3-(2S,3R,5S)-3-hydroxy-2,5,9-trimethyl-
8-decenoyl)-1,3-oxazolidin-2-one 9b. Reaction of 3-propionyl-
1,3-oxazolidin-2-one 2a (0.300 g, 2.10 mmol) with a 0.5 M
solution of 9-BBN-OTf in hexanes (5.03 mL, 2.52 mmol),
N,N-diisopropylethylamine (0.51 mL, 2.94 mmol) and (S)-
citronellal (0.42 mL, 2.31 mmol) in CH2Cl2 (10 mL), according
to general procedure B, afforded after purification through silica
gel chromatography (gradient, 20–30% ethyl acetate–petrol)
the title compounds 8b/9b (0.576 g, 1.94 mmol) in 93%
yield as a low viscosity colourless oil, as a 1 : 1 mixture of
(2E,5S)-N-(2-Hydroxyethyl)-2,5,9-trimethyl-2,8-decadienamide
10b. Reaction of aldols 8b/9b (0.150 mg, 0.51 mmol) with a
0.5 M solution of KHMDS in toluene (1.52 mL, 0.76 mmol)
in THF (3 mL), according to general procedure C, gave the
title compound (S,E)-10b (0.121 mg, 0.48 mmol) in 60% de.
The crude product was purified by silica gel chromatography
(60% ethyl acetate–petrol) to afford the title compound
(S,E)-10b (0.071 g, 0.28 mmol) in 55% yield and >95% de as
diastereoisomers, mmax(neat)/cm−1 3502 (br, OH), 1771 (C O)ox,
=
a colourless oil, [a]D +2.7 (c 2.61, CH2Cl2), mmax(neat)/cm−1
21
=
1695 (C O); dH(300 MHz, CDCl3) 0.92 (6H, app t, J 7.0,
=
=
=
3402 (br, OH, NH), 1657 (C O), 1615 (C C), 1538 (C O);
CHCH3, 8b + 9b), 1.05–1.28 (4H, m, Alk-H), 1.20 (3H, d, J
dH(300 MHz, CDCl3) 0.90 (3H, d, J 6.5, CHCH3), 1.12–
=
=
7.0, O CCHCH3, 8b), 1.21 (3H, d, J 7.0, O CCHCH3, 9b),
=
1.27 (1H, m, CHAHBCH2CH C(CH3)2), 1.30–1.42 (1H, m,
=
1.30–1.48 (4H, m, Alk-H), 1.60 (6H, s, CH C(CH3)CH3), 1.68
(6H, s, CH C(CH3)CH3), 1.54–1.70 (2H, m, CHCH3), 1.92–
2.08 (4H, m, CH2CH C(CH3)2), 2.73 (1H, d, J 2.3, OH, 8b),
2.80 (1H, d, J 3.0, OH, 9b), 3.73–3.83 (2H, m, O CCHCH3),
4.00–4.11 (6H, m, CHOH, CH2N), 4.44 (4H, app t, J 8.0,
CH2O), 5.10 (2H, t, J 7.0, CH C(CH3)2); dC(CDCl3) 10.6,
=
CHAHBCH2CH C(CH3)2), 1.55–1.65 (1H, m, CHCH3), 1.60
=
=
=
(3H, s, CH C(CH3)2), 1.68 (3H, s, CH C(CH3)2), 1.85 (3H, s,
=
=
=
CH CCH3), 1.90–2.05 (2H, m, CH2CH C(CH3)2), 2.10–2.19
=
=
(2H, m, CH2CH CCH3), 3.48 (2H, app q, J 5.5, 5.0, CH2NH),
3.61 (1H, br s, OH), 3.72–3.76 (2H, m, CH2OH), 5.07 (1H,
=
=
t, J 7.0, CH C(CH3)2), 6.41 (1H, br s, NH), 6.44 (1H, t, J
11.0, 18.1, 19.3, 20.6, 25.7, 25.9, 26.0, 26.1 (2C), 29.3, 29.6,
36.9, 38.3, 41.4, 41.5, 42.2 (2C), 42.9, 43.0, 62.3, 68.4, 69.6,
69.8, 125.1, 131.6, 131.6, 153.6, 153.6, 177.9, 178.0; m/z (EI+)
=
6.5, CH C); dC(CDCl3) 13.2, 18.1, 20.0, 26.0, 26.1, 33.1, 36.1,
37.2, 43.1, 62.8, 124.9, 131.1, 131.8, 136.6, 171.0; m/z (EI+) 253
•
•
•
•
(46, M+ ), 238 (18, M+ –CH3 ), 193 (5, M+ –HOCH2CH2NH•),
•
297.2 (11, M+ ), 143 (100%); HRMS (ES+) C16H28NO4 [MH+]
•
•
+
=
170 (41, M –(CH3)2C CHCH2CH2 ), 109 (100%); HRMS
requires 298.2013; found 298.2009.
(ES+) C15H28NO2 [MH+] requires 254.2115; found 254.2112.
(2R,3R)-3-{3-[(4R)-2,2-Dimethyl-1,3-dioxolan-4-yl]-3-hydroxy-
2-methylpropanoyl}-1,3-oxazol-idin-2-one 8c and (2S,3S)-3-{3-
[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]-3-hydroxy-2-methylpropan-
oyl}-1,3-oxazolidin-2-one 9c. Reaction of 3-propionyl-1,3-
oxazolidin-2-one 2a (0.200 g, 1.40 mmol) with a 0.5 M
solution of 9-BBN-OTf in CH2Cl2 (3.36 mL, 1.68 mmol),
N,N-diisopropylethylamine (0.34 mL, 1.96 mmol) and (R)-
(+)-2,2-dimethyl-1,3-dioxolane-4-carboxaldehyde (0.19 mL,
1.54 mmol) in hexanes (7 mL), according to general procedure
B, afforded after purification through silica gel chromatography
(gradient, 40–50% ethyl acetate–petrol) the title compounds
8c/9c (0.222 g, 0.81 mmol) in 58% yield as a thick colourless oil,
as a 2 : 1 mixture of diastereoisomers, mmax(neat)/cm−1 3447 (br,
(E)-3-[(4S)-2,2-Dimethyl-1,3-dioxolan-4-yl]-N-(2-hydroxyethyl)-
2-methyl-2-propenamide 10c. Reaction of aldols 8c/9c
(0.100 g, 0.37 mmol) with a 0.5 M solution of KHMDS
(1.10 mL, 0.55 mmol) in THF (2 mL), according to general
procedure C, gave the title compound (S,E)-10c in 80% de. The
crude mixture was purified by silica gel chromatography (70%
ethyl acetate–petrol) to afford the title compound (S,E)-10c
(0.035 g, 0.15 mmol) in 42% yield and >95% de as a colourless
oil, [a]D +4.5 (c 1.54, CH2Cl2); mmax(neat)/cm−1 3305 (br, OH,
21
=
=
=
NH), 1668 (C O), 1622 (C C), 1538 (C O); dH(300 MHz,
CDCl3) 1.41 (3H, s, CH3), 1.44 (3H, s, CH3), 1.93 (3H, d, J
=
1.2, C C(CH3)), 3.27 (1H, s, OH), 3.47 (2H, app q, J 5.0,
CH2NH), 3.61 (1H, app t, J 8.0, CHAHBO), 3.74 (2H, app t,
J 5.0, CH2OH), 4.15 (1H, dd, J 8.0, 6.0, CHAHBO), 4.84 (1H,
=
=
OH), 1771 (C O)ox, 1699 (C O); dH(300 MHz, CDCl3) 1.28
(3H, d, J 6.5, CHCH3, 8c), 1.34 (6H, s, CH3), 1.38 (3H, d, J 6.5,
CHCH3, 9c), 1.43 (6H, s, CH3), 2.55 (1H, d, J 6.5, OH, 8c), 3.11
(1H, d, J 3.0, OH, 9c), 3.72–4.18 (10H, m, CHCH3, CHOH,
CHOH, 2 × CH2O), 4.05 (4H, app t, J 7.5, CH2N), 4.44 (4H,
app t, J 7.5, CH2O); dC(CDCl3) 11.2, 12.1, 25.6, 25.8, 26.8, 27.1,
39.5, 41.3, 43.1, 62.3, 62.4, 66.6, 67.8, 68.4, 72.0, 73.1, 75.6,
77.2, 109.8, 110.1, 153.2, 153.6, 175.6, 178.0; m/z (CI+, NH3)
=
=
td, J 8.0, 6.0, CHOCH ), 6.25 (1H, dq, J 8.0, 1.2, CH C),
6.52 (1H, br s, NH); dC(CDCl3) 13.8, 26.2, 27.0, 43.0, 62.3,
69.2, 72.9, 110.1, 132.8, 135.1, 170.1; m/z (CI+, iso-butane)
•
230 (98, MH+), 214 (20, M+–CH3 ), 172 (68, M+–(CH3)2CO),
141 (63, M+–HOCH2CH2NHCO), 88 (100%); HRMS (ES+)
C11H20NO4 [MH+] requires 230.1387; found 230.1389.
2 9 8 6
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 9 7 6 – 2 9 8 9

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syn-3-(2-Hydroxyethyl)-5-methyl-6-phenyl-1,3-oxazinane-
2,4-dione 1627. Reaction of syn-3-(3-hydroxy-2-methyl-3-
phenylpropanoyl)-1,3-oxazolidin-2-one 3b (0.150 g, 0.60 mmol)
with a 1.0 M solution of Et2Zn in toluene (0.06 mL, 0.06 mmol)
in CH2Cl2 (3 mL), according to general procedure D, afforded
the title compound syn-16 (0.147 g, 0.58 mmol) in 97% yield
and 95% de as a colourless oil, mmax(neat)/cm−1 3447 (br, OH),
anti-3-(2-Hydroxyethyl)-5-methyl-6-phenyl-1,3-oxazinane-
2,4-dione 1927. Reaction of anti-3-(3-hydroxy-2-methyl-3-
phenylpropanoyl)-1,3-oxazolidin-2-one 18 (0.050 g, 0.20 mmol)
with a 1.0 M solution of Et2Zn in toluene (0.02 mL, 0.02 mmol)
in CH2Cl2 (1 mL), according to general procedure D, afforded
the title compound anti-19 (0.047 g, 0.19 mmol) in 96% yield
and >95% de as a white solid, mmax(neat)/cm−1 3435 (br, OH),
=
=
=
=
1755 (C O)ox, 1703 (C O); dH(300 MHz, CDCl3) 1.01 (3H,
d, J 7.5, CH3), 2.17 (1H, s, OH), 2.99 (1H, qd, J 7.5, 3.5,
CHCH3), 3.75–3.82 (2H, m, CH2OH), 3.97 (1H, app dt, J 14.0,
5.5, CHAHBN), 4.05 (1H, app dt, J 14.0, 5.5, CHAHBN), 5.62
(1H, d, J 3.5, CHPh), 7.24–7.38 (5H, m, Ar–H); dC(CDCl3)
10.4, 41.5, 44.6, 61.2, 78.1, 126.0, 129.2, 129.4, 134.4, 152.4,
1755 (C O)ox, 1694 (C O); dH(300 MHz, CDCl3) 1.02 (3H,
d, J 7.0, CH3), 2.21 (1H, br s, OH), 2.89 (1H, qd, J 11.5, 7.0,
CH(CH3)), 3.77–3.80 (2H, app t, J 5.5, CH2OH), 3.94 (1H,
ddd, J 14.0, 6.0, 4.5, CHAHBN), 4.06 (1H, app dt, J 14.0, 5.5,
CHAHBN), 5.04 (1H, d, J 11.5, CHPh), 7.24–7.38 (5H, m, Ar–
H); dC(CDCl3) 10.1, 40.4, 43.5, 59.6, 80.5, 126.1, 127.9, 128.7,
173.2; m/z (CI+, NH3) 267 (15, MNH4 ), 206 (47, MH+–CO2),
134.2, 151.1, 170.5; m/z (CI+, NH3) 267 (MNH4 , 100%), 250
+
+
105 (100%); HRMS (ES+) C13H16NO4 [MH+] requires 250.1079,
found 250.1081. Reaction of syn-1,3-oxazinane-2,4-dione 16
(0.100 g, 0.40 mmol) with a 0.5 M solution of KHMDS in
toluene (0.91 mL, 0.6 mmol) in THF (3 mL), according to
general procedure C, gave (E)-4b (0.068 g, 0.33 mmol) in 82%
yield and in 95% de.
(46, MH+), 208 (55), 206 (87%, MH+–CO2); HRMS C13H16NO4
(ES+) [MH+] requires 250.1079, found 250.1077. Reaction of
anti-1,3-oxazinane-2,4-dione 19 (0.020 g, 0.075 mmol) with a
0.5 M solution of KHMDS in toluene (0.18 mL, 0.012 mmol)
in THF (3 mL), according to general procedure C, gave (E)-4b
(0.012 g, 0.006 mmol) in 80% yield and in 95% de.
(E)-3-Cyclohexyl-2-isopropyl-2-propenoic acid 26a38. Hy-
drolysis of (E)-3-cyclohexyl-N-(2-hydroxyethyl)-2-isopropyl-2-
propenamide 4a (0.053 g, 0.22 mmol) in 6.0 M HCl (2 mL),
according to general procedure E, afforded the title compound
(E)-26a (0.043 g, 0.22 mmol) in 99% yield and >95% de as a
syn-3-(2-Hydroxyethyl)-5-isopropyl-6-[(E)-1-propenyl]-1,3-
oxazinane-2,4-dione 17. Reaction of syn-3-[(E)-3-hydroxy-
2-isopropyl-4-hexenoyl]-1,3-oxazolidin-2-one 3i (0.200 g,
0.83 mmol) with a 1.0 M solution of Et2Zn in toluene (0.08 mL,
0.08 mmol) in CH2Cl2 (5 mL), according to general procedure
D, afforded the title compound syn-17 (0.129 g, 0.54 mmol) in
65% yield and >95% de as a colourless oil, mmax(neat)/cm−1 3430
colourless oil, mmax(neat)/cm−1 3450 (br, OH), 1677 (C O), 1621
=
=
(C C)conj; dH(300 MHz, CDCl3) 0.90–1.30 (6H, m, Cy-H), 1.13
(6H, d, J 7.0, CH(CH3)2), 1.52–1.72 (4H, m, Cy-H), 2.33 (1H,
dtt, J 10.5, 10.0, 3.5, CH), 2.84 (1H, septet, J 7.0, CH(CH3)2),
=
=
(br, OH), 1755 (C O)ox, 1699 (C O); dH(300 MHz, CDCl3) 0.97
(3H, d, J 7.0, CH(CH3)2), 1.03 (3H, d, J 7.0, CH(CH3)2), 1.71
=
6.54 (1H, d, J 10.0, CH CCH3), 10.26 (1H, br s, COOH);
=
(3H, d, J 7.0, CH3CH CH), 1.97 (1H, t, J 5.5, OH), 2.10 (1H,
dC(CDCl3) 20.2, 24.5, 26.4, 31.3, 31.9, 36.4, 134.1, 148.2, 172.7.;
m, J 7.0, 4.5, CH(CH3)2), 2.55 (1H, dd, J 7.0, 4.5, CHiPr), 3.74
(2H, app dt, J 5.5, 5.5, CH2OH), 3.94–3.98 (2H, m, CH2N),
•
•
•
m/z (EI+ ) 197.3 (15%, MH+ ), 196.3 (15%, M+ ); HRMS (ES+)
C12H20O2 [MH+] requires 196.1458; found 196.1454.
=
4.92 (1H, app t, J 7.0, CHCH CHCH3), 5.47 (1H, dd, J 15.0,
=
=
7.0, CH3CH CH), 5.91 (1H, dq, J 15.0, 7.0, CH3CH CH);
dC(CDCl3) 17.0, 19.7, 20.3, 24.8, 43.2, 49.5, 60.1, 76.6, 122.1,
(E)-2-Methyl-3-phenyl-2-propenoic acid 26b. Hydrolysis of
(E)-N-(2-hydroxyethyl)-2-methyl-3-phenyl-2-propenamide 4b
(0.048 g, 0.23 mmol) in 6.0 M HCl (3 mL), according to general
procedure E, afforded the title compound (E)-26b (0.036 g,
0.22 mmol) in 95% yield and >95% de as a colourless oil,
•
•
•
132.7, 151.3, 169.7; m/z (EI+ ) 241 (41, M+ ), 198 (100%, M+ –
•
CO2 ); HRMS (ES+) C12H19NO4 [MH+] requires 241.1314,
found 241.1313. Reaction of syn-1,3-oxazinane-2,4-dione 17
(0.010 g, 0.04 mmol) with a 0.5 M solution of KHMDS in
toluene (0.09 mL, 0.06 mmol) in THF (3 mL), according to
general procedure C, gave (2E,4E)-4i (0.007 g, 0.035 mmol) in
88% yield and in 60% de.
mmax(neat)/cm−1 3445 (br, OH), 1668 (C O), 1616 (C C)conj
;
=
=
=
dH(300 MHz, CDCl3) 2.08 (s, 3H, CH CCH3), 7.26–7.36 (5H,
=
m, Ar–H), 7.77 (1H, s, CH CCH3), 11.36 (1H, br s, COOH);
dC(CDCl3) 12.7, 126.5, 127.4, 127.7, 128.8, 134.5, 140.1, 173.4;
•
•
m/z (EI+) 162.1 (68%, M+ ), 161.0 (36%, M+ –H•), 117.2
•
anti-3-(3-Hydroxy-2-methyl-3-phenylpropanoyl)-1,3-oxazolidin-
2-one 1827. Magnesium chloride (0.033 g, 0.35 mmol),
triethylamine (0.97 mL, 6.99 mmol), benzaldehyde (0.43 mL,
4.19 mmol) and trimethylsilyl chloride (0.67 mL, 5.24 mmol)
were added to a solution of 3-propionyl-1,3-oxazolidin-2-one
2a (0.500 g, 3.50 mmol) in ethyl acetate (7 mL). The reaction
mixture was stirred for 24 hours, and then filtered through a plug
of silica which was then washed with Et2O (10 ml). The organic
layer was concentrated in vacuo, before addition of methanol (2
drops) and trifluoroacetic acid. The solvent was then removed
before purification through silica gel chromatography (30%
ethyl acetate–petrol) to afford the title compound anti-18
(0.290 g, 1.16 mmol) in 33% yield as a white crystalline solid,
mp 102–104 ◦C (lit,27 107–107.5 ◦C); mmax(KBr disc)/cm−1 3446
(58%, M+ –COOH•); HRMS (ES+) C10H10O2 [MH+] requires
162.0675; found 162.0672.
(E)-2-Methylpenten-2-oic acid 26c. Hydrolysis of (E)-N-(2-
hydroxyethyl)-2-methyl-2-pentenamide 4c (0.300 g, 1.91 mmol)
in 6.0 M HCl (5 mL), according to general procedure E, afforded
the title compound (E)-26c (0.230 g, 2.02 mmol) in 91% yield and
>95% de as a low-melting white solid, mmax(neat)/cm−1 3429 (br,
=
=
OH), 1700 (C O), 1646 (C C); dH(300 MHz, CDCl3) 0.99 (3H,
=
t, J 7.5, CH2CH3), 1.76 (3H, d, J 1.0, CH CCH3), 2.14 (2H,
=
app pentet, J 7.5, CH2CH3), 6.83 (1H, tq, 7.5, 1.0, CH CCH3),
11.70 (1H, br s, COOH); dC(CDCl3) 12.2, 13.2, 22.6, 126.8,
147.2, 174.3.
(E)-2-Benzyl-2-decenoic acid 26d. Hydrolysis of (E)-2-benzyl-
N-(2-hydroxyethyl)-2-decenamide 4d (0.200 g, 0.58 mmol) in
6.0 M HCl (5 mL), according to general procedure E, afforded
the title compound (E)-26d (0.143 mg, 0.55 mmol) in 95% yield
and >95% de, dH(300 MHz, CDCl3) 0.80 (3H, t, J 7.0, CH3),
=
=
(s, OH), 1783 (C O)ox, 1665 (C O); dH(300 MHz, CDCl3) 1.05
(3H, d, J 7.0, CH3), 2.87 (1H, d, J 5.0, OH), 4.00–4.06 (2H,
m, CH2N), 4.28 (1H, dq, J 8.5, 7.0, CHCH3), 4.36–4.45 (2H,
m, CH2O), 4.78 (1H, dd, J 8.5, 5.0, CHOH), 7.26–7.43 (5H,
m, Ar–H); dC(CDCl3) 15.2, 43.1, 44.8, 62.4, 77.5, 127.1, 128.5,
=
1.12–1.25 (8H, m, Alk-H), 1.29–1.38 (2H, m, CH2CH2CH C),
129.0, 142.1, 153.9, 176.9; m/z (CI+, NH3) 267 (94, MNH4 ),
2.19 (2H, app q, J 7.5, CH2CH C), 3.58 (2H, s, CH2Ph), 6.70
+
=
250 (48, MH+), 105.1 (100%); HRMS (ES+) C13H16NO4 [MH+]
requires 250.1079, found 250.1079. Reaction of anti-aldol 18
(0.100 g, 0.4 mmol) with a 0.5 M solution of KHMDS in
toluene (1.20 mL, 0.6 mmol) in THF (3 mL), according to
general procedure C, gave (E)-4b (0.061 g, 0.3 mmol) in 74%
yield and in 95% de.
(1H, s, CH CBn); 6.97–7.17 (5H, m, Ar–H); 10.70 (1H, br s,
=
COOH); dC(CDCl3) 13.0, 21.6, 27.5, 28.0, 28.2, 28.3, 30.7, 31.2,
•
125.0, 127.2, 127.3, 129.2, 138.5, 146.1, 171.9; m/z (EI+ ) 260.3
•
•
•
•
(66, M+ ), 242 (9, M+ –H2O), 161 (14, M+ –CH3(CH2)6 ), 91
+
(100%); HRMS (ES+) C17H28NO2 [MNH4 ] requires 278.2120;
found 278.2118.
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 9 7 6 – 2 9 8 9
2 9 8 7

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(2E,4E)-2-Methyl-5-phenyl-2,4-pentadienoic acid 2739. Hy-
drolysis of (E,E)-N-(2-hydroxyethyl)-2-methyl-5-phenyl-2,4-
pentadienamide 4j (0.200g, 0.85 mmol) in 6.0 M HCl (5 mL),
according to general procedure E, afforded the title compound
(E,E)-27 (0.158 g, 0.45 mmol) in 77% yield and >95% de as
F. G. West, J. Am. Chem. Soc., 1999, 121, 7443; L. Tan, C. Y. Chen,
R. D. Larsen, T. R. Verhoeven and P. J. Reider, Tetrahedron Lett.,
1998, 39, 3961.
5 M. Periasamy, U. Radhakrishnan, C. Rameshkumar and J. J. Brunet,
Tetrahedron Lett., 1997, 38, 1623; P. J. Kocienski, C. J. Love, R. J.
Whitby, G. Costello and D. A. Roberts, Tetrahedron, 1989, 45,
3839.
◦
a pale brown solid, mp 158–160 C (lit,39 160.0–162.5 ◦C);
mmax(KBr disc)/cm−1 3445 (br, OH), 1683 (C O), 1622 (C C)conj
dH(300 MHz, CDCl3) 1.98 (3H, d, J 1.1, CH3), 6.83 (1H,
;
=
=
6 D. Basavaiah, P. K. S. Sarma and A. K. D. Bhavani, J. Chem. Soc.,
Chem. Commun., 1994, 1091.
7 A. K. Chatterjee, J. P. Morgan, M. Scholl and R. H. Grubbs, J. Am.
Chem. Soc., 2000, 122, 3783; T. L. Choi, C. W. Lee, A. K. Chatterjee
and R. H. Grubbs, J. Am. Chem. Soc., 2001, 123, 10417.
8 C. J. Kowalski and S. Sakdarat, J. Org. Chem., 1990, 55, 1977; C. J.
Kowalski and K. W. Fields, J. Am. Chem. Soc., 1982, 104, 321.
9 H. Sai and H. Ohmizu, Tetrahedron Lett., 1999, 40, 5019.
10 C. Harcken and R. Bru¨ckner, Tetrahedron Lett., 2001, 42, 3967.
11 G. Bartoli, M. C. Bellucci, M. Petrini, E. Marcantoni, L. Sambri and
E. Torregiani, Org. Lett., 2000, 2, 1791.
=
d, J 15.5, CHCH CHPh), 7.00 (1H, dd, J 15.5, 11.5,
=
=
CH–CH CHPh), 7.17–7.45 (6H, m, CH–CH CHPh, Ar–
H), 11.00 (1H, br s, COOH); dC(CDCl3) 11.5, 122.7, 125.4,
•
126.2, 127.8, 127.9, 135.4, 139.2, 139.6, 173.0; m/z (EI+ ) 188
•
•
•
(33, M+ ), 143 (62, M+ –COOH•), 128 (80, M+ –COOH–CH3),
•
115 (100%, M+ –C(CH3)COOH–H+); HRMS (ES+) C12H16NO2
+
[MNH4 ] requires 206.1176; found 206.1175.
12 J. M. Concello´n, H. Rodr´ıguez-Solla, M. Huerta and J. A. Pe´rez-
Andre´s, Eur. J. Org. Chem., 2002, 67, 1839; J. M. Concello´n, J. A.
Pe´rez-Andre´s and H. Rodr´ıguez-Solla, Angew. Chem., Int. Ed., 2000,
39, 2773.
13 J. M. Langenhan and S. H. Gellman, J. Org. Chem., 2003, 68, 6440;
T. Jenn and D. Heissler, Tetrahedron, 1998, 54, 107; I. E. Marko and
A. Chesney, Synlett, 1992, 275; D. Heissler, T. Jenn and H. Nagano,
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14 P. Kisanga, B. D’Sa and J. Verkade, Tetrahedron, 2001, 57, 8047.
15 Y. Hu and H. G. Floss, J. Am. Chem. Soc., 2004, 126, 3837; T. Leibold,
F. Sasse, H. Reichenbach and G. Ho¨fle, Eur. J. Org. Chem., 2004, 431;
B. Han, K. L. McPhail, A. Ligresti, V. Di Marzo and W. H. Gerwick,
J. Nat. Prod., 2003, 66, 1364; M. B. Andrus, E. L. Meredith, E. J.
Hicken, B. L. Simmons, R. R. Glancey and W. Ma, J. Org. Chem.,
2003, 68, 8162; J. Chen and C. J. Forsyth, J. Am. Chem. Soc., 2003,
125, 8734.
2-[(E)-1-Methyl-2-phenyl-1-ethenyl]-4,5-dihydro-1,3-oxazole
28. Reaction of (E)-N-(2-hydroxyethyl)-2-methyl-3-phenyl-
2-propenamide 4b (0.570 g, 2.78 mmol) with thionyl chloride
(0.89 mL, 12.20 mmol) in CH2Cl2 (15 mL), according to
general procedure F, gave the title compound (E)-28 (0.503 g,
2.69 mmol) in 97% yield and >95% de as a pale yellow
oil, mmax(neat)/cm−1 1707 (C N), 1640 (C C); dH(300 MHz,
=
=
=
CDCl3) 2.21 (3H, d, J 1.5, CH CCH3), 4.01 (2H, app t, J
9.5, CH2N), 4.36 (2H, app t, J 9.5, CH2O), 7.12 (1H, d, J 1.5,
=
CH C(Me)), 7.35–7.40 (5H, m, Ar–H); dC(CDCl3) 15.4, 55.4,
•
67.9, 125.7, 128.2, 128.7, 129.9, 135.6, 136.7, 167.3; m/z (EI+ )
•
•
•
187 (27, M+ ), 186 (100, M+ –H•), 129 (7, M+ –OCH2CH2N),
115 (25%, CH3CCPh+); HRMS (ES+) C12H13NO [MH+] requires
187.0997; found 187.0998.
16 J. A. Nieman, J. E. Coleman, D. J. Wallace, E. Piers, L. Y. Lim, M.
Roberge and R. J. Anderson, J. Nat. Prod., 2003, 66, 183; Y. F. Shealy,
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Hill, J. Med. Chem., 2003, 46, 1931; P. T. Meinke, M. B. Ayer, S. L.
Colletti, C. Li, J. Lim, D. Ok, S. Salva, D. M. Schmatz, T. L. Shih,
W. L. Shoop, L. M. Warmke, M. J. Wyvratt, M. Zakson-Aiken and
M. H. Fisher, Bioorg. Med. Chem. Lett., 2000, 10, 2371; H. Takami,
H. Koshimura, N. Kishibayashi, A. Ishii, H. Nonaka, S. Aoyama, H.
Kase and T. Kumazawa, J. Med. Chem., 1996, 39, 5047; B. H. Jaynes,
C. B. Cooper, S. J. Hecker, K. T. Blair, N. C. Elliott, S. C. Lilley, M. L.
Minich, D. L. Schicho and K. M. Werener, Bioorg. Med. Chem. Lett.,
1993, 3, 1531.
2-[(E)-1-Methyl-1-butenyl]-4,5-dihydro-1,3-oxazole 29. Re-
action of (E)-N-(2-hydroxyethyl)-2-methyl-2-pentenamide 4c
(0.112 g, 0.71 mmol) with thionyl chloride (0.26 mL, 3.57 mmol)
in CH2Cl2 (4 mL), according to general procedure F, gave the
title compound (E)-29 (0.087 g, 0.63 mmol) in 88% yield and
>95% de as a colourless oil, mmax(neat)/cm−1 1700 (C N), 1653
=
=
(C C); dH(300 MHz, CDCl3) 0.97 (3H, t, J 7.6, CH2CH3), 1.85
(3H, s, CH CCH3), 2.12 (2H, app pentet, J 7.5, CH2CH3),
=
3.86 (2H, t, J 9.5, CH2N), 4.20 (2H, t, J 9.5, CH2O), 6.34 (1H,
=
t, J 7.4, CH CCH3); dC(CDCl3) 13.5, 13.7, 22.1, 55.1, 67.5,
17 M. B. Andrus, T. M. Turner, D. Asgari and W. Li, J. Org. Chem.,
1999, 64, 2978.
18 A. Ashimori, B. Bachand, L. E. Overman and D. J. Poon, J. Am.
Chem. Soc., 1998, 120, 6477.
•
•
•
123.9, 140.1, 166.8; m/z (EI+ ) 139 (55%, M+ ), 124 (100%, M+ –
•
CH3 ); HRMS (ES+) C8H14NO [MH+] requires 140.1070; found
140.1072.
19 C. Grison, S. Geneve, E. Halbin and P. Coutrot, Tetrahedron, 2001,
57, 4903; R. W. Hoffmann, T. Rohde, E. Haeberlin and F. Scha¨fer,
Org. Lett., 1999, 1, 1713; P. Coutrot, C. Grison, C. Gerardrin-
Charbonnier and M. Lecouvey, Tetrahedron Lett., 1993, 34, 2767;
M. K. Tay, E. About-Jaudet, N. Collingdon and P. Savignac,
Tetrahedron, 1989, 45, 4415.
20 A. Balsomo, P. Crotti, A. Lapucci, B. Macchia, F. Macchia, A.
Cuttica and N. Passerini, J. Med. Chem., 1981, 24, 525.
21 J. M. Concello´n and E. Bardales, Eur. J. Org. Chem., 2004, 1523;
J. M. Concello´n, J. A. Pe´rez-Andre´s and H. Rodr´ıguez-Solla, Chem.–
Eur. J., 2001, 7, 3062.
Acknowledgements
We would like to thank the EPSRC (MC), the University of Bath
(FJPF), and the Royal Society (SDB) for funding, and the Mass
Spectrometry Service at the University of Wales, Swansea for
their assistance.
References
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25 These conditions have been employed previously for asymmetric syn-
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28 Pure samples of (E,E)-4i and (Z,E)-5 isomers were found to darken
and isomerise on standing so that they could only be characterised
by 1H NMR spectroscopy.
29 In our original communication (see ref. 23) the structure of com-
i
pound 2e (R = Pr, R1 = Ph) reported in Table 1 (entry 5) was
i
incorrect and should have been reported as R = Pr, R1 = Me
2 9 8 8
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 9 7 6 – 2 9 8 9

View Article Online
which corresponds to the structure of aldol 3i reported in this paper.
Furthermore, we were unable to reproduce the >95% de reported for
the elimination reaction of syn-aldol 3i to afford (E)-amide 4i, and
have concluded that this value is also incorrect, and must have arisen
from unintentional fractional crystallisation of the crude reaction
product prior to 1H NMR spectroscopic analysis.
35 For a previous example of a base mediated elimination of an 1,3-
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36 The configuration of anti-aldol 18 was confirmed from its large
coupling constant of J(2,3) = 8.5 Hz, which compares with the smaller
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30 The ratio of aldol diastereomers 8a/9a and 8c/9c produced in these
reactions was inferred from observation of the relative heights of the
resonances of each diastereoisomer in the 13C NMR spectra of each
crude reaction product.
31 It is known that the reaction of boron enolates of N-acyl-oxazolidin-
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affords syn-aldol products with no loss in stereochemical integrity,
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38, 6577.
32 Treatment of a purified sample of amide (E,S)-10c with KHMDS
in THF at −78 ◦C, followed by work-up, resulted in recovery of
amide (E,S)-10c with an unchanged specific rotation, indicating that
racemisation is unlikely to have occurred during this elimination
reaction.
37 Care must be taken during removal of organic solvent from these (E)-
acids because their volatility can lead to significant losses in product
on exposure to reduced pressure over time.
38 F. Henin, R. Mortezaei, J. Muzart, J. P. Pete and O. Piva, Tetrahedron,
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O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 9 7 6 – 2 9 8 9
2 9 8 9