N-acyl-5,5-dimethyloxazolidin-2-ones as latent aldehyde equivalents

Article abstract of DOI:10.1039/b301119d

A study of the properties of N-hydrocinnamoyl- derivatives of 5,5-dimethyloxazolidin-2-one, 4,4-dimethyloxazolidin-2-one and oxazolidin-2-one upon hydride reduction with DIBAL-H demonstrates that the 5,5-dimethyl-group is essential for inhibition of endocyclic nucleophilic attack. For instance, treatment of N-hydrocinnamoyl-5,5-dimethyl-oxazolidin-2-one with DIBAL-H results in the selective formation of the stable N-1′-hydroxyalkyl derivative which may be regarded as a masked hydrocinnamaldehyde equivalent, as treatment under basic conditions affords the parent aldehyde in excellent yield. Treatment of N-hydrocinnamoyl-4,4-dimethyloxazolidin-2-one with DIBAL-H under identical conditions affords a complex mixture of products, including the formate ester product of endocyclic cleavage. As an alternate strategy, DIBAL-H reduction of straight chain and branched N-acyl-5,5-dimethyloxazolidin-2-one derivatives, followed by a Horner-Wadsworth-Emmons reaction affords α,β-unsaturated esters in good yields. Branching α- to the exocyclic carbonyl in N-acyl-oxazolidinones inhibits DIBAL-H reduction, but this can be overcome by precomplexation with ZnCl₂, with subsequent fragmentation generating either the corresponding aldehyde or α,β-unsaturated esters. The addition of ZnCl₂ has been shown to increase the diastereoselectivity observed in Wadsworth-Horner-Emmons reactions of lithiated phosphonates.

Full text of DOI:10.1039/b301119d

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N-Acyl-5,5-dimethyloxazolidin-2-ones as latent aldehyde
equivalents
Jordi Bach, Cécile Blachère, Steven D. Bull, Stephen G. Davies,* Rebecca L. Nicholson,
Paul D. Price, Hitesh J. Sanganee and Andrew D. Smith
The Dyson Perrins Laboratory, University of Oxford, South Parks Road, Oxford,
UK OX1 3QY
Received 30th January 2003, Accepted 3rd April 2003
First published as an Advance Article on the web 17th April 2003
A study of the properties of N-hydrocinnamoyl- derivatives of 5,5-dimethyloxazolidin-2-one, 4,4-dimethyloxazol-
idin-2-one and oxazolidin-2-one upon hydride reduction with DIBAL-H demonstrates that the 5,5-dimethyl-group is
essential for inhibition of endocyclic nucleophilic attack. For instance, treatment of N-hydrocinnamoyl-5,5-dimethyl-
oxazolidin-2-one with DIBAL-H results in the selective formation of the stable N-1Ј-hydroxyalkyl derivative which
may be regarded as a masked hydrocinnamaldehyde equivalent, as treatment under basic conditions affords the
parent aldehyde in excellent yield. Treatment of N-hydrocinnamoyl-4,4-dimethyloxazolidin-2-one with DIBAL-H
under identical conditions affords a complex mixture of products, including the formate ester product of endocyclic
cleavage. As an alternate strategy, DIBAL-H reduction of straight chain and branched N-acyl-5,5-dimethyloxazol-
idin-2-one derivatives, followed by a Horner–Wadsworth–Emmons reaction affords α,β-unsaturated esters in good
yields. Branching α- to the exocyclic carbonyl in N-acyl-oxazolidinones inhibits DIBAL-H reduction, but this can
be overcome by precomplexation with ZnCl2, with subsequent fragmentation generating either the corresponding
aldehyde or α,β-unsaturated esters. The addition of ZnCl2 has been shown to increase the diastereoselectivity
observed in Wadsworth–Horner–Emmons reactions of lithiated phosphonates.
Introduction
The use of N-acyl derivatives of chiral auxiliaries to prepare
homochiral molecular fragments is well established within
organic synthesis.1 Most recyclable auxiliaries readily allow the
release of attached molecular fragments at either the carboxylic
acid or the alcohol oxidation level upon hydrolysis or exhaust-
ive reduction respectively. However direct transformation to the
corresponding aldehyde is an equally desirable synthetic trans-
formation, as demonstrated by the reductions of N-acylsultam2
and pseudoephedrine3 fragments to the corresponding alde-
hydes. The conversion of N-acyloxazolidin-2-ones to the corre-
sponding aldehydes can typically be achieved using only two
step protocols, involving reduction to the alcohol followed
by re-oxidation to aldehyde4 or conversion of the carboxylic
acid fragment to its Weinreb amide followed by reduction with
DIBAL-H.5 The reductive cleavage properties of Weinreb
Fig. 1
amides are thought to arise from the stability of the tetrahedral,
possibly chelated, intermediates such as 1, which fragment
upon hydrolytic work-up to release the aldehyde.6 As part of
our ongoing studies concerning the utility of oxazolidinones in
synthesis, it was reasoned that N-acyloxazolidin-2-ones could
be engineered to exhibit identical cleavage properties to those
of Weinreb amides, while, in contrast,7 simultaneously being
amenable to enolate based reactions. It was proposed that a
lone-pair of the endocyclic oxazolidin-2-one carbonyl of 2
would have the capacity to stabilise the tetrahedral intermediate
3 arising from reduction of the exocyclic carbonyl of 2 with
DIBAL-H, with the resulting chelated aluminium complex
being inert to further reduction. This would enable N-acyl-
oxazolidin-2-ones to function as latent aldehyde equivalents,
avoiding over-reduction to the corresponding alcohol (Fig. 1).
At the onset of this programme of research, limited literature
precedent existed for the direct reduction of N-acyloxazolidin-
2-ones to aldehydes,8 although Meyers et al. had reported an
isolated example of the reduction of an N-acyloxazolidin-2-one
with Red-Al in THF at Ϫ78 ЊC to the corresponding aldehyde.9
The structurally related N-acyloxazolidin-2-thiones allow the
direct synthesis of aldehydes upon reductive treatment with
either DIBAL-H or lithium tri-tert-butoxyaluminium hydride,10
although the wide applicability of this class of auxiliary within
synthesis is yet to be realised.11 In the light of these reports, a
full investigation concerning the reductive behaviour of a range
of achiral oxazolidin-2-ones upon treatment with DIBAL-H
was initiated. Part of this work concerning the stability of
the tetrahedral intermediate arising from DIBAL-H reduction
of N-acyl-5,5-dimethyloxazolidin-2-ones (similar tetrahedral
carbinols have been reported subsequently by Evans et al.
upon reduction of N-acylpyrroles)12 has been the subject of a
preliminary communication.13
Results and discussion
Evaluation of N-hydrocinnamoyl derivatives of 5,5-dimethyl-
oxazolidin-2-one, 4,4-dimethyloxazolidin-2-one and oxazolidin-
2-one as latent aldehyde equivalents
Previous studies from within this laboratory concerning the use
of oxazolidin-2-ones for asymmetric transformations have
shown that the presence of the gem-dimethyl groups at C(5) of
T h i s j o u r n a l i s © T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 3
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oxazolidinone auxiliaries is crucial to inhibit endocyclic attack
in hydrolytic cleavage reactions of N-acyloxazolidin-2-ones.14
The presence and position of the gem-dimethyl groups were
expected to affect the reductive cleavage properties of N-acyl-
oxazolidin-2-ones upon treatment with DIBAL-H in the same
manner. In order to investigate this structural requirement,
parent oxazolidin-2-one 7,15 4,4-dimethyloxazolidinone 8,16
and 5,5-dimethyloxazolidinone 917 were prepared following
literature procedures and subsequently deprotonated with
n-BuLi at Ϫ78 ЊC before being N-acylated with hydrocinnamoyl
chloride18 to furnish N-hydrocinnamoyloxazolidin-2-ones
10–12 respectively in high yield (Scheme 1).
oxazolidinone 10 was similarly determined by integration of the
characteristic peaks in the H 400 MHz NMR spectrum of
1
the crude reaction mixture, with 1Ј-hydroxyalkyloxazolidinone
13 {νmax (C᎐Oendocyclic) 1730 cmϪ1, δC C(1Ј) 77.0} being isolated
᎐
in 52% yield after chromatography. While the proportions of
endocyclic cleavage product 14 and 17 arising from reduc-
tion of the unsubstituted and 4,4-dimethyl substituted N-acyl-
oxazolidinones 10 and 11 are identical, the proportion of
aldehyde 15 is greater from reduction of 11, suggesting that
the presence of substituents at C(4) of the oxazolidin-2-one
fragment destabilizes the intermediate tetrahedral com-
plex, facilitating fragmentation to aldehyde 15. In contrast,
DIBAL-H reduction of N-hydrocinnamoyl 5,5-dimethyloxazol-
idinone 12 {νmax (C᎐Oendocyclic) 1757 cmϪ1, (C᎐Oexocyclic) 1697
᎐
᎐
cmϪ1, δC C(1Ј) 152.8} yielded the 1Ј-hydroxyalkyloxazolidin-
one 18 {νmax (C᎐Oendocyclic) 1730 cmϪ1, δC C(1Ј) 76.7} as the
᎐
exclusive product, which was isolated in 74% yield after
purification by chromatography. Furthermore, reduction of
N-hydrocinnamoyl 5,5-dimethyloxazolidinone 12 with LiAlH4
(1 equivalent relative to hydride) also returned 1Ј-hydroxy-
alkyloxazolidinone 18 as the sole reaction product in 80% yield
(Scheme 2).
Having demonstrated the 5,5-dimethyloxazolidinone auxil-
iary successfully suppresses endocyclic C᎐O reduction in its
᎐
N-hydrocinnamoyl derivative 12, the controlled fragmentation
of 1Ј-hydroxyalkyloxazolidin-2-one 18 to the corresponding
aldehyde was investigated. Initial attempts concentrated upon
the use of basic reaction conditions, with NaH in THF return-
ing a complex mixture of products, although the use of K2CO3
in MeOH efficiently promoted the desired fragmentation,
giving hydrocinnamaldehyde 15 in 82% yield. An alternative
synthetic protocol for the production of aldehyde 15 from
oxazolidinone 18 allowed for its in situ trapping, via formation
of an intermediate bisulfite adduct. Treatment of 18 with sodium
hydrogen sulfate (adjusted to pH 9.0 with sodium hydroxide)
and subsequent treatment with 1 M HCl(aq) and chromato-
graphy gave aldehyde 15 in 90% yield. This procedure was fur-
ther modified to allow a ‘one-pot’ process involving consecutive
treatment of 12 with DIBAL-H in DCM at Ϫ78 ЊC, followed
immediately by the bisulfite trapping protocol, to afford
aldehyde 15 in 91% yield upon acidic work-up (Scheme 3).
Scheme
1
Reagents and conditions: (i). n-BuLi, THF, Ϫ78 ЊC;
(ii). PhCH2CH2COCl, THF, Ϫ78 ЊC to rt.
Treatment of N-hydrocinnamoyloxazolidin-2-ones 10–12
with DIBAL-H allowed the relative propensity of each oxazol-
idinone auxiliary to discourage endocyclic attack over exocyclic
attack to be determined by analysis of the product distri-
bution. Both the parent N-hydrocinnamoyl oxazolidinone 1019
and N-hydrocinnamoyl 4,4-dimethyloxazolidinone 11 {νmax
(C᎐Oendocyclic) 1777 cmϪ1, (C᎐Oexocyclic) 1703 cmϪ1, δC C(1Ј)
᎐
᎐
154.1} afforded complex mixtures of products upon treatment
with DIBAL-H, with purification of the crude reaction mix-
ture resulting from reduction of 11 by repeated silica gel
chromatography affording the formate ester product of endo-
cyclic cleavage 17, 1Ј-hydroxyalkyl-4,4-dimethyloxazolidinone
A DIBAL-H Wadsworth–Horner–Emmons homologation
protocol
Since aldehydes such as 15 are highly reactive species, readily
undergoing a variety of reactions including aldol and tri-
merisation reactions, they are typically generated as reactive
synthetic intermediates, immediately being prepared and
16 {νmax (C᎐Oendocyclic) 1737 cmϪ1, δC C(1Ј) 77.6}, hydrocinnam-
᎐
aldehyde 15 and 4,4-dimethyloxazolidinone 8. The product
distribution formed from reduction of N-hydrocinnamoyl-
Scheme 2 Reagents and conditions: (i) DIBAL-H, DCM, Ϫ78 ЊC; ratio of products determined by integration of resonances in the 1H NMR
400 MHz spectra of the crude product mixtures; isolated yields of components given in brackets.
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Having demonstrated that N-hydrocinnamoyl-5,5-dimethyl-
oxazolidin-2-one 12 can be regarded as a latent aldehyde equiv-
alent via fragmentation of its N-1Ј-hydroxyalkyl derivative and
trapping with a phosphonate anion, the generality of this
protocol was investigated. A series of N-acyl-5,5-dimethyl-
oxazolidinones were therefore prepared by deprotonation of
5,5-dimethyloxazolidinone 9 with n-BuLi and subsequent
N-acylation with a range of straight chain and branched acid
chlorides, furnishing N-acyl-5,5-dimethyloxazolidin-2-ones
21–24 in good yields (Scheme 5).
Scheme 3 Reagents and conditions: (i) DIBAL-H, DCM, Ϫ78 ЊC;
(ii) K2CO3, MeOH, rt; (iii) NaOH, NaHSO3 then 1 M HCl(aq)
.
transformed, for instance by the use of Wittig or Wadsworth–
Horner–Emmons methodologies. In this case, the development
of a DIBAL-H/Wadsworth–Horner–Emmons strategy for the
transformation of N-hydrocinnamoyloxazolidin-2-one 12 to its
corresponding α,β-unsaturated ester was investigated, as it was
reasoned that deploying the lithium anion of a phosphonate to
promote the fragmentation of 1Ј-hydroxyalkyloxazolidin-2-one
18 would afford aldehyde 15 in situ, which would be immedi-
ately trapped by excess phosphonate anion to afford the
desired α,β-unsaturated ester. To test this theory, 1Ј-hydroxy-
alkyloxazolidin-2-one 18 was treated with 2.5 equivalents of the
lithium anion of triethyl phosphonoacetate, giving a mixture of
the chromatographically separable (E) and (Z)-α,β-unsatur-
ated esters 19 and 20 in 71% overall yield and 74% de, plus
the parent oxazolidin-2-one 9 in 70% yield. Both the yield
and diastereoselectivity obtained from this protocol were
identical to those obtained for reaction of the parent aldehyde
15 with the lithium anion of triethyl phosphonoacetate. Exten-
sion of this DIBAL-H/Wadsworth–Horner–Emmons method-
ology to the development of a ‘one-pot’ protocol involving
sequential treatment of N-hydrocinnamoyloxazolidin-2-one 12
with DIBAL-H and the lithium anion of triethyl phosphono-
acetate similarly gave 19–20 in 70% yield and in 74% de
(Scheme 4).
Scheme
5 Reagents and conditions: (i) n-BuLi, THF, Ϫ78 ЊC;
(ii) RCH2COCl, THF, Ϫ78 ЊC to rt.
Treatment of N-acyl-5,5-dimethyloxazolidin-2-ones 21–24
with DIBAL-H at Ϫ78 ЊC in DCM furnished the correspond-
ing 1Ј-hydroxyalkyloxazolidinones as the sole reaction products
upon standard work up. However, although 1Ј-hydroxyalkyl-
oxazolidinone 18 exhibits a high degree of stability towards
mildly acidic conditions thereby allowing purification by flash
column chromatography, attempted purification of 1Ј-hydroxy-
alkyloxazolidinones 25 and 26 on silica promoted partial
decomposition and furnished
a mixture of unidentified
products. Therefore 25 {νmax (C᎐Oendocyclic) 1741 cmϪ1, δC C(1Ј)
᎐
76.7} and 26 {νmax (C᎐Oendocyclic) 1732 cmϪ1, δC C(1Ј) 75.3} were
᎐
characterised directly from the crude reaction mixture. As a
result of the propensity of 1Ј-hydroxyalkyloxazolidinones 25
and 26 to fragmentation upon purification, application of
the tandem DIBAL-H/Wadsworth–Horner–Emmons reaction
protocol was considered. Thus, successive treatment of 21–24
with DIBAL-H and the lithium anion of triethyl phosphono-
acetate gave the requisite α,β-unsaturated esters 27–34 in
43–70% overall yield, and in 82–90% de (Scheme 6).
1
Analysis of the H NMR spectra of the crude reaction mix-
tures arising from these reactions, in conjunction with observed
losses in mass balance during purification were ascribed to the
Scheme 4 Reagents and conditions: (i) DIBAL-H, DCM, Ϫ78 ЊC;
(ii) DIBAL-H, THF, Ϫ78 ЊC; (iii) (EtO)2POCH(Li)CO2Et, THF,
Ϫ78 ЊC to rt.
Scheme 6 Reagents and conditions: (i) DIBAL-H, DCM, Ϫ78 ЊC;
(ii) DIBAL-H, THF, Ϫ78 ЊC; (iii) (EtO)2POCH(Li)CO2Et, THF,
Ϫ78 ЊC to rt.
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volatility of the target α,β-unsaturated ethyl esters. As a result,
the tandem DIBAL-H–Wittig protocol was repeated on N-
butyroyl-5,5-dimethyloxazolidin-2-one 21 using the lithium
anion of tert-butyl dimethylphosphonoacetate, furnishing the
α,β-unsaturated-tert-butyl esters 35–36 in 96% isolated yield
and in 68% de (Scheme 7).
Scheme 7 Reagents and conditions: (i) DIBAL-H, THF, Ϫ78 ЊC;
t
(ii) (MeO)2POCH(Li)CO2 Bu, THF, Ϫ78 ЊC to rt.
Scheme 9 Reagents and conditions: (i) DIBAL-H, DCM, Ϫ78 ЊC;
(ii) DIBAL-H, THF, Ϫ78 ЊC; (iii) NaOH, NaHSO3 then 1 M HCl(aq)
(iv) (EtO)2POCH(Li)CO2Et, THF, Ϫ78 ЊC to rt.
;
The tandem protocol using tert-butyl dimethylphosphono-
acetate therefore represents the most efficient in situ Wadsworth–
Horner–Emmons trap for fragmentation of N-butyryl-5,5-di-
methyloxazolidinone 21 (96% yield), with much improved
efficiency with respect to the use of triethyl phosphonoacetate
(45% yield).
returned only starting material with no evidence of any reduc-
tion, even after treatment with excess DIBAL-H (3 eq.) at rt for
15 hours. It was proposed that the low propensity of N-acyl-
oxazolidin-2-one 38 towards reduction with DIBAL-H may be
overcome by increasing its reactivity via precoordination with a
Lewis acid. ZnCl2 was chosen as the activating agent for this
transformation, since Arai et al. have used the DIBAL-H–
ZnCl2 combination to great effect for the diastereoselective
reductions of the carbonyl group in β-ketosulfoxides.21 Based
on this literature protocol, α-allylated N-acyloxazolidin-2-one
38 was treated successively with ZnCl2 and then DIBAL-H
in THF at Ϫ30 ЊC, giving an inseparable 3 : 2 mixture of
the chromatographically stable diastereoisomeric 1Ј-hydroxy-
Synthesis of ꢀ-substituted aldehydes
Having shown that straight chain and branched N-acyl-5,5-di-
methyloxazolidin-2-ones may be regarded as latent aldehyde
equivalents, attention turned to the reductive cleavage of their
α-substituted analogues. As Weinreb amides are incompatible
with enolate formation and hence cannot be taken through
many general synthetic protocols,7 the development of latent
aldehyde equivalents compatible with such methodology would
prove synthetically useful.20 N-Hydrocinnamoyl-5,5-dimethyl-
oxazolidin-2-one 12 was therefore treated with LHMDS at
0 ЊC followed by alkylation with either methyl iodide or allyl
bromide to afford the α-alkylated oxazolidinones 37 and 38
respectively (Scheme 8).
alkyloxazolidinones 44–45 {νmax (C᎐Oendocyclic) 1717 cmϪ1
;
᎐
δC C(1Ј) major diastereoisomer 79.1, δC C(1Ј) minor diastereo-
isomer 79.5} in 92% isolated yield. Treatment of this
diastereoisomeric mixture with the lithium anion of triethyl
phosphonoacetate gave the γ-allyl-α,β-unsaturated esters 46–47
in 80% yield and 50% de, while application of the ZnCl2
activation protocol to a ‘one pot’ procedure on the allylated
derivative 38 furnished 46–47 in 82% yield, but with a
notable increase in diastereoselectivity, giving 46–47 in 88% de
(Scheme 10).
Scheme 8 Reagents and conditions: (i) LHMDS, THF, 0 ЊC; (ii) MeI,
THF, 0 ЊC; (iii) CH2᎐᎐CHCH2Br, THF, 0 ЊC.
Treatment of α-methyloxazolidinone 37 with DIBAL-H in
THF at Ϫ78 ЊC gave a chromatographically stable 3 : 1 dia-
stereomeric mixture of 1Ј-hydroxyalkyloxazolidinones 39 : 40
{νmax (C᎐Oendocyclic) 1754 cmϪ1; δC C(1Ј) major diastereoisomer
᎐
81.0, δC C(1Ј) minor diastereoisomer 81.3}. Treatment of this
diastereoisomeric mixture with NaOH–NaHSO3 afforded,
after acidic work up, 2-methylhydrocinnamaldehyde 41 in
91% isolated yield. The corresponding ‘one pot’ procedure
afforded the desired aldehyde 41 in 83% yield directly from
N-α-methylhydrocinnamoyl-5,5-dimethyloxazolidin-2-one 37.
Application of the tandem DIBAL-H/Wadsworth–Horner–
Emmons methodology similarly proved efficient, affording the
γ-methyl-α,β-unsaturated ester 42 : 43 in 71% overall yield and
in 60% de (Scheme 9).
Scheme 10 Reagents and conditions: (i) ZnCl2; DIBAL-H, THF,
Ϫ30 ЊC; (ii) (EtO)2POCH(Li)CO2Et, THF, Ϫ78 ЊC.
This remarkable increase in diastereoselectivity between the
stepwise (50% de) and ZnCl2 initiated tandem (88% de) reaction
manifolds for this Wadsworth–Horner–Emmons olefination
reaction deserved further investigation. The ZnCl2–DIBAL-H/
Wadsworth–Horner–Emmons procedure was therefore per-
formed on N-hydrocinnamoyl-5,5-dimethyloxazolidinone 12,
furnishing the α,β-unsaturated esters 19–20 in 70% yield and in
However, treatment of the α-allylated N-acyloxazolidin-2-
one 38 with DIBAL-H under the standard reduction conditions
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86% de, a marked improvement upon the 74% de previously
seen without the presence of ZnCl2. Further to this observ-
ation, hydrocinnamaldehyde 15 was treated with ZnCl2
followed by the lithium anion of triethyl phosphonoacetate,
similarly furnishing α,β-unsaturated esters 19–20 in 86% de,
identical to that noted in the tandem ZnCl2–DIBAL-H/
Wadsworth–Horner–Emmons protocol (Scheme 11).
nitrogen via standard vacuum line techniques. All glassware
was flame-dried and allowed to cool under vacuum. THF was
distilled under an atmosphere of dry nitrogen from sodium
benzophenone ketyl. All other solvents were used as supplied
(Analytical or HPLC grade), without prior purification. All
organometallic reagents were used as supplied. Thin layer
chromatography (TLC) was performed on aluminium or plastic
sheets coated with 60 F254 silica. Sheets were visualised
using iodine, UV light or 1% aqueous KMnO4 solution. Flash
chromatography was performed on Kieselgel 60 silica. Nuclear
magnetic resonance (NMR) spectra were recorded on a Bruker
DPX 400 (1H: 400 MHz and 13C: 100.6 MHz) spectrometer or a
Bruker AC 200 (1H: 200 MHz and 13C: 50.3 MHz) spectrometer
in the deuterated solvent stated. All chemical shifts (δ) are
quoted in ppm and coupling constants (J) in Hz. Residual
signals from the solvents were used as an internal reference.
13C multiplicities were assigned using a DEPT sequence.
Infrared spectra were recorded on a Perkin-Elmer 1750 IR
Fourier Transform spectrophotometer using either films on
NaCl plates (film) or KBr discs (KBr), while solution spectra
were recorded in the solvent stated using 1.0 mm NaCl
cells, with only the characteristic peaks quoted. Low resolution
mass spectra (m/z) were recorded on VG MassLab 20–250 or
Micromass Platform 1 spectrometers and high resolution mass
spectra (HRMS) on a Micromass Autospec 500 OAT spectro-
meter. Techniques used were chemical ionisation (CI, NH3),
or atmospheric pressure chemical ionisation (APCI) using
partial purification by HPLC with methanol–acetonitrile–water
(40 : 40 : 20) as eluent. Optical rotations were recorded on a
Perkin-Elmer 241 polarimeter with a path length of 1 dm. Con-
centrations are quoted in g 100 mLϪ1. Melting points were
recorded on a Leica VMTG Galen III apparatus and are un-
corrected. Elemental analyses were performed by the micro-
analysis service of either the Dyson Perrins Laboratory or the
Inorganic Chemistry Laboratory, Oxford.
Scheme 11 Reagents and conditions: (i) ZnCl2, DIBAL-H, THF,
Ϫ30 ЊC; (ii) (EtO)2POCH(Li)CO2Et, THF, Ϫ78 ЊC to rt; (iii) ZnCl2,
Ϫ30 ЊC then (EtO)2POCH(Li)CO2Et, THF, Ϫ78 ЊC to rt.
Previous investigations by Masamune et al. concerning the
reactivity of Wadsworth–Horner–Emmons reactions have
shown that the addition of LiCl allows the use of mild bases
such as DBU to promote efficient olefination reactions,22 while
Nagao et al. have shown that Sn(OSO2CF3)2 and N-ethyl-
piperidine23 has a similar effect. In this case, however, it appears
that the addition of ZnCl2 plays an additional role in increasing
the diastereoselectivity of the Wadsworth–Horner–Emmons
reaction. Although a related effect has been reported by
Seebach et al., with the addition of ZnBr2 increasing the
diastereoselectivity upon alkylation of chiral N-acyloxazol-
idinones,24 the scope and limitations of the ZnCl2 modification
of the Wadsworth–Horner–Emmons olefination protocol, and
the exact role of ZnCl2 in this procedure, are currently under
investigation.
4,4-Dimethyloxazolidin-2-one 8,16 5,5-dimethyloxazolidin-2-
one 917 and 3-(3Ј-phenylpropionyl)oxazolidin-2-one 1019 were
prepared by the literature procedures.
Representative procedure 1
n-BuLi (1.1 eq.) was added to a stirred solution of the oxazol-
idin-2-one (1.0 eq.) in anhydrous THF at Ϫ78 ЊC. After 15
minutes, the acid chloride (1.3 eq.) was added dropwise via
syringe and left at Ϫ78 ЊC for 30 minutes before being warmed
to rt. After 2 hours, the reaction mixture was quenched with
saturated aqueous NH4Cl solution and acetic acid, extracted
with EtOAc, washed sequentially with saturated aqueous
NaHCO3 solution and brine and dried over MgSO4. The
organic extracts were concentrated in vacuo and purified
either by recrystallization (hexane–Et2O) or by flash column
chromatography on silica gel to give the required product.
Conclusion
N-Acyl-5,5-dimethyloxazolidin-2-ones can be considered as
latent aldehyde equivalents. Direct DIBAL-H reduction of
N-acyl-5,5-dimethyloxazolidin-2-ones produces the corre-
sponding 1Ј-hydroxyalkyloxazolidinone, which may be frag-
mented to the parent aldehyde and the oxazolidinone auxiliary
by treatment with either K2CO3 in MeOH or sodium hydrogen
sulfate (adjusted to pH 9.0 with sodium hydroxide) and
subsequent acidic work up. Alternatively, treatment of the
1Ј-hydroxyalkyloxazolidinones with lithiated triethyl phos-
phonoacetate gives α,β-unsaturated esters. The presence of a
substituent α- to the exocyclic carbonyl in N-acyloxazol-
idinones may inhibit DIBAL-H reduction, but this can be
overcome by precomplexation with ZnCl2 to give the corre-
sponding 1Ј-hydroxyalkyloxazolidinone, which may be frag-
mented to generate either the corresponding aldehyde or
α,β-unsaturated esters. The addition of ZnCl2 also serves to
increase the diastereoselectivity observed in Wadsworth–
Horner–Emmons reactions.
Representative procedure 2
DIBAL (1 M in DCM, 2.0 eq.) was added dropwise to a stirred
solution of the N-acyloxazolidin-2-one (1.0 eq.) in anhydrous
DCM at Ϫ78 ЊC and stirred for 10 minutes. After quenching
with saturated aqueous NH4Cl solution at Ϫ78 ЊC, the resultant
mixture was stirred at rt for 2 hours with Rochelles salt. The
reaction mixture was extracted with DCM, washed with brine,
dried over MgSO4 and concentrated in vacuo.
Representative procedure 3
DIBAL (1 M in THF, 1.2 eq.) was added to a stirred solution of
N-acyl-5,5-dimethyloxazolidin-2-one (1.0 eq.) in anhydrous
THF at 0 ЊC. After 20 minutes, a solution of the lithiated phos-
phonate, prepared by addition of n-BuLi (2.5 eq.) to a solution
of phosphonate (2.5 eq.) in anhydrous THF at Ϫ78 ЊC and
stirred for 30 minutes, was added via cannula. The reaction
Experimental
General experimental
All reactions involving organometallic or other moisture
sensitive reagents were performed under an atmosphere of
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 2 0 0 1 – 2 0 1 0
2005

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mixture was warmed to rt and stirred for 1 hour. After quench-
ing with water at Ϫ78 ЊC, addition of Rochelles salt solution
and stirring for 2 hours, the reaction mixture was extracted with
EtOAc, washed with brine, dried with MgSO4 and concentrated
in vacuo before purification by flash column chromatography on
silica gel.
DIBAL reduction of 3-(3Ј-phenylpropionyl)-4,4-dimethyloxazol-
idin-2-one 11
Following Representative Procedure 2, DIBAL (1 M in DCM,
1.62 mL, 1.62 mmol) and 11 (200 mg, 0.81 mmol) gave, after
purification by repeated flash column chromatography on silica
(hexane–EtOAc 7 : 1 increasing to 1 : 1, then 1.5 : 1) four major
components identified as:
(i). Hydrocinnamaldehyde 15 (5 mg, 5%); δH (200 MHz,
CDCl3) 2.76–2.83 (2H, m, PhCH2), 2.83–3.02 (2H, m,
PhCH2CH2), 7.18–7.37 (5H, m, Ph), 9.84 (1H, s, CHO).25
(ii). Formic acid 2-methyl-2-(3Ј-phenylpropionyl amino)-
propyl ester 17 (5 mg, 2%); Rf 0.53 (1.5 : 1 hexane–EtOAc);
Representative procedure 4
LHMDS (1.5 eq.) was added to a stirred solution of N-acyl-5,5-
dimethyloxazolidin-2-one (1.0 eq.) in anhydrous THF at 0 ЊC.
After stirring at 0 ЊC for 1 hour, the alkyl halide (3.0 eq.) was
added via syringe. After 4 hours, the reaction was quenched
with saturated aqueous NH4Cl solution at 0 ЊC. The reaction
mixture was extracted with EtOAc, washed with brine, dried
over MgSO4 and concentrated in vacuo before purification by
flash column chromatography on silica gel.
νmax (film) 3326 (N–H), 1728 (C᎐O endocyclic), 1654 (C᎐O exo-
᎐
᎐
cyclic); δH (400 MHz, CDCl3) 1.30 (6H, s, NHC(CH3)2), 2.43
(2H, t, J 7.5, PhCH2), 2.94 (2H, t, J 7.5, PhCH2CH2), 4.27 (2H,
s, CH2OCHO), 5.21 (1H, br s, NH ), 7.19–7.31 (5H, m, Ph),
8.03 (1H, s, OCHO); δC (100 MHz, CDCl3) 24.1 (C(CH3)2),
31.6 (PhCH2), 39.2 (PhCH2CH2), 53.0 (CMe2), 68.1
(CH2OCHO), 126.2 (Phpara), 128.4, 128.5 (Phmeta, Phortho), 140.7
(Phipso), 160.8 (CONH), 171.8 (OCHO); HRMS (CIϩ)
C14H20NO3 (MHϩ) requires 250.1443, found 250.1450; m/z
(APCIϩ) 272.1 (MNaϩ, 30%), 250.1 (MHϩ, 100%).
Preparation of 3-(3Ј-phenylpropionyl)-4,4-dimethyloxazolidin-2-
one 11
Following representative procedure 1, n-BuLi (1.66 M, 4.44
mL, 7.10 mmol), 8 (0.74 g, 6.45 mmol) and hydrocinnamoyl
chloride (1.25 mL, 8.39 mmol) gave, after purification by flash
column chromatography on silica (3 : 2 Et2O–40–60 petroleum;
Rf 0.43) and recrystallisation (hexane–Et2O), 11 as white crys-
tals (1.19 g, 75%); mp 45–46 ЊC (hexane–Et2O); C14H17NO3
requires C 68.0, H 6.9, N 5.7%, found C 68.0, H 6.9, N 5.7%;
(iii).
idin-2-one 16 (48 mg, 24%); νmax (CHCl3) 3392 (O–H), 1737
(C᎐O); δ (400 MHz, CDCl ) 1.25 (3H, s, C(CH ) ), 1.38 (3H, s,
3-(1Ј-Hydroxy-3Ј-phenylpropyl)-4,4-dimethyloxazol-
᎐
H
3
3 2
C(CH3)2), 2.18–2.27 (1H, m, CHAHBCH2Ph), 2.42–2.51 (1H, m,
CHAHBCH2Ph), 2.65–2.82 (2H, m, CH2CH2Ph), 3.94 (1H, AB,
J 8.3, OCHAHB), 4.01 (1H, AB, J 8.3, OCHAHB), 4.62 (1H, dd,
J1,OH 6.1, J1,2 7.5, CHOH), 5.7 (1H, br s, OH ), 7.18–7.31 (5H,
m, Ph); δC (100 MHz, CDCl3) 25.6 (C(CH3)2), 27.5 (PhCH2),
28.1 (CH2C(OH)), 59.1 (CMe2), 75.3 (CH2OCO), 77.6
(CH2C(OH)), 126.0 (Phpara), 128.4, 128.6 (Phmeta, Phortho), 140.8
(Phipso), 157.3 (OCON); HRMS (CIϩ) C14H20NO3 (MHϩ)
requires 250.1443, found 250.1444; m/z (APCIϩ) 272.1 (MNaϩ,
5%), 250.1 (MHϩ, 10%).
νmax (film) 1777 (C᎐O endocyclic), 1703 (C᎐O exocyclic);
᎐
᎐
δH (400 MHz, CDCl3) 1.56 (6H, s, C(CH3)2), 2.97 (2H, t, J 7.7,
CH2CH2Ph), 3.20 (2H, t, J 7.7, CH2CH2Ph), 3.99 (2H, s,
OCH2), 7.19–7.31 (5H, m, Ph); δC (100 MHz, CDCl3) 24.8
(C(CH3)2), 30.4 (PhCH2), 38.5 (PhCH2CH2), 60.4 (OCH2),
75.2 (CMe2), 126.2 (Phpara), 128.4, 128.5 (Phmeta, Phortho), 140.6
(Phipso), 154.1 (CON), 173.4 (OCON); m/z (APCIϩ) 248.1
(MHϩ, 10%).
(iv). 4,4-Dimethyloxazolidin-2-one 8 (22 mg, 24%).
Preparation of 3-(3Ј-phenylpropionyl)-5,5-dimethyloxazolidin-2-
one 12
Preparation of 3-(1Ј-hydroxy-3Ј-phenylpropyl)-5,5-dimethyl-
oxazolidin-2-one 18
Following Representative Procedure 1, n-BuLi (2.5 M,
2.0 mL, 4.77 mmol), 9 (0.50 g, 6.45 mmol) and hydrocinnamoyl
chloride (0.84 mL, 5.64 mmol) gave, after recrystallisation
(EtOAc–hexane) 12 as a white solid (0.90 g, 84%); mp 71 ЊC
(EtOAc–hexane); C14H17NO3 requires C 68.0, H 6.9, N 5.7%,
Following Representative Procedure 2, DIBAL (1 M in DCM,
4.05 mL, 4.05 mmol) and 12 (500 mg, 2.02 mmol) gave 18 as a
white solid (490 mg, 98%). Purification by column chromato-
graphy on silica gel (EtOAc–40 : 60 petrol) gave 18 (370 mg,
74%); mp 96 ЊC; C14H19NO3 requires C, 67.45, H, 7.7, N, 5.6%;
found C 68.4, H 6.8, N 5.4%; ν
(film) 1757 (C᎐O endo-
᎐
max
cyclic), 1697 (C᎐O exocyclic); δ (200 MHz; CDCl3) 1.48
found C 67.7, H, 7.8, N, 5.5%; νmax (film) 1730 (C᎐O); δ (400
᎐
᎐
H
H
(6H, s, C(CH3)2), 2.99 (2H, t, J 7.6, PhCH2), 3.28 (2H, t,
J 7.6, PhCH2CH2), 3.74 (2H, s, C(4)H2), 7.20–7.30 (5H, m, Ph);
δC (50 MHz, CDCl3) 27.2 (C(CH3)2), 30.2 (PhCH2), 36.9
(PhCH2CH2), 54.3 (NCH2), 78.7 (CMe2), 126.4 (Phpara), 128.7,
128.8 (Phmeta, Phortho), 140.8 (Phipso), 152.8 (CON), 173.2
(OCON); m/z (APCIϩ) 248.1 (MHϩ, 20%).
MHz, CDCl3) 1.43 (3H, s, C(CH3)2), 1.47 (3H, s, C(CH3)2),
1.79–2.15 (2H, m, PhCH2CH2), 2.57–2.87 (2H, m, PhCH2), 3.16
(1H, AB, J 8.4, NCHAHB), 3.52 (1H, AB, J 8.4, NCHAHB), 4.51
(1H, d, J 2.3, CHOH ), 5.33–5.39 (1H, m, CHOH), 7.20–7.35
(5H, m, Ph); δC (50 MHz, CDCl3) 27.1 (C(CH3)2), 31.5
(PhCH2), 35.3 (CH2C(OH)), 50.7 (NCH2), 76.7 (CH2C(OH)),
78.8 (CMe2), 126.3, 128.7 (Phortho-,meta-,para-), 141.3 (Phipso), 158.2
(OCON); m/z (APCIϩ) 232.1 (MHϩ Ϫ H2O, 10%).
Preparation of 3-(1Ј-hydroxy-3Ј-phenylpropyl)oxazolidin-2-one
13
Preparation of hydrocinnamaldehyde 15 from 12
Following Representative Procedure 2, DIBAL (1 M in DCM,
1.65 mL, 1.65 mmol) and 10 (180 mg, 0.82 mmol) furnished,
after purification by flash column chromatography on silica
(EtOAc–40:60 petrol 2 : 1), 13 (94 mg, 52%) as a white solid; mp
DIBAL (1 M in DCM, 2 mL, 2 mmol) was added dropwise
to a stirred solution of 12 (250 mg, 1.0 mmol) in anhydrous
DCM at Ϫ78 ЊC and stirred for 10 minutes before the addition
of saturated aqueous NH4Cl (5 mL). After warming to rt,
the reaction was extracted with DCM (3 × 25 mL), washed
with brine, dried and concentrated in vacuo. To the residue
was added NaHSO3 (20 mmol in 10 mL H2O) and the mix-
ture stirred at rt and NaOH (1 M) was added until pH 9.
After 3 hours the mixture was extracted with DCM (20 mL),
HCl (1 M) was added to the aqueous layer until pH 1 and
the products extracted with DCM (3 × 20 mL). The com-
bined organic extracts were washed with saturated aqueous
NH4Cl, dried, and concentrated in vacuo. Purification by flash
105 ЊC; νmax (DCM) 1756 (C᎐O); δ (200 MHz, CDCl3) 1.81–
᎐
H
2.14 (2H, m, C(2Ј)H2CH2Ph), 2.57–2.87 (2H, m, CH2C(3Ј)-
H2Ph), 3.39 (1H, td, J 8.6, J 5.4, C(4)HAHB), 3.76 (1H, app
q, J 8.6, C(4)HAHB), 4.14–4.38 (2H, m, C(5)H2), 4.47 (1H,
s, OH ), 5.34 (1H, t, J 6.7, C(1Ј)H ), 7.17–7.35 (5H, m, Ph);
δC (50 MHz, CDCl3) 27.5 (C(3Ј)H2), 28.1 (C(2Ј)H2),
38.8 (C(4)H2), 62.7 (C(5)H2), 77.0 (C(1Ј)H), 126.3, 128.6
(Phortho-,meta-,para-), 141.2 (Phipso), 159.1 (OCON); HRMS
(CIϩ) C12H14NO2 (MHϩ Ϫ H2O) requires 204.1024, found
204.1032.
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 2 0 0 1 – 2 0 1 0
2006

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chromatography gave auxiliary 9 (90 mg, 78%) and hydro-
cinnamaldehyde 15 (122 mg, 91%).
chromatography on silica (2 : 1 hexane–Et2O), 22 (498 mg, 97%)
as a colourless oil; C10H15NO3 requires C, 60.9, H, 7.7, N,
7.10%, found C, 60.9, H, 7.95, N, 6.9%; δH (400 MHz, CDCl3)
1.48 (6H, s, C(CH ) ), 2.37–2.42 (2H, m, C(3Ј)H CH᎐CH ),
Preparation of hydrocinnamaldehyde 15 from 18
᎐
3
2
2
2
3.02 (2H, t, J 7.4, C(2Ј)H2), 3.71 (2H, s, C(4)H2), 4.97–5.08 (2H,
m, J5Ј,5Ј 14.5; J5Ј,4Ј 10.2, J5Ј,3Ј 1.5, CH᎐C(5Ј)H ), 5.80–5.84 (1H,
(a). NaHSO3 (20 mmol in 10 mL H2O) and 18 (250 mg,
1.0 mmol) were stirred at rt and NaOH (1 M) was added until
pH 9 and the reaction stirred for 6 hours before extraction
with DCM (20 mL). HCl (1 M) was added to the aqueous layer
until pH 1 and the products extracted with DCM (3 × 20 mL).
The organic extracts were washed with saturated aqueous
NH4Cl, dried, and concentrated in vacuo. Purification by flash
chromatography gave auxiliary 9 (83 mg, 75%) and hydro-
cinnamaldehyde 15 (120 mg, 90%).
(b). 18 (60 mg, 0.24 mmol) was added to a suspension of
K2CO3 (47 mg, 0.34 mmol) in 4 : 1 MeOH–H2O (10 mL)
and stirred for 30 minutes before being partitioned with DCM
(3 × 20 mL), washed with brine, dried, and concentrated
in vacuo. Purification by flash chromatography gave auxiliary 9
(22 mg, 80%) and hydrocinnamaldehyde 15 (26 mg, 82%).
᎐
2
m, C(4Ј)H᎐CH ); δ (50 MHz, CDCl3) 27.1 (C(CH3)2), 28.1
᎐
2
C
(C(3Ј)H2), 34.5 (C(2Ј)H2), 54.2 (C(4)H2), 78.7 (C(5)Me2), 115.8
(CH᎐C(5Ј)H ), 137.0 (C(4Ј)H᎐CH ), 153.0 (NCO), 173.3
᎐
᎐
2
2
(OCON); νmax (film) 1700 (C᎐O exocyclic), 1778 (C᎐O endo-
᎐
᎐
cyclic), 1642 (C=C); m/z (APCIϩ) 220.1 (MNaϩ, 20%), 198.0
(MHϩ, 15%).
Preparation of 3-(4Ј-methylpentanoyl)-5,5-dimethyloxazolidin-
2-one 23
Following Representative Procedure 1, n-BuLi (1.66 M, 3 mL,
4.8 mmol), 9 (500 mg, 4.35 mmol) and 4-methylpentyl chloride
(1.46 g, 10.9 mmol) gave, after purification by flash column
chromatography on silica (3 : 1 hexane–Et2O), 23 (577 mg, 62%)
as a yellow solid; C11H19NO3 requires C, 61.95, H, 9.0, N, 6.6%,
found C, 62.15, H, 9.1, N, 6.50%; mp 31 ЊC; δH (400 MHz,
CDCl3) 0.92 (6H, d, J 6.4, C(4Ј)H(CH3)2), 1.50 (6H, s,
C(5)Me2), 1.52–1.64 (3H, m, C(3Ј)H2C(4Ј)HMe2), 2.93 (2H, m,
C(2Ј)H2), 3.73 (2H, s, C(4)H2CMe2); δC (50 MHz, CDCl3) 22.1
(C(4Ј)H(CH3)2), 27.0 (C(CH3)2), 27.4 (C(4Ј)H), 32.9, 33.2
(C(2Ј)H2, C(3Ј)H2), 54.2 (C(4)H2), 78.4 (C(5)Me2), 152.9
Preparation of (E )- and (Z )-ethyl 5-phenylpent-2-enoate 19 and
20 from 18
Following Representative Procedure 3, triethyl phosphono-
acetate (0.32 mL, 1.61 mmol), n-BuLi (2.5 M, 0.63 mmol, 1.57
mmol) and 18 (200 mg, 0.80 mmol) in anhydrous THF (30 mL)
gave, after purification by flash column chromatography on
silica (30 : 1 hexane–Et2O), (Z)-2026 (36 mg, 22%); δH (400
MHz, CDCl3) 1.29 (3H, t, J 7.2, CO2CH2CH3), 2.78 (2H, t,
J 7.7, C(5)H2), 2.97–3.03 (2H, m, C(4)H2), 4.17 (2H, q, J 7.1,
CO2CH2Me), 5.79 (1H, dt, J2,3 11.4, J2,4 1.6, C(2)H ), 6.25 (1H,
dt, J3,2 11.4, J3,4 7.4, C(3)H ), 7.18–7.31 (5H, m, Ph) and a more
polar fraction (E)-1926 (79 mg, 49%); δH (400 MHz, CDCl3)
1.29 (3H, t, J 7.2, CO2CH2CH3), 2.35–2.76 (4H, m, C(4)-
H2C(5)H2Ph), 4.19 (2H, q, J 7.1, CO2CH2Me), 5.86 (1H, dt,
J2,315.6, J2,41.4, C(2)H ), 7.02 (1H, dt, J3,2 15.6, J3,4 6.8, C(3)H ),
7.18–7.32 (5H, m, Ph). Further elution gave 5,5-dimethyl-
oxazolidin-2-one 9 (65 mg, 70%).
(CON), 174.2 (OCON); νmax (film) 1778 (C᎐O endocyclic), 1699
᎐
(C᎐O exocyclic); m/z (APCIϩ) 236.1 (MNaϩ, 25%), 214.1
᎐
(MHϩ, 30%).
Preparation of 3-(3Ј,3Ј-dimethylbutyryl)-5,5-dimethyloxazol-
idin-2-one 24
Following Representative Procedure 1, n-BuLi (2.5 M, 0.77 mL,
1.91 mmol), 9 (200 mg, 1.74 mmol) and tert-butylacetyl chlor-
ide (0.40 mL, 2.26 mmol) gave, after recrystallization (hexane–
Et2O), 24 as a white solid (340 mg, 93%); C11H19NO3 requires
C, 61.95, H, 9.0, N, 6.6%, found C, 61.9, H, 8.7, N, 6.45%;
mp 52–54 ЊC (hexane–Et2O); δH (200 MHz, CDCl3) 1.05 (9H,
s, CH2C(CH3)3), 1.48 (6H, s, C(CH3)2), 2.90 (2H, s, CH2CMe2),
Preparation of (E )- and (Z )-ethyl 5-phenylpent-2-enoate 19 and
20 from 12
t
3.72 (2H, s, CH2 Bu); δC (50 MHz, CDCl3) 27.0 (C(CH3)2),
29.4 (CH2C(CH3)3), 31.2 (CH2CMe3), 45.9 (CH2CMe2), 54.3
t
Following Representative Procedure 3, DIBAL (1.0 M in THF,
0.73 mmol), 12 (150 mg, 0.61 mmol), n-BuLi (2.5 M, 0.49 mL,
1.22 mmol) and triethyl phosphonoacetate (0.25 mL, 1.22
mmol) in anhydrous THF (15 mL) gave a yellow oil. Purifi-
cation by flash column chromatography on silica (30 : 1 hexa-
ne–Et2O) furnished (Z)-20 (11 mg, 9%) and (E)-19 (76 mg,
61%).
(CH2 Bu), 77.8 (CMe2), 153.0 (OCN), 172.7 (OCON); νmax
(KBr) 1760 (C᎐O endocyclic), 1692 (C᎐O exocyclic); m/z
᎐
᎐
(APCIϩ) 236.1 (MNaϩ, 25%), 214.1 (MHϩ, 45%).
Preparation of 3-(1Ј-hydroxybutyroyl)-5,5-dimethyloxazolidin-
2-one 25
Following Representative Procedure 2, DIBAL (1 M in DCM,
2.2 mL, 2.2 mmol) and 21 (200 mg, 1.1 mmol) in anhydrous
DCM (10 mL) gave 25 (190 mg, 94%) as a colourless oil; δH (400
MHz, CDCl3) 0.94 (3H, t, J 7.3, C(4Ј)H3), 1.44, 1.47 (2 × 3H, s,
C(CH3)2), 1.24–1.57 (3H, m, C(3Ј)HA and C(2Ј)H2), 1.64–1.73
(1H, m, C(3Ј)HB), 3.19 (1H, d, J 8.5, C(4)HA), 3.48 (1H, d,
J 8.5, C(4)HB), 4.27 (1H, d, J 3.8, OH ), 5.30–5.35 (1H, m,
C(1Ј)HOH); δC (100 MHz, CDCl3) 13.7 (C(4Ј)H3), 18.4
(C(3Ј)H2), 27.2, 27.3 (C(CH3)2), 35.5 (C(2Ј)H2), 50.8 (C(4)H2),
Preparation of 3-butyroyl-5,5-dimethyloxazolidin-2-one 21
Following Representative Procedure 1, n-BuLi (2.5 M, 1.14 mL,
2.86 mmol), 9 (300 mg, 2.60 mmol) and butyryl chloride
(0.35 mL, 3.38 mmol) gave, after purification by flash column
chromatography on silica (5 : 1 hexane–Et2O), 21 (420 mg, 88%)
as a yellow oil; δH (400 MHz, CDCl3) 0.95 (3H, t, J 7.4,
CH2CH2CH3), 1.47 (6H, s, C(CH3)2), 1.63–1.68 (2H, m, CH2-
CH2Me), 2.87 (2H, t, J 7.4, CH2CH2Me), 3.70 (2H, s, C(4)H2);
δC (100 MHz, CDCl3) 13.6 (CH2CH2CH3), 17.6 (CH2CH2Me),
27.2 (C(CH3)2), 37.1 (CH2CH2Me), 54.2 (C(4)H2), 78.4
76.7 (C(1Ј)H), 78.5 (C(5)Me ), 157.8 (C᎐O); ν
(film) 1741
᎐
2
max
(C᎐O); m/z (APCIϩ) 187.2 (MHϩ, 5%), 170.2 (MHϩ Ϫ H2O,
᎐
100%); HRMS C9H15NO2 (MHϩ Ϫ H2O) requires 170.1181,
(CMe2), 152.7 (OCN), 173.6 (OCON); νmax (film) 1778 (C᎐O
found 170.1180.
᎐
endocyclic), 1702 (C᎐O exocyclic); m/z (APCIϩ) 208.0
᎐
(MNH4ϩ, 50%), 186.1 (MHϩ, 100%); HRMS C9H16NO3 (MHϩ)
requires 186.1130, found 186.1128.
Preparation of 3-(1Ј-hydroxy-3Ј,3Ј-dimethylbutyl)-5,5-di-
methyloxazolidin-2-one 26
Following Representative Procedure 2, DIBAL (1 M in DCM,
1.9 mL, 1.9 mmol) and 24 (200 mg, 0.94 mmol) in anhydrous
DCM (10 mL) gave 26 (120 mg, 60%) as white needles; mp 100–
104 ЊC; δH (400 MHz, CDCl3) 0.97 (9H, s, C(CH3)3), 1.42, 1.43
(2 × 3H, s, C(CH3)2), 1.43–1.49 (1H, m, C(2Ј)HA), 1.59 (1H, dd,
Preparation of 3-pent-4Ј-enoyl-5,5-dimethyloxazolidin-2-one 22
Following Representative Procedure 1, n-BuLi (1.6 M, 1.8 mL,
2.87 mmol), 9 (300 mg, 2.61 mmol) and pent-4-enoyl chloride
(770 mg, 6.53 mmol) gave, after purification by flash column
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 2 0 0 1 – 2 0 1 0
2007

View Article Online
J2ЈB,2ЈA14.1, J2ЈB,1ЈЈ6.5, C(2Ј)HB), 3.24 (1H, d, J 8.6, C(4)HA), 3.50
(1H, d, J 8.6, C(4)HB), 4.24 (1H, d, J 3.7, OH ), 5.44–5.48 (1H,
m, C(1Ј)H ); δC (100 MHz, CDCl3) 27.2, 27.3 (C(5)(CH3)2), 29.6
(C(3Ј)), 29.8 (C(3Ј)(CH3)3), 46.6 (C(2Ј)H2), 50.8 (C(4)H2), 75.3
(C(1Ј)H), 78.5 (C(5)Me2), 157.6 (OCON); νmax (KBr) 3352
Preparation of (E )- and (Z )-ethyl 5,5-dimethylhex-2-enoate 33
and 34 from 24
Following Representative Procedure 3, DIBAL (1.0 M in THF,
1.69 mL, 1.69 mmol), 24 (300 mg, 1.41 mmol), triethyl
phosphonoacetate (0.71 mL, 3.53 mmol) and n-BuLi (2.5 M,
1.41 mL, 3.53 mmol) in anhydrous THF (20 mL) gave, after
purification by flash column chromatography on silica (30 : 1
hexane–Et2O), (Z)-3428 (11 mg, 7%); δH (500 MHz, CDCl3)
0.95 (9H, s, C(CH3)3), 1.25 (3H, t, J 7.2, CO2CH2CH3), 2.59
(2H, dd, J4,37.8, J4,21.2, C(4)H2), 4.16 (2H, q, J 7.2, CO2-
CH2Me), 5.84 (1H, dt, J2,3 11.6, J2,4 1.7, C(2)H ), 6.29 (1H, dt,
J3,2 11.6, J3,4 7.8, C(3)H ). Further elution gave polar fraction
(E)-3328 (90 mg, 36%); δH (500 MHz, CDCl3) 0.93 (9H, s,
C(CH3)3), 1.29 (3H, t, J 7.2, CO2CH2CH3), 2.08 (2H, dd, J4,3
6.6, J4,2 1.2, C(4)H2), 4.18 (2H, q, J 7.2, CO2CH2Me), 5.80 (1H,
dt, J2,3 15.5, J2,4 1.2, C(2)H ), 6.98 (1H, dt, J3,2 15.5, J3,4 7.8,
C(3)H ).
(O–H), 1732 (C᎐O); m/z (APCIϩ) 170.0 (MHϩ, 5%).
᎐
Preparation of (E )- and (Z )-ethyl hex-2-enoate 27 and 28 from
22
Following Representative Procedure 3, DIBAL (1.0 M in THF,
1.95 mL, 1.95 mmol), 22 (300 mg, 1.62 mmol), triethyl
phosphonoacetate (0.81 mL, 4.05 mmol) and n-BuLi (2.5 M,
1.62 mL, 4.05 mmol) in anhydrous THF (20 mL) gave, after
purification by flash column chromatography on silica (30 : 1
hexane–Et2O), (Z)-2827 (10 mg, 4%); δH (400 MHz, CDCl3)
0.95 (3H, t, J 7.3, C(6)H3), 1.30 (3H, t, J 7.1, CO2CH2CH3),
1.43–1.54 (2H, m, C(5)H2), 2.61–2.67 (2H, m, C(4)H2), 4.17
(2H, q, J 7.1, CO2CH2CH3), 5.78 (1H, dt, J2,310.0, J2,41.7,
C(2)H ), 6.23 (1H, dt, J2,111.5, J2,37.5, C(3)H ). Further elution
gave (E)-2727 (92 mg, 40%); δH (400 MHz, CDCl3) 0.94 (3H, t,
J 7.4, C(6)H3), 1.29 (3H, t, J 7.1, CO2CH2CH3), 1.45–1.54 (2H,
m, C(5)H2), 2.15–2.21 (2H, m, C(4)H2), 4.19 (2H, q, J 7.1,
CO2CH2Me), 5.82 (1H, dt, J2,3 15.6, J2,4 1.5, C(2)H ), 6.97 (1H,
dt, J3,2 15.6, J3,4 7.0, C(3)H ). Further elution gave 5,5-dimethyl-
oxazolidin-2-one 9 (55 mg, 0.48 mmol, 56%).
Preparation of (E )- and (Z )-tert-butyl hex-2-enoate 35 and 36
from 21
Following Representative Procedure 3, DIBAL (1.0 M in THF,
1.95 mL, 1.95 mmol), 21 (300 mg, 1.15 mmol), tert-butyl di-
methoxyphosphonoacetate (910 mg, 4.05 mmol) and n-BuLi
(1.6 M, 2.6 mL, 4.05 mmol) in anhydrous THF (20 mL) gave,
after purification by flash column chromatography on silica
(150 : 1 hexane–Et2O) (Z)-3629 (56 mg, 20%); δH (400 MHz,
CDCl3) 0.95 (3H, t, J 7.4, CH2CH2CH3), 1.49 (9H, s, C(CH3)3),
Preparation of (E )- and (Z )-ethyl hepta-2,6-dienoate 29 and 30
from 22
1.40–1.57 (2H, obscured m, CH2CH2Me), 2.56–2.62 (2H, m,
t
CH2CH2Me), 5.69 (1H, d, J2,31.6, CH᎐CHCO Bu), 6.12 (1H,
᎐
2
Following Representative Procedure 3, DIBAL (1.0 M in THF,
1 mL, 1.5 mmol), 22 (200 mg, 1.02 mmol), triethyl phosphono-
acetate (0.51 mL, 2.54 mmol) and n-BuLi (1.66 M, 1.6 mL, 2.54
mmol) in anhydrous THF (15 mL) gave, after purification by
flash column chromatography on silica (30 : 1 hexane–Et2O),
(Z)-30 (12 mg, 8%); δH (400 MHz, CDCl3) 1.30 (3H, t, J 7.2,
t
dt, J3,2 11.6, J3,4 7.5, CH᎐CHCO Bu). Further elution gave
᎐
2
(E)-35 (210 mg, 76%); δH (400 MHz, CDCl3) 0.94 (3H, t, J 7.4,
CH2CH2CH3), 1.20–1.40 (2H, m, CH2CH2Me), 1.49 (9H, s,
C(CH3)3), 2.13–2.18 (2H, m, CH2CH2Me), 5.74 (1H, dt, J2,3
t
12.6, J2,41.5, CH᎐CHCO Bu), 6.86 (1H, dt, J3,215.6, J3,47.0,
᎐
2
t
CH᎐CHCO Bu).
᎐
2
CO CH CH ), 2.21–2.43 (4H, m, CH CH CH᎐CH ), 3.49 (2H,
᎐
2
2
3
2
2
2
q, J 7.0, CO CH Me), 4.95–5.08 (2H, m, CH᎐CH ), 5.77–5.86
᎐
2
2
2
Preparation of 3-(2Ј-benzylpropionyl)-5,5-dimethyloxazolidin-2-
one 37
(2H, m, CH᎐CH and CH᎐CHCO Et), 6.22 (1H, dt, J 11.5,
᎐
᎐
2
2
3,2
J3,4 7.4, CH᎐CHCO Et). Further elution gave (E)-29 (96 mg,
᎐
2
62%); δH (400 MHz, CDCl3) 1.33 (3H, t, J 7.1, CO2CH2CH3),
Following Representative Procedure 4, LHMDS (1 M, 1.21
mL, 1.21 mmol), 12 (200 mg, 0.81 mmol) and MeI (0.15 mL,
2.43 mmol) in anhydrous THF (10 mL) gave, after purification
by flash column chromatography on silica (2 : 1 40–60 petrol–
EtOAc), 37 (190 mg, 90%) as a colourless oil; νmax (film) 1783
2.24–2.38 (4H, m, CH ᎐CHCH CH ), 4.23 (2H, q, J 7.1,
᎐
2
2
2
CO CH Me), 5.04–5.13 (2H, m, CH ᎐CH), 5.80–5.90 (2H, m,
᎐
2
2
2
CH =CH and CH᎐CHCO Et), 7.00 (1H, dt, J3,215.6; J3,4 6.7,
᎐
2
2
CH᎐CHCO Et); δ (100 MHz, CDCl3) 22.6 (CO2CH2CH3),
᎐
2
C
31.4, 32.0 (CH CH CH᎐CH ), 60.2 (CO CH Me), 115.5
᎐
2
2
2
2
2
(C᎐O endocyclic), 1703 (C᎐O exocyclic); δH (200 MHz, CDCl3)
᎐ ᎐
(CH᎐CH ), 121.7 (CH᎐CH ), 137.1 (CH᎐CHCO Et), 148.2
᎐
᎐
᎐
2
2
2
1.19 (3H, d, J 6.8, C(3Ј)H3), 1.34, 1.43 (2 × 3H, s, C(CH3)2),
2.67 (1H, dd, JA,B13.2, JA,2Ј7.7, CHAHBPh), 3.04 (1H, dd,
JB,A13.2, JB,2Ј7.3, CHAHBPh), 3.58–3.72 (2H, m, C(4)H2), 4.09–
4.20 (1H, m, C(2Ј)H ), 7.16–7.32 (5H, m, Ph); δC (50 MHz,
CDCl3) 16.7 (C(3Ј)H3), 26.9, 27.0 (C(CH3)2), 39.3 (C(2Ј)H),
40.0 (C(2Ј)CH2Ph), 54.4 (C(4)H2), 78.3 (C(5)), 126.3, 128.1,
128.3 (Phortho-,meta-,para-), 139.2 (Phipso), 152.3 (CO), 176.8
(OCON); HRMS (APCIϩ), C15H20NO3 requires 262.1443,
found 262.1448.
(CH᎐CHCO Et), 166.6 (CO Et); ν
(film) 1716 (C᎐O), 1656
᎐
᎐
2
2
max
(C ᎐C ); HRMS C H O (MHϩ) requires 155.1072, found
᎐
2
3
9
15
2
155.1073; m/z (APCIϩ) 155.1 (MHϩ, 100%).
Preparation of (E )- and (Z )-ethyl 6-methylhept-2-enoate 31 and
32 from 23
Following Representative Procedure 3, DIBAL (1.0 M in THF,
1.41 mL, 1.41 mmol), 23 (200 mg, 0.94 mmol), triethyl
phosphonoacetate (0.47 mL, 2.35 mmol) and n-BuLi (1.6 M,
1.47 mL, 2.35 mmol) in anhydrous THF (15 mL) gave, after
purification by flash column chromatography on silica (30 : 1
hexane–Et2O), (Z)-32 (10 mg, 6%); δH (400 MHz, CDCl3)
0.91 (6H, d, J 6.6, C(6)H(CH3)2), 1.20–1.66 (6H, obscured m,
CO2CH2CH3, C(5)H2CHMe2 and CH2C(6)HMe2), 2.64–2.69
(2H, m, C(4)H2CH2CHMe2), 4.18 (2H, q, J 7.1, CO2CH2Me),
Preparation of 3-(2Ј-benzylpent-4Ј-enoyl)-5,5-dimethyloxazol-
idin-2-one 38
Following Representative Procedure 4, LHMDS (1.0 M,
3.0 mL, 3.0 mmol), 12 (0.50 g, 2.02 mmol) and allyl bromide
(0.53 mL, 6.07 mmol) in anhydrous THF (25 mL) gave 38 as a
yellow solid (0.47 g, 1.65 mmol, 82%) after purification by flash
column chromatography on silica (3 : 1 hexane–Et2O; Rf 0.33);
mp 53–55 ЊC; δH (400 MHz, CDCl3) 1.25 (3H, s, C(CH3)2), 1.43
5.75 (1H, dt, J2,311.5, J2,41.7, CH᎐C(2)HCO Et), 6.22 (1H, dt,
᎐
2
J3,211.5, J3,47.6, C(3)H᎐CHCO Et). Further elution gave (E)-31
᎐
2
(71 mg, 45%); δH (400 MHz, CDCl3) 0.90 (6H, d, J 6.6,
C(6)H(CH3)2), 1.29 (3H, t, J 7.1, CO2CH2CH3), 1.31–1.37 (2H,
obscured m, C(5)H2CHMe2), 1.54–1.61 (1H, m, C(6)HMe2),
2.17–2.23 (2H, m, C(4)H2CH2CHMe2), 4.18 (2H, q, J 7.1,
(3H, s, C(CH ) ), 2.28–2.34 (1H, m, CH H CH᎐CH ), 2.44–
᎐
3 2 A B 2
2.51 (1H, m, CH H CH᎐CH ), 2.8 (1H, dd, JA,B13.4, JA,26.6,
᎐
A
B
2
CHAHBPh), 2.96 (1H, dd, JB,A13.4, JB,2 8.7, CHAHBPh), 3.58
(2H, ABq, J 11.0, CH2CMe2), 4.34–4.12 (1H, m, CHCH2-
CO2CH2Me), 5.82 (1H, dt, J2,314.1, J2,41.5, CH᎐C(2)HCO Et),
CH᎐CH ), 5.01–5.10 (2H, m, CH᎐CH ), 5.76–5.86 (1H, m,
᎐ ᎐
2 2
᎐
2
6.97 (1H, dt, J3,2 15.6, J3,47.0, C(3)H᎐CHCO Et).
CH᎐CH ), 7.16–7.28 (5H, m, Ph); δ (100 MHz, CDCl3)
᎐
2 C
᎐
2
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 2 0 0 1 – 2 0 1 0
2008

View Article Online
26.7, 26.9 (C(CH ) ), 36.3 (CH Ph), 38.3 (CH CH᎐CH ), 44.1
phosphonoacetate (0.58 mL, 1.38 mmol) and n-BuLi (1.6 M,
᎐
3
2
2
2
2
(CHCH CH᎐CH ), 54.3 (CH CMe ), 78.3 (CMe ), 117.3
1.8 mL, 2.88 mmol) in anhydrous THF (20 mL) gave, after
purification by flash column chromatography on silica (30 : 1
hexane–Et2O), (Z)-43 (15 mg, 6%); δH (400 MHz, CDCl3) 1.01
(3H, d, J 6.6, C(4)Me), 1.28 (3H, t, J 7.1, CO2CH2CH3), 2.58
(1H, dd, JA,B13.4, J5,47.6, C(5)HA), 2.70 (1H, dd, JB,A13.4,
J5,46.8, C(5)HB), 3.82–3.89 (1H, m, C(4)H ), 4.14 (2H, q, J 7.1,
CO2CH2CH3), 5.69 (1H, d, J 11.5, C(2)H ), 6.05 (1H, dd, J3,2
11.5, J3,4 10.1, C(3)H ), 7.17–7.29 (5H, m, Ph); δC (100 MHz,
CDCl3) 14.2 (C(4)CH3), 19.6 (CO2CH2CH3), 34.3 (C(5)H2Ph),
42.9 (C(4)H), 59.8 (CO2CH2Me), 76.7 (C(2)H), 118.6 (C(3)H),
125.9 (Phpara), 128.1, 129.2 (Phmeta, Phortho), 139.8 (Phipso), 154.9
᎐
2
2
2
2
2
(CH᎐CH ), 126.6 (Phpara), 128.6, 129.3 (Phmeta, Phortho), 135.5
᎐
2
(CH᎐CH ), 139.2 (Phipso), 152.6 (NCO), 176.1 (OCON); νmax
᎐
2
(KBr disc) 1771 (C᎐O endocyclic), 1693 (C᎐O exocyclic), 1639
᎐
᎐
(C᎐C); HRMS C H NO (MHϩ) requires 288.1600, found
᎐
17 22
3
288.1602; m/z (APCIϩ) 310.2 (MNaϩ, 30%), 288.2 (MHϩ, 40%).
Preparation of 3-(1Ј-hydroxy-2Ј-benzylpropyl)-5,5-dimethyl-
oxazolidin-2-ones 39 and 40
Following Representative Procedure 2, DIBAL (1 M in DCM,
1.15 mmol) and 37 (150 mg, 0.56 mmol) in anhydrous DCM
(7 mL) gave, after purification by flash column chromatography
(5 : 1 hexane–Et2O) 39–40 (112 mg, 76%) as a colourless oil and
a 3 : 1 mixture of diastereoisomers; Found C, 68.3, H, 8.2,
N, 5.1%; C15H21NO3 requires C, 68.4, H, 8.0, N, 5.3%; m/z
(CO2Et); νmax (film) 1719 (C᎐O), 1651 (C᎐C); HRMS C H O
᎐
᎐
14 19
2
(MHϩ) requires 219.1385, found 219.1380; m/z (APCIϩ) 236.2
(MNH4ϩ, 70%), 219.2 (MHϩ, 100%). Further elution gave
(E)-42 (162 mg, 65%); δH (400 MHz, CDCl3) 1.05 (3H, d, J 6.4,
C(4)Me), 1.29 (3H, t, J 7.1, CO2CH2CH3), 2.55–2.66 (1H,
obscured m, C(5)HA), 2.78 (1H, dd, JA,B 12.2, J5,4 5.5, C(5)HB),
4.12–4.21 (1H, obscured m, C(4)H ), 4.19 (2H, q, J 7.1,
CO2CH2Me), 5.76 (1H, dd, J2,315.7, J2,41.0, C(2)H ), 6.97 (1H,
dd, J3,2 11.5, J3,4 7.0, C(3)H ), 7.17–7.33 (5H, m, Ph); δC (100
MHz, CDCl3) 14.2 (C(4)CH3), 38.2 (CO2CH2CH3), 42.3
(C(5)H2), 60.2 (CO2CH2Me), 119.9 (C(3)H), 126.1 (Phpara),
(APCIϩ) 246 (MHϩ Ϫ H2O); νmax (DCM) 1754 (C᎐O); Data for
᎐
major diastereoisomer; δH (400 MHz, CDCl3) 0.78 (3H, d, J 6.8,
C(3Ј)H3), 1.45, 1.49 (2 × 3H, s, C(CH3)2), 1.95–2.05 (1H, m,
C(2Ј)H ), 2.33–2.41 (1H, obscured m, CHAHBPh), 3.18 (1H, d,
J 8.6, C(4)HA), 3.2 (1H, dd, JB,A13.6, JB,2Ј3.7, CHAHBPh), 3.56
(1H, d, J 8.6, C(4)HB), 4.31 (1H, d, J 3.8, OH ), 5.03–5.10 (1H,
obscured m, CHOH), 7.14–7.39 (5H, m, Ph); δC (50 MHz,
CDCl3) 14.3 (C(3Ј)H3), 27.1, 27.3 (C(CH3)2), 38.4 (C(2Ј)H),
38.8 (C(2Ј)CH2Ph), 50.9 (C(4)H2), 78.7 (C(5)), 81.0 (C(1Ј)),
128.3, 128.5 (Phmeta, Phortho), 139.4 (Phipso), 155.1 (C᎐O); ν
᎐
max
(film) 1720 (C᎐O), 1651 (C᎐C); HRMS C H O (MHϩ)
᎐
᎐
14 19
2
requires 219.1385, found 219.1380; m/z (APCIϩ) 219.2 (MHϩ,
126.1, 128.5, 129.7 (Phortho-,meta-,para-), 140.4 (Phipso), 158.5 (C᎐O);
᎐
100%).
Data for minor diastereoisomer; δH (400 MHz, CDCl3) 1.02
(3H, d, J 6.6, C(3Ј)H3), 1.40, 1.48 (2 × 3H, s, C(CH3)2), 1.95–
2.05 (1H, m, C(2Ј)H ), 2.33–2.41 (1H, obscured m, CHAHBPh),
2.75 (1H, dd, JB,A 13.7, JB,2Ј 4.5, CHAHBPh), 3.13 (1H, d, J 8.6,
C(4)HA), 3.55 (1H, d, J 8.6, C(4)HB), 4.26 (1H, d, J 3.9, OH ),
5.03–5.10 (1H, obscured m, CH ), 7.14–7.39 (5H, m, Ph); δC (50
MHz, CDCl3) 15.9 (C(3Ј)H3), 27.1, 27.3 (C(CH3)2), 38.4
(C(2Ј)H), 38.9 (C(2Ј)CH2Ph), 51.1 (C(4)H2), 78.7 (C(5)), 81.3
(C(1Ј)), 126.3, 128.6, 129.3 (Phortho-,meta-,para-), 140.2 (Phipso),
Preparation of 3-(1Ј-hydroxy-2Ј-benzylpent-4Ј-enyl)-5,5-di-
methyloxazolidin-2-ones 44 and 45
ZnCl2 (1.0 M in Et2O, 1.74 mL, 1.74 mmol) was added dropwise
to a stirred solution of 38 (250 mg, 0.87 mmol) in anhydrous
THF (10 mL) at Ϫ30 ЊC. After 30 minutes, DIBAL (1.0 M in
THF, 1.74 mL, 1.74 mmol) was added and the reaction mixture
stirred for a further hour. Following quenching with saturated
aqueous NH4Cl solution, the reaction mixture was stirred for
2 hours with Rochelles salt at rt, extracted with EtOAc, washed
with brine and dried over MgSO4. Concentration in vacuo, fol-
lowed by purification by flash column chromatography on silica
(1 : 1 hexane: Et2O; Rf 0.32) furnished 44 and 45 as an insepar-
able 3 : 2 mixture of diastereoisomers (230 mg, 92%); mp 79–
158.5 (C᎐O).
᎐
Preparation of 2-benzylpropionaldehyde 41 from 39–40
NaHSO3 (23.2 mmol in 15 mL H2O) and 39–40 (304 mg, 1.16
mmol) were stirred at rt and NaOH (1 M) was added until pH 9
and the reaction stirred for 6 hours before extraction with
DCM (20 mL). HCl (1 M) was added to the aqueous layer until
pH 1 and the products extracted with DCM (3 × 20 mL) and
the combined organic extracts were washed with saturated
aqueous NH4Cl, dried, and concentrated in vacuo. Purification
by flash chromatography gave auxiliary 9 (107 mg, 81%) and 41
(155 mg, 91%).
82 ЊC; νmax (KBr) 3341 (OH), 1717 (C᎐O); HRMS C H NO
᎐
17 22
2
(MHϩ Ϫ H2O) requires 272.1651; found 272.1651; m/z (APCIϩ)
272.2 (MHϩ Ϫ H2O, 100%); δH (400 MHz, CDCl3) {Major
diastereoisomer} 1.46 and 1.49 (2 × 3H, s, C(CH3)2), 1.80
(1H, br s, OH ), 2.25–2.33 (2H, m, CH CH᎐CH ), 2.55–2.69
᎐
2
2
(obscured m, CHAHBPh), 3.06 (1H, dd, JA,B 13.7, JA,2Ј 3.7,
CHAHBPh), 3.21 (1H, d, J 8.5, C(4)HA), 3.57 (1H, d, J 8.5,
C(4)HB), 4.19 (1H, d, J 8.4, C(1Ј)H ), 5.02–5.21 (obscured m,
Preparation of 2-benzylpropionaldehyde 41 from 37
CH᎐CH and CHCH᎐CH ), 5.85–5.96 (1H, m, CH᎐CH ),
7.15–7.31 (5H, m, Ph); δH (400 MHz, CDCl3) {Minor
diastereoisomer} 1.27, 1.43 (2 × 3Hs, C(CH3)2), 1.82 (1H, br s,
᎐
᎐
᎐
2
2
2
DIBAL (1 M in DCM, 3.07 mL, 3.07 mmol) was added drop-
wise to a stirred solution of 37 (400 mg, 1.53 mmol) in
anhydrous DCM (15 mL) at Ϫ78 ЊC and stirred for 10 minutes
before the addition of saturated aqueous NH4Cl (5 mL). After
warming to rt, the reaction was extracted with DCM (3 ×
25 mL), washed with brine, dried and concentrated in vacuo. To
the residue was added NaHSO3 (30.7 mmol in 10 mL H2O) and
the mixture stirred at rt and NaOH (1 M) was added until pH 9.
After 3 hours the mixture was extracted with DCM (20 mL),
HCl (1 M) was added to the aqueous layer until pH 1 and the
products extracted with DCM (3 × 20 mL). The combined
organic extracts were washed with saturated aqueous NH4Cl,
dried, and concentrated in vacuo. Purification by flash chromato-
graphy gave auxiliary 9 (147 mg, 83%) and 2-benzylpropion-
aldehyde 41 (186 mg, 83%).
OH ), 1.96–2.18 (3H, m, CH CH᎐CH and CH H Ph), 2.55–
᎐
2
2
A
B
2.69 (1H, obscured m, CHAHBPh), 2.86 (1H, d, J 8.5, C(4)HA),
3.46 (1H, d, J 8.5, C(4)HB), 4.19 (1H, d, J 8.4, C(1Ј)H ), 5.02–
5.21 (3H, obscured m, CH᎐CH and CHCH᎐CH ), 5.72–5.82
᎐
᎐
2
2
(1H, m, CH᎐CH ), 7.15–7.31 (5H, m, Ph); δ (100 MHz,
᎐
2
C
CDCl ) 27.1, 27.3 (C(5)(CH ) ), 32.5, 33.7 (CH CH᎐CH ),
᎐
3
3
2
2
2
34.9, 35.2 (CH2Ph), 42.7, 42.9 (CHCH2Ph), 50.9, 51.3
(C(4)H2), 78.6 (C(5)Me2), 79.1, 79.5 (C(1Ј)H), 117.7, 117.8
(CH᎐CH ), 125.9, 126.0 (CH᎐CH ), 128.3, 128.4, 128.9, 129.6
᎐
᎐
2
2
(Phmeta, Phortho), 135.0, 135.2 (Phpara), 139.8, 140.1 (Phipso), 158.1
(OCON).
Preparation of (E )- and (Z )-ethyl 4-benzylhepta-2,6-dienoate 46
Preparation of ethyl (E )- and (Z )-4-methyl-5-phenylpent-2-
and 47 from 44 and 45
enoate 42 and 43 from 37
Following Representative Procedure 3, triethyl phosphono-
acetate (0.35 mL, 1.73 mmol), n-BuLi (1.6 M, 1.1 mL, 1.73
mmol) and 44 and 45 (200 mg, 0.69 mmol) gave, after purifi-
Following Representative Procedure 3, DIBAL (1.0 M in
THF, 1.38 mL, 1.38 mmol), 37 (300 mg, 1.15 mmol), triethyl
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 2 0 0 1 – 2 0 1 0
2009

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3 A. G. Myers, B. H. Yang and H. Chen and J. L. Gleason, J. Am.
Chem. Soc., 1994, 116, 9361.
4 For example see D. A. Evans and A. E. Weber, J. Am. Chem. Soc.,
1986, 108, 6757; D. A. Evans, R. P. Polniaszek, K. M. DeVries,
D. E. Guinn and D. J. Mathre, J. Am. Chem. Soc., 1991, 113, 7613;
D. Schinzer, A. Bauer, O. M. Böhm, A. Limberg and M. Cordes,
Chem. Eur. J., 1999, 5, 2483.
5 D. A. Evans, S. J. Miller and M. D. Ennis, J. Org. Chem., 1993, 58,
471; D. A. Evans and S. L. Bender, Tetrahedron Lett., 1986, 27, 799;
D. A. Evans, S. L. Bender and J. Morris, J. Am. Chem. Soc., 1988,
110, 2506.
6 S. Nahm and S. M. Weinreb, Tetrahedron Lett., 1981, 22,
3815.
7 For leading references see S. L. Graham and T. H. Scholz,
Tetrahedron Lett., 1990, 31, 6269; G. E. Keck, S. F. McHardy and
J. A. Murry, Tetrahedron Lett., 1993, 34, 6215.
8 For a recent related example see G.-J. Lee, T. H. Kim, J. N. Kim and
U. Lee, Tetrahedron: Asymmetry, 2002, 13, 9.
9 A. I. Meyers, R. F. Spohn and R. J. Linderman, J. Org. Chem., 1985,
50, 3633.
10 T. Izawa and T. Mukaiyama, Bull. Chem. Soc. Jpn., 1979, 52,
555.
cation by flash column chromatography on silica (30 : 1 40–60
petrol–Et2O); (Z)-47 (38 mg, 23%); δH (400 MHz, CDCl3) 1.26
(3H, t, J 7.2, CO2CH2CH3), 2.02–2.09 (1H, m, C(5)HA), 2.21–
2.28 (1H, m, C(5)HB), 2.65 (1H, dd, JA,B13.6, JA,47.3, CHAHB-
Ph), 2.74 (1H, dd, JB,A13.6, JB,47.0, CHAHBPh), 3.89–3.94 (1H,
m, C(4)H ), 4.13 (2H, q, J 7.2, CO2CH2Me), 5.00–5.05 (2H, m,
C(7)H2), 5.71–5.81 (2H, m, C(2)H and C(6)H ), 6.00 (1H, dd,
J3,2 11.6, J3,4 10.2, C(3)H ); δC (100 MHz, CDCl3) 14.2 (CO2-
CH2CH3), 38.5, 38.9, 40.7 (C(5)H2, CH2Ph and C(4)H), 59.8
(CO2CH2Me), 116.4 (C(7)H2), 120.0 (C(2)HCO2Et), 126.0
(Phpara), 128.1, 129.2 (Phmeta, Phortho), 136.1 (C(6)H), 139.6
(Phipso), 153.0 (C(3)H), 166.2 (CO2Et). Further elution gave
(E)-46 (97 mg, 58%); δH (400 MHz, CDCl3) 1.28 (3H, t, J 7.1,
CO CH CH ), 2.11–2.29 (2H, m, CH CH᎐CH ), 2.54–2.63
᎐
2
2
3
2
2
(1H, m, CHCH CH᎐CH ), 2.66–2.80 (2H, m, CH Ph), 4.17
᎐
2
2
2
(2H, q, J 7.1, CO CH Me), 5.02–5.07 (2H, m, CH᎐CH ), 5.68–
᎐
2
2
2
5.79 (2H, m, CH᎐CHCO Et and CH=CH ), 6.86 (1H, dd,
᎐
2
2
J3,215.7, J3,48.4, CH=CHCO2Et); δC (100 MHz, CDCl3) 14.2
(CO CH CH ), 37.8, 40.1, 43.7 (CH CH᎐CH , CH Ph and,
᎐
2
2
3
2
2
2
11 For selected papers see Y. Nagao, T. Kumagai, S. Yamada,
E. Fujita, Y. Inoue, Y. Nagase, S. Aoyagi and T. Abe, J. Chem. Soc.,
Perkin Trans. 1, 1985, 2361; A. B. Holmes, A. Nadin, P. J. O’Hanlon
and N. D. Pearson, Tetrahedron: Asymmetry, 1992, 3, 1289;
Á. González, J. Aiguadé, F. Urpí and J. Vilarrasa, Tetrahedron Lett.,
1996, 37, 8949.
CHCH CH᎐CH ), 60.2 (CO CH Me), 117.1 (CH᎐CH ), 121.5
᎐
᎐
2
2
2
2
2
(CH᎐CHCO Et), 126.2 (Phpara), 128.3, 129.1 (Phmeta, Phortho),
᎐
2
135.5 (CH᎐CH ), 139.3 (Ph ), 151.5 (CH᎐CHCO Et), 166.5
᎐
᎐
2
ipso
2
(CO2Et); νmax (film) 1715 (C᎐O), 1654 (C᎐C); HRMS C H O
᎐
᎐
16 21
2
(MHϩ) requires 245.1542, found 245.1538; m/z (APCIϩ) 262.2
(100%, MNH3ϩ), 245.1 (100%, MHϩ).
12 D. A. Evans, G. Borg and K. A. Scheidt, Angew. Chem., Int. Ed.,
2002, 41, 3188.
13 J. Bach, S. D. Bull, S. G. Davies, R. L. Nicholson, H. J. Sanganee
and A. D. Smith, Tetrahedron Lett., 1999, 40, 6677; S. G. Davies,
R. L. Nicholson and A. D. Smith, Synlett, 2002, 1637.
14 S. D. Bull, S. G. Davies, S. Jones and H. J. Sanganee, J. Chem. Soc.,
Perkin Trans. 1, 1999, 387.
15 Commercially available from the Aldrich Chemical company.
16 D. J. Chadwick and R. I. Ngochindo, J. Chem. Soc., Perkin Trans. 1,
1984, 481.
17 S. D. Bull, S. G. Davies, S. Jones, M. E. C. Polywka, R. S. Prasad and
H. J. Sanganee, Synlett, 1998, 519.
18 Following the procedure by D. A. Evans and J. R. Gage, Org. Synth.,
1990, 68, 83.
19 C. Kashima, X. C. Huang, Y. Harada and A. Hosomi, J. Org.
Chem., 1993, 58, 793; T. Yura, N. Iwasawa, R. Clark and
T. Mukaiyama, Chem. Lett., 1986, 1809.
20 For other Weinreb amide equivalents see M. Sawamura,
Y. Nakayama, T. Kato and Y. Ito, J. Org. Chem., 1995, 60, 1727;
A. Abiko, O. Moriya, S. A. Filla and S. Masamune, Angew. Chem.,
Int. Ed. Engl., 1995, 34, 793; A. Abiko, J.-F. Liu, G. Wang and
S. Masamune, Tetrahedron Lett., 1997, 38, 3261.
Formation of (E )- and (Z )-ethyl 4-benzylhepta-2,6-dienoate 46
and 47 from 38
ZnCl2 (1.0 M in Et2O, 1.4 mL, 1.40 mmol) was added to a
stirred solution of 38 (200 mg, 0.70 mmol) in anhydrous THF
(10 mL) at Ϫ30 ЊC. After 30 minutes, DIBAL (1.0 M in THF,
1.4 mL, 1.40 mmol) was added. After an additional hour, the
phosphonate ylide {prepared from triethyl phosphonoacetate
(0.35 mL, 1.75 mmol) and n-BuLi (1.6 M, 1.1 mL, 1.75 mmol)
in THF (10 mL) at Ϫ78 ЊC for 30 minutes} was added and the
reaction mixture warmed to rt. After two hours H2O (20 mL)
and a saturated solution of Rochelles salt (20 mL) were added.
After stirring for 2 hours, the reaction mixture was extracted
with EtOAc, washed with brine, dried over MgSO4 and concen-
trated in vacuo. Purification by flash column chromatography
on silica (40 : 1 40–60 petrol–Et2O) gave (Z)-47 (9 mg, 4%) and
(E)-46 (162 mg, 78%).
21 Y. Arai, A. Suzuki, T. Masuda, Y. Masaki and M. Shiro,
Chem. Pharm. Bull., 1996, 44, 1765.
Acknowledgements
22 M. A. Blanchette, W. Choy, J. T. Davis, A. P. Essenfield,
S. Masamune, W. R. Roush and T. Sakai, Tetrahedron Lett., 1984,
25, 2183 . The addition of either LiCl, NaBr or NaI improves the
Z-olefination selectivity observed upon reaction of aldehydes with
ethyl (diphenylphosphono)acetate and DBU; see K. Ando, T. Oishi,
M. Hirama, H. Ohno and T. Ibuka, J. Org. Chem., 2000, 65,
4745.
The authors wish to thank Zeneca Pharmaceuticals (H. J. S.),
the Catalonian Government (J. B.) for financial support
and New College, Oxford for a Junior Research Fellowship
(A. D. S.).
23 S. Sano, K. Yokohama, M. Fukushima, T. Yagi and Y. Nagao,
Chem. Commun., 1997, 559.
24 T. Hintermann and D. Seebach, Helv. Chim. Acta, 1998, 81, 2093.
25 Identical to a commercially available sample.
26 J. T. Pinhey and M. J. Stoermer, J. Chem. Soc., Perkin Trans. 1, 1989,
2456.
27 E. Breuer and D. M. Bannet, Tetrahedron, 1978, 34, 997.
References and notes
1 For reviews of the use of chiral auxiliaries in synthesis see:
A. Studer, Synthesis, 1996, 793; D. J. Ager, I. Prakash and D. R.
Schaad, Aldrichimica Acta, 1997, 30, 1,3; D. J. Ager, I. Prakash and
D. R. Schaad, Chem. Rev., 1996, 96, 835.
2 W. Oppolzer, C. Darcel, P. Rochet, S. Rosset and J. De Brabander,
Helv. Chim. Acta, 1997, 80, 1319.
28 R. S. Marmor, J. Org. Chem., 1972, 37, 2901.
29 U. Widmer, Synthesis, 1983, 2, 135.
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 2 0 0 1 – 2 0 1 0
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