Diastereoselectivity in unusual intermolecular tandem Michael reactions

Article abstract of DOI:10.1016/j.tet.2011.12.046

Highly stereoselective consecutive or tandem Michael (MIMI) reactions are reported. A variety of initial nucleophiles react with chiral acylated 1,3-oxazolidin-2-ones to generate a reactive enolate. The enolate then reacts stereoselectively with a second

Full text of DOI:10.1016/j.tet.2011.12.046

Tetrahedron 68 (2012) 1979e1987
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Diastereoselectivity in unusual intermolecular tandem Michael reactions
,
a
b
Andrew B. Hughes a , Christopher M. Verdon , Jonathan M. White
*
a Department of Chemistry, La Trobe Institute of Molecular Sciences, La Trobe University, Kingsbury Drive, Melbourne, Victoria 3086, Australia
b Department of Chemistry, University of Melbourne, Parkville 3010, Australia
a r t i c l e i n f o
a b s t r a c t
Article history:
Highly stereoselective consecutive or tandem Michael (MIMI) reactions are reported. A variety of initial
nucleophiles react with chiral acylated 1,3-oxazolidin-2-ones to generate a reactive enolate. The enolate
then reacts stereoselectively with a second equivalent of the acylated 1,3-oxazolidin-2-one to afford
‘dimeric’ adducts. The adducts have three new contiguous stereogenic centers formed with a high level of
control. Single crystal X-ray crystallographic analysis confirmed this controlled formation of novel tan-
dem acyclic conjugate addition or MIMI products in several examples.
Received 16 September 2011
Received in revised form 29 November 2011
Accepted 19 December 2011
Available online 23 December 2011
Keywords:
Ó 2011 Elsevier Ltd. All rights reserved.
Tandem Michael reaction
Diastereoselective
Dimeric adducts
Tandem conjugate addition
X-ray diffraction
1. Introduction
Since their discovery by Komnenos in 1883,1 conjugate addition
reactions have found many and varied applications in organic
synthesis.2,3 In 1941, Kharash and Tawney showed that Grignard
reagents could undergo 1,4-conjugate addition reactions to
a,b-
unsaturated ketones in the presence of a copper(I) salt.4 Numerous
other combinations of nucleophile and metal salt have also resulted
in 1,4-conjugate addition to a,b-unsaturated carbonyl systems, and
now various ways of conducting these additions stereoselectively
Fig. 1. Michael mechanism for enolate formation and electrophile interception.
are also known.5e11 Investigations into the mechanism of asym-
metric 1,4-conjugate additions to a,b-unsaturated carbonyl systems
have been reported.12 The use of 2-oxazolidinone chiral auxiliaries
covalently bound to the Michael or conjugate acceptor has become
a mainstay among effective methods for achieving stereocontrolled
additions.13 A second generation of the 2-oxazolidinone chiral
auxiliary, the SuperQuat auxiliary, has emerged as a most effective
synthetic tool.14
Alternatively, the enolate could react with a Michael acceptor, such
as a second
a,b
-unsaturated carbonyl compound.15 The enolate
formed as a result of this second addition is generally quenched
during work-up. Examples of cascades that extend the enolate re-
action to oligomeric structures (or polymers) are rare. A ring-closing
Aldol reaction is one of the most prevalent ways in which this eno-
late can react and the overall process has become known as the
MichaeleMichael-Ring-Closure (MIMIRC). Although there are some
examples of the second Michael addition being intermolecular,15,16
most cases involve an initial intermolecular Michael addition fol-
lowed by an intramolecular ring-closing Michael addition.17
One natural product synthesis project in our laboratory required
a stereoselective addition of the cuprate 3 to a crotonoyl moiety
covalently bound to the chiral auxiliary 1 to give the adduct 4a. The
‘SuperQuat’ chiral auxiliary was selected for its ease of preparation,
coupling efficiency, and ease of removal as well as for its recycla-
bility and generation of high facial selectivity (Scheme 1).
It is commonly accepted that the product of 1,4-conjugate ad-
dition is an enolate e.g., 2. Most often, the enolate is quenched
during work-up affording a carbonyl compound alkylated in the
position. However, it is also possible for the enolate to perform
a nucleophilic attack through the -carbon (Fig. 1).
b-
a
Electrophiles, such as methyl iodide and methyl triflate are
commonly used in reaction with the first-formed enolate 2.
* Corresponding author. Tel.: þ613 94551630; e-mail address: andrew.hughes2@
optusnet.com.au (A.B. Hughes).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.12.046

1980
A.B. Hughes et al. / Tetrahedron 68 (2012) 1979e1987
2. Results and discussion
Organocuprates were added to 1 (Scheme 2) as described by
Bull et al.23 Through the program of reactions a number of dis-
coveries were made, the most significant of which was the
marked effect the cuprate loading had on the isolated yields of
the mono-addition adducts 4 and the TMA adduct (e.g., 5).
Through variation in the cuprate loading in the reaction depicted
in Scheme 2, where R¼2-propenyl, the following graph was
produced (Fig. 2).
Scheme 1.
The desired addition reaction quickly became a problem as only
low yields of the desired product 4a were obtained. However,
percentage conversion of the starting material 1 was high and just
one novel product was being formed. It was decided to elucidate
the structure of this unknown crystalline compound. The data
collected indicated the cuprate had added and that there were two
‘SuperQuat’ auxiliary units present in the structure. The molecular
weight of the novel product was indicative of the structure 5 and
that structure was subsequently confirmed by single crystal X-ray
crystallography.
Scheme 2.
The graph indicates that when there is 1 equiv or less of the 2-
propenyl cuprate present the formation of both 4a and 5 is negli-
gible. As the cuprate loading is increased, the formation of the TMA
adduct 5 increases to a maximum 60% conversion at 1.75 equiv of
cuprate. Cuprate loads above 1.75 equiv yielded an increase in the
formation of the Michael adduct 4a and a decrease in the TMA
adduct 5 to a point whereby at a cuprate load of about 5 equiv, no
TMA adduct 5 was produced.
This chart (Fig. 2) may be understood by the consideration of two
competing processes during conversion of 1. In the first process, the
cuprate 3 reacts with the substrate1 to form an intermediate enolate
2. In the other process, the enolate 2, generated by the first Michael
addition, reacts with substrate 1 forming the pseudo-dimeric or
TMA adducts 5e15 (Scheme 2). That is, the cuprate 3 and the enolate
2 compete for reaction with the substrate 1.
Three new asymmetric centers are formed in the construction
of this product 5, thus eight diastereoisomers could have been
produced. However, only one diastereomer was isolated and
characterized. The three new stereocenters formed in this re-
action are contiguous. Three other reports have been made on
a similar reaction, which can generate up to four contiguous
stereocenters.15,18,19
The formation of 5 was rationalized by the occurrence of a tan-
dem Michael addition (TMA), in a fashion similar to that depicted
above (Fig. 1). This process is known to occur in conjugate additions
and is often the cause of lower yields of mono-addition products in
such reactions.20 To the best of our knowledge, there has been no
literature report of an attempt to optimize this carbon-based in-
termolecular TMA, or to investigate the scope and utility of the
reaction. We now wish to report our attempts to improve this TMA
reaction.
Throughout the study, reaction conditions were varied for
maximum TMA yield and a range of TMA adducts were generated
by varying the cuprate, which initiated the reaction. Additions of
alkyl, vinyl, allyl, and aromatic cuprates were conducted. Previous
reports by Munch-Petersen,21 Miginiac and Daviaud,20 and Hruby
et al.22 have suggested mechanisms for TMA adduct formation.
Through the current study, stereochemical considerations have
been utilized in order to rationalize the mode of TMA adduct
formation.
For the 2-propenylcuprate derived from 2-propenyl magnesium
bromide, maximum conversion toTMA adduct 5 was achieved with
a loading of 1.75 equiv of cuprate. Cuprates from a range of other
Grignard reagents were also added to 1 and it was found the
maximum conversion was not achieved at consistent cuprate loads.
Table
2 shows the maximum conversion to TMA adducts
(majorþminor isomers) for various cuprates.
The variation in cuprate loadings required to produce maxi-
mum TMA adduct formation may be rationalized by consider-
ation of the reactivity of the cuprate. It was noted that the more
reactive cuprates were generally found to require lower loadings
than the less reactive cuprates. Since the cuprate and enolate 2

A.B. Hughes et al. / Tetrahedron 68 (2012) 1979e1987
1981
100
90
80
70
60
50
40
30
20
10
0
conversions of dimer
yields of mono adduct
0.5
1
1.5
1.75
2
equivalents of RMgX
3
5
10
20
Fig. 2. Effect of varying cuprate loading during conjugate addition reaction.
compete for reaction with the substrate 1, it is expected that the
more reactive cuprates compete more effectively for the sub-
strate and thus rapidly reduce the possibility of reaction with
the enolate, subsequently reducing conversion to the TMA
adduct.
Addition of 1.75 equiv of the 2-propenyl cuprate resulted in
formation of 5 as one of eight possible stereoisomers. The other
cuprates in Table 1 each formed two stereoisomers; the major
product being the TMA adducts 6e10, and the minor product being
compounds 11e15 (Table 2). This implies that the cuprate R group
has some influence on the formation of the TMA adduct.
Table 1
Maximum TMA adduct conversion for cuprates added to substrate 1
Cuprate
Equiv
% Conversion (to adduct)
2-Propenyl
Vinyl
Allyl
Isopropyl
Methyl
Phenyl
1.5
2.5
2.0
2.25
1.5
1.5
60
61
54
91
66
32
Table 3
Configurations of TMA adducts from X-ray crystallography
Cuprate
Configuration (C30,C29,C65)a
Major
Minor
2-Propenyl
Vinyl
Allyl
Isopropyl
Methyl
Phenyl
R,S,S (5)
S,S,S (6)
S,R,S (7)
S,S,S (8)
d,S,S (9)
d
d
d
d
d
Table 2
Conversion to major and minor TMA adducts by cuprates
d,S,R (14)
R,S,R (15)
Cuprate
% Conversion (adduct)
Major
a
Numbering of new stereocenters for comparison of different cuprate reactions;
Minor
see structure 16.
2-Propenyl
Vinyl
Allyl
Isopropyl
Methyl
Phenyl
60 (5)
37 (6)
48 (7)
87 (8)
43 (9)
30 (10)
d
The assignment of configurations of the three new stereocenters
in the TMA adducts can vary as priorities change leading to a degree
of confusion. Analysis of the stereogenic centers revealed that the
spatial arrangement in each of the major isomers was always the
same. A number of conclusions were drawn from the stereo-
chemical outcome;
24 (11)
6 (12)
4 (13)
23 (14)
2 (15)
ꢀ The R group does have an influence on TMA adduct formation
because the ratio of the major to minor isomer varies with
different cuprates.
ꢀ The TMA adducts form by a specific mechanism as seen
through the consistent spatial arrangement about the new
stereogenic centers in the TMA adducts.
Single crystal X-ray crystallographic data were collected for
compounds 5e9, 14, and 15. Through the crystallographic studies
the absolute configuration of each stereogenic center in the TMA
adducts was determined by relation to the known stereocenter of
the auxiliary (see structure 16 and Table 3). For the purpose of
comparison of the different cuprate reactions and TMA adducts,
a consistent numbering system has been employed for all TMA
adducts (16).
ꢀ Since it is the third center (C65) in the TMA adducts that has
variable configuration, it is most likely this asymmetric center,

1982
A.B. Hughes et al. / Tetrahedron 68 (2012) 1979e1987
that is, formed last. This means the cuprate adds to the sub-
strate then the resulting enolate reacts.
ꢀ The cuprate always approaches the Michael acceptor from the
less hindered side of the auxiliary. Thus center 1 (C30) was
always the same configuration in accord with literature models
and Experimental data.
ꢀ The ‘dimerisation’ occurs after initial cuprate addition because
center 2 (C29) is the same configuration in all isomers, major or
minor. This occurs because the second equivalent of substrate
(Michael acceptor) approaches the enolate from the same face
as the initial cuprate addition.
is presented in Fig. 4. In all the structures the five-membered
oxazolidinones adopt similar conformations with the phenyl sub-
stituent occupying a pseudoaxial orientation, in addition in those
‘dimeric’ structures (except 4a and 4e, which are ‘monomeric’) the
conformation of the substituted 5-carbon chain (C4 to C8) linking
the two substituted oxazolidinone rings, which is represented by
the dihedral angles; [N1eC4eC5eC6, 126.8(2); C4eC5eC6eC7,
e66.0(2); C5eC5eC7eC8, 161.4(2); C6eC7eC8eN2, 170.0(2)] is
essentially conserved in all structures.
ꢀ It is the spatial arrangement or relationship of the second Mi-
chael acceptor as it approaches the enolate that controls for-
mation of the third contiguous asymmetric center (C65).
ꢀ There is a 2:1 major/minor ratio of TMA adducts 9 and 14 using
the methyl cuprate. This means the auxiliaries are exerting
some control, independent of the cuprate R group, as in the
methyl cuprate reaction, a stereogenic center is not generated
in the first Michael addition and so there is no stereofacial bias
in the subsequent enolate addition coming from a new asym-
metric center.
2.1. Stereocontrol
When forming the TMA adducts, the enolate generated from the
initial cuprate addition reacts with a second equivalent of the
substrate (Fig. 1). Stereogenic centers C29 and C65 are created in
this step of the reaction. As C29 has the same configuration in each
of the TMA adducts (Table 3), the second equivalent of substrate
must approach the same face of the enolate 2 in each example. The
enolate face that the substrate approaches in this second step of the
reaction is the equivalent face of the substrate that the cuprate
approaches in the first step.
Fig. 4. Thermal ellipsoid plot for 5, ellipsoids are at the 20% probability level.
3. Conclusion
Stereogenic center C65 is the one stereocenter that varies
among the various TMA adducts. We suggest that it is the way the
second Michael acceptor is oriented in relation to the enolate 2 that
dictates the stereochemistry of the newly formed C65 center. This
rationale is depicted in Fig. 3 above.
Examples of highly diastereoselective intermolecular tandem
Michael addition reactions have been shown. These reactions are
a subset of more common MichaeleMichael-Ring Closing reactions,
however they do not include the ring closing element but rather
produce three new contiguous asymmetric centers in an acyclic
environment. The synthetic work described was rationalized and
supported by X-ray crystallographic studies.
4. Experimental section
4.1. General methods
Melting points (mp) were recorded on a hot stage apparatus
and are uncorrected. Optical rotations were measured at the stated
temperatures in the stated solvent using polarimeter at the sodium
D-line (589 nm); [a] g
values are given in 10ꢁ1 deg cm2 ꢁ1. Ele-
D
Fig. 3. Enolate 2 attack on second Michael acceptor 1.
mental analyses were performed by Chemical and Microanalytical
Services, Melbourne using a Carlo Erba NA1106 Elemental Analy-
ser. Infrared spectra (nmax) were recorded on a Fourier-Transform
spectrometer. Samples were analyzed as KBr disks (for solids) or
as thin films on NaCl plates (for liquids/oils). Unless otherwise
specified, proton (1H), and carbon (13C) NMR spectra were recor-
ded on a 300 MHz spectrometer operating at 300 MHz for proton
and 75 MHz for carbon nuclei. Chemical shifts were recorded as
From this depiction it might initially be concluded that ar-
rangement 17 would lead to formation of the minor stereoisomer as
the two auxiliaries are in a ‘stacked’ arrangement, which ought to
give significant steric interactions. However, it is arrangement 18,
which results in the formation of the minor stereoisomer. The model
proposed in this figure does not take into account anychelationwith
metals like copper ions, which are certainly available and, which
would alter the conformation and reactivity of the reaction partners.
d
values in parts per million (ppm). Spectra were acquired in
deuterated chloroform (CDCl3) at 20 ꢂC unless otherwise stated.
For 1H NMR spectra recorded in CDCl3, the peak due to residual
CHCl3 (dH 7.24) was used as the internal reference, while the
2.2. X-ray crystallography
central peak (dC 77.0) of the CDCl3 triplet was used as the reference
for proton-decoupled 13C NMR spectra. Low- and high-resolution
mass spectra (LSIMS) were measured at 70 eV using a mobile
phase consisting of water/methanol/acetic acid in a ratio of 0/99/1
The structures of 4a, 4e, 5e9, 14, and 15 were established by
single crystal X-ray analysis, of which a thermal ellipsoid plot for 5

A.B. Hughes et al. / Tetrahedron 68 (2012) 1979e1987
1983
or 50/50/1 in the positive mode unless otherwise indicated. Elec-
trospray ionization mass spectrometry (ESMS) were measured on
a triple quadrupole mass spectrometer using acetonitrile/water
mixtures as the mobile phase and 1% formic acid to form Mþ1 ions.
Solvents were dried over standard drying agents24 and freshly
distilled before use. Ethyl acetate and hexane used for chroma-
tography were distilled prior to use. All solvents were purified by
distillation. Reactions were monitored by TLC on silica gel 60 F254
plates with detection by UV fluorescence or charring with a basic
potassium permanganate or alcoholic molybdatophosphoric acid
stain. Flash column chromatography25 was performed on silica gel
possible. The solution instantly became homogeneous but
remained black in color. TLC analysis revealed that the starting
material had been consumed instantly. The reaction was quenched
with saturated aqueous ammonium chloride (5.00 mL) and 30%
ammonium hydroxide solution (5.00 mL). After stirring for 30 min
at room temperature the blue solution was diluted with brine and
the aqueous phase was extracted with ether. The combined ethereal
extracts were washed with brine then dried (MgSO4), filtered, and
concentrated to afford a white solid, which was either recrystallized
with ethyl acetate/hexane or subjected to column chromatography
eluting with 15% ethyl acetate/hexane to afford the title compound
60 particle size 0.040e0.063
m
m (230e400 mesh).
4b as a colorless solid (189 mg, 66% yield) mp 55e56 ꢂC; ½a D28
þ50.2
ꢃ
(c 1, CHCl3); Rf 0.51 (25% EtOAc/hexane); nmax (KBr) 2982, 1778,
4.2. Synthesis
;
1706, 1458, 1368, 1326, 1220 cmꢁ1 1H NMR (300 MHz, CDCl3)
d
7.32e7.24 (3H, m), 7.11e7.09 (2H, m), 5.81e5.70 (1H, m), 5.04 (1H,
4.2.1. (S)-3-((R)-3,4-Dimethylpent-4-enoyl)-5,5-dimethyl-4-phenylo-
xazolidin-2-one (4a). A dry two-necked round-bottomed flask fit-
ted with a reflux condenser and a magnetic stirrer bar was charged
with magnesium turnings (146 mg, 6.00 mmol) and an argon at-
mosphere. Dry THF (5.00 mL) was added followed by 2-
bromopropene (1.25 mL, 14.0 mmol) via syringe and the mixture
s), 4.97e4.86 (2H, m), 3.06 (1H, dd, J 6.8, 15.6 Hz), 2.88 (1H, dd, J 6.8,
15.6 Hz), 2.71 (1H, sextet, J 6.8 Hz), 1.55 (3H, s), 1.00 (3H, d, J 6.8 Hz),
d 171.6, 153.0, 142.4, 136.2,
128.6,128.4,126.2,113.2, 82.1, 66.9, 41.9, 33.8, 28.8, 23.5,19.6; HRMS
0.95 (3H, s); 13C NMR (75 MHz, CDCl3);
(LSIMS): calcd for C17H22NO3 288.1600 (MþH), found 288.1604.
was heated to reflux. 2-Bromopropene portions (100
m
L) were then
4.2.3. (S)-5,5-Dimethyl-3-((S)-3-methylhex-5-enoyl)-4-phenyloxazo-
lidin-2-one (4c). A dry two-necked round-bottomed flask was filled
with an argon atmosphere. A magnetic stirrer bar was added to the
flask followed by allylmagnesium bromide (3.47 mL of a 1 M solu-
tion in diethyl ether). The Grignard was diluted with dry THF
(1.03 mL) and dry Me2S (1.83 mL, 25.0 mmol) then cooled to
ꢁ40 ꢂC, which caused some precipitation. CuBr$Me2S complex
(358 mg, 1.74 mmol) was added under a flow of argon and the
heterogeneous solution became dark green/black. After 10 min at
ꢁ40 ꢂC the monocuprate was allowed to warm to ꢁ15 ꢂC and
oxazolidinone 1 (150 mg, 0.58 mmol) in dry THF (1.00 mL) was
added as rapidly as possible. The solution instantly became ho-
mogeneous but remained black in color. TLC analysis revealed that
the starting material had been consumed instantly. The reaction
was quenched with saturated aqueous ammonium chloride
(2.50 mL) and 30% ammonium hydroxide solution (2.50 mL). After
stirring for 30 min at room temperature the blue solution was di-
luted with brine and the aqueous phase was extracted with ether.
The combined ethereal extracts were washed with brine then dried
(MgSO4), filtered, and concentrated to afford a white solid, which
was either recrystallized with ethyl acetate/hexane or subjected to
column chromatography eluting with 15% ethyl acetate/hexane to
afford the title compound 4c as a colorless solid (27.0 mg, 15% yield)
mp 94 ꢂC; Rf 0.58 (25% EtOAc/hexane); nmax (KBr): 2977, 1782, 1701,
added every hour until no magnesium remained and the flask was
then heated at reflux for a further 1 h. The resulting THF solution of
isopropenylmagnesium bromide was diluted with dry Me2S
(5.00 mL, 68.2 mmol) and then cooled to ꢁ40 ꢂC, which caused
some of the Grignard reagent to precipitate. The reflux condenser
was replaced with a stopper and CuBr$Me2S complex (620 mg,
3.00 mmol) was added to the cooled Grignard reagent under a flow
of argon gas. The heterogeneous solution became red. After 10 min
at ꢁ40 ꢂC the monocuprate was allowed to warm to ꢁ15 ꢂC and
a solution of the oxazolidinone 1 (310 mg, 1.20 mmol) in dry THF
(10.0 mL) was added as rapidly as possible. The reaction mixture
instantly became homogeneous but remained orange in color. TLC
analysis revealed that the starting material had been consumed.
The reaction was quenched with saturated aqueous ammonium
chloride (15.0 mL) and 30% ammonium hydroxide solution
(15.0 mL). After stirring for 2 h at room temperature the blue so-
lution was diluted with brine and the aqueous phase was extracted
with ether. The combined ethereal extracts were washed with brine
then dried (MgSO4), filtered, and concentrated to afford a white
solid, which was either recrystallized with ethyl acetate/hexane or
subjected to column chromatography eluting with 15% ethyl ace-
tate/hexane to afford the title compound 4a as a colorless solid
(307 mg, 85%) mp 114e115 ꢂC; ½a D29:5
þ64.2 (c 1, CHCl3); Rf 0.57 (25%
ꢃ
EtOAc/hexane), 0.48 (20% EtOAc/hexane); nmax (KBr): 3069, 3034,
1389, 1326, 1268, 1220 cmꢁ1
;
1H NMR (300 MHz, CDCl3):
2971, 2937, 1777, 1704, 1458, 1368, 1334, 1224 cmꢁ1
;
1H NMR
d 7.38e7.30 (3H, m), 7.13e7.10 (2H, m), 5.79e5.66 (1H, m), 5.06 (1H,
(300 MHz, CDCl3): 7.36e7.26 (3H, m), 7.12e7.09 (2H, m), 5.04 (1H,
d
s), 4.97 (2H, apparent dd, J 1.8, 13.7 Hz), 3.01 (1H, dd, J 5.4, 16.1 Hz),
2.75 (1H, dd, J 7.9, 16.1 Hz), 2.18e1.92 (3H, m), 1.58 (3H, s), 0.97 (3H,
s), 4.67 (2H, apparent d, J 7.6 Hz), 3.11 (1H, dd, J 7.0, 15.6 Hz), 2.95
(1H, dd, J 7.0, 15.6 Hz), 2.71 (1H, sextet, J 7.0 Hz), 1.68 (3H, s), 1.57
(3H, s), 1.02 (3H, d, J 7.0 Hz), 0.96 (3H, s); 13C NMR (75 MHz, CDCl3):
s), 0.90 (3H, d, J 6.5 Hz); 13C NMR (75 MHz, CDCl3);
d 172.4, 153.2,
136.4(2), 128.8, 128.6, 126.3, 116.5, 82.2, 67.0, 41.9, 41.0, 29.4, 29.0,
23.7, 19.4; HRMS (LSIMS): calcd for C18H24NO3 302.1756 (MþH),
found 302.1755.
d
171.9, 153.1, 148.7, 136.3, 128.7, 128.5, 126.3, 109.6, 82.2, 67.0, 40.7,
37.1, 28.9, 23.6, 19.3, 15.7; HRMS (LSIMS): calcd for C18H24NO3
302.1756 (MþH), found 302.1757.
4.2.4. (S)-3-((R)-3,4-Dimethylpentanoyl)-5,5-dimethyl-4-phenyloxa-
zolidin-2-one (4d). A dry two-necked round-bottomed flask was
filled with an argon atmosphere. A magnetic stirrer bar was added
to the flask followed by isopropylmagnesium bromide (2.00 mL, as
a 1 M solution in THF). The Grignard was diluted with dry THF
(2.00 mL) and dry Me2S (1.5 mL, 20.5 mmol) then cooled to ꢁ40 ꢂC,
which caused some precipitation. CuBr$Me2S complex (206 mg,
1.00 mmol) was added under a flow of argon and the heteroge-
neous solution became satin-blue. After 10 min at ꢁ40 ꢂC the
monocuprate was allowed to warm to ꢁ15 ꢂC and oxazolidinone 1
(259 mg, 1.00 mmol) in dry THF (1.50 mL) was added as rapidly as
possible. The solution instantly became homogeneous and turned
4.2.2. (S)-5,5-Dimethyl-3-((R)-3-methylpent-4-enoyl)-4-phenyloxaz-
olidin-2-one (4b). A dry two-necked round-bottomed flask was
filled with an argon atmosphere. A magnetic stirrer bar was added
to the flask followed by vinylmagnesium bromide (3.50 mL, of a 1 M
solution in THF). The Grignard was diluted with dry THF (1.50 mL)
and dry Me2S (1.50 mL, 20.5 mmol) then cooled to ꢁ40 ꢂC, which
caused some precipitation. CuBr$Me2S complex (180 mg,
0.88 mmol) was added under a flow of argon and the heteroge-
neous solution became dark green/black. After 10 min at ꢁ40 ꢂC the
monocuprate was allowed to warm to ꢁ15 ꢂC and oxazolidinone 1
(259 mg, 1.00 mmol) in dry THF (1.50 mL) was added as rapidly as

1984
A.B. Hughes et al. / Tetrahedron 68 (2012) 1979e1987
black in color. TLC analysis revealed that the starting material had
been consumed. The reaction was quenched with saturated aque-
ous ammonium chloride (5.00 mL) and 30% ammonium hydroxide
solution (5.00 mL). After stirring for 30 min at room temperature
the blue solution was diluted with brine and the aqueous phase was
extracted with ether. The combined ethereal extracts were washed
with brine then dried (MgSO4), filtered, and concentrated at re-
duced pressure to afford a white solid, which was either recrys-
tallized with ethyl acetate/hexane or subjected to column
chromatography eluting with 15% ethyl acetate/hexane to afford
the title compound 4d (156 mg, 51% yield) as a colorless solid: mp
ammonium chloride (5.00 mL) and 30% ammonium hydroxide so-
lution (5.00 mL). After stirring for 30 min at room temperature the
blue solution was diluted with brine and the aqueous phase was
extracted with ether. The combined ethereal extracts were washed
with brine then dried (MgSO4), filtered, and concentrated to afford
a white solid, which was either recrystallized with ethyl acetate/
hexane or subjected to column chromatography eluting with 15%
ethyl acetate/hexane to afford the title compound 4f (255 mg, 76%
yield) as a colorless solid mp 119e120 ꢂC; ½a D28:5
þ23.9 (c 1, CHCl3);
ꢃ
Rf 0.60 (25% EtOAc/hexane); nmax (KBr) 2980, 2938, 1778, 1698,
1372, 1332, 1268, 1223, 1168 cmꢁ1
;
1H NMR (300 MHz, CDCl3)
83e84 ꢂC; ½a 2D9
ꢃ
þ49.9 (c 1, CHCl3). Rf 0.64 (25% EtOAc/hexane) nmax
d 7.30e7.17 (8H, m), 6.96e6.95 (2H, m), 5.06 (1H, s), 3.55 (1H, dd, J
7.0, 15.5 Hz), 3.38 (1H, sextet, J 7.0 Hz), 3.14 (1H, dd, J 7.0, 15.5 Hz),
1.56 (3H, s), 1.29 (3H, d, J 7.0 Hz), 0.94 (3H, s); 13C NMR (75 MHz,
(KBr): 2972, 2873, 1777, 1703, 1467, 1379, 1327, 1270, 1218 cmꢁ1; 1H
NMR (300 MHz, CDCl3) d 7.37e7.24 (3H, m), 7.13e7.10 (2H, m), 5.06
(1H, s), 3.00 (1H, dd, J 4.7, 15.6 Hz), 2.73 (1H, dd, J 9.3, 15.6 Hz),
2.01e1.88 (1H, m), 1.63e1.52 (4H, m), 0.97 (3H, s), 0.84e0.76 (9H,
CDCl3) d 171.5, 152.9, 145.4, 135.9, 128.5, 128.3, 128.1, 126.8, 126.1,
125.9, 81.9, 66.7, 43.0, 35.9, 28.7, 23.5, 21.7; HRMS (LSIMS): calcd for
C21H24NO3 338.1756 (MþH), found 338.1753.
m); 13C NMR (75 MHz, CDCl3):
d
173.0, 153.1, 136.5, 128.8, 128.5,
126.3, 82.1, 67.0, 40.1, 35.1, 32.2, 29.0, 23.6, 19.9, 18.2, 15.4; HRMS:
calcd for C18H26NO3 304.1913 (MþH), found 304.1915.
4.2.7. 1,5-Bis((S)-5,5-dimethyl-2-oxo-4-phenyloxazolidin-3-yl)-3-
methyl-2-((R)-3-methylbut-3-en-2-yl)pentane-1,5-dione (5). A dry
two-necked round-bottomed flask fitted with a reflux condenser
and a magnetic stirrer bar was charged with magnesium turnings
(42.9 mg, 1.75 mmol) and an argon atmosphere. Dry THF (3.50 mL)
4.2.5. (S)-5,5-Dimethyl-3-(3-methylbutanoyl)-4-phenyloxazolidin-2-
one (4e). A dry two-necked round-bottomed flask was filled with
an argon atmosphere. A magnetic stirrer bar was added to the flask
followed by methylmagnesium bromide (2.00 mL of a 3 M solution
in Et2O). The Grignard was diluted with dry THF (1.50 mL) and dry
Me2S (1.50 mL, 20.5 mmol) then it was cooled to ꢁ40 ꢂC. No pre-
cipitation of the Grignard was observed. CuBr$Me2S complex
(206 mg, 1.00 mmol) was added under a flow of argon and the
heterogeneous solution became yellow. After 10 min at ꢁ40 ꢂC the
monocuprate was allowed to warm to ꢁ15 ꢂC and oxazolidinone 1
(259 mg, 1.00 mmol) in dry THF (1.00 mL) was added dropwise. The
solution became homogeneous and pale yellow in color. TLC anal-
ysis revealed that the starting material had been consumed. The
reaction was quenched with saturated aqueous ammonium chlo-
ride (7.50 mL) and 30% ammonium hydroxide solution (7.50 mL).
After stirring for 30 min at room temperature the blue solution was
diluted with brine and the aqueous phase was extracted with ether.
The combined ethereal extracts were washed with brine then dried
(MgSO4), filtered, and concentrated in vacuo to afford a white solid,
which was either recrystallized with ethyl acetate/hexane or sub-
jected to column chromatography eluting with 15% ethyl acetate/
hexane to afford the title compound 4e (212 mg, 77% yield) as
was added followed by 2-bromopropene (156
syringe and the mixture was heated to reflux. 2-Bromopropene
portions (100 L) were then added every hour until no magne-
mL, 1.75 mmol) via
m
sium remained and the flask was then heated at reflux for a further
1 h. The resulting THF solution of 2-propenylmagnesium bromide
was diluted with dry Me2S (1.00 mL, 13.6 mmol) and then cooled to
ꢁ40 ꢂC, which caused some of the Grignard reagent to precipitate.
The reflux condenser was replaced with a stopper and CuBr$Me2S
complex (104 mg, 0.88 mmol) was added to the cooled Grignard
reagent under a flow of argon gas. The heterogeneous solution
became red. After 10 min at ꢁ40 ꢂC the monocuprate was allowed
to warm to ꢁ15 ꢂC and a solution of the oxazolidinone 1 (150 mg,
0.60 mmol) in dry THF (1.00 mL) was added as rapidly as possible.
The solution instantly became homogeneous but remained orange
in color. TLC analysis revealed that the starting material had been
consumed. The reaction was quenched with saturated aqueous
ammonium chloride (3.00 mL) and 30% ammonium hydroxide so-
lution (3.00 mL). After stirring for 30 min at room temperature the
blue solution was diluted with brine and the aqueous phase was
extracted with ether. The combined ethereal extracts were washed
with brine then dried (MgSO4), filtered, and concentrated to afford
a white solid, which was either recrystallized with ethyl acetate/
hexane or subjected to column chromatography eluting with 15%
ethyl acetate/hexane to afford the title compound 5 as a colorless
a colorless solid mp 62e64 ꢂC; ½a D26
þ45.1 (c 1, CHCl3). Rf 0.55 (25%
ꢃ
EtOAc/hexane); nmax (KBr) 2959, 2872, 1780, 1704, 1458, 1391, 1368,
1267, 1223 cmꢁ1 1H NMR (300 MHz, CDCl3)
; d 7.37e7.27 (3H, m),
7.13e7.10 (2H, m), 5.05 (1H, s), 2.91 (1H, dd, J 6.6, 15.8 Hz), 2.78 (1H,
dd, J 7.3, 15.8 Hz), 2.20e2.09 (1H, m), 1.57 (3H, s), 0.96 (3H, s), 0.92
(3H, d, J 4.4 Hz), 0.90 (3H, d, J 4.4 Hz); 13C NMR (75 MHz, CDCl3);
solid (97.0 mg, 60% conversion). Mp 63e65 ꢂC; ½a D31
þ83.2 (c 1,
ꢃ
d
172.1, 152.8, 136.1, 128.5, 128.2, 125.9, 81.8, 66.6, 43.7, 28.6, 24.8,
CHCl3); Rf 0.26 (25% EtOAc/hexane), 0.20 (20% EtOAc/hexane); nmax
23.3, 22.2, 21.9; HRMS (LSIMS): calcd for C16H22NO3 276.1600
(KBr) 3035, 2972, 2938, 1774, 1703, 1458, 1392, 1369, 1326 cmꢁ1; 1H
(MþH), found 276.1593.
NMR (300 MHz, CDCl3) d 7.34e7.03 (10H, m), 5.01 (1H, s), 4.94 (1H,
s, 1H), 4.74 (2H, apparent d, J 3.7 Hz), 4.32 (1H, apparent t, J 6.7 Hz),
2.93e2.90 (2H, m), 2.58 (1H, quintet, J 6.7 Hz), 2.31 (1H, septet, J
6.7 Hz), 1.72 (3H, s), 1.51 (3H, s), 1.47 (3H, s), 1.02 (3H, d, J 6.7 Hz),
0.93 (3H, s), 0.90 (3H, s), 0.83 (3H, d, J 6.7 Hz); 13C NMR (75 MHz,
4.2.6. (4S)-5,5-Dimethyl-4-phenyl-3-(3-phenylbutanoyl)oxazolidin-
2-one (4f). A dry two-necked round-bottomed flask was filled with
an argon atmosphere. A magnetic stirrer bar was added to the flask
followed by phenylmagnesium bromide (2.00 mL of a 1 M solution
in THF). The Grignard was diluted with dry THF (1.00 mL) and dry
Me2S (1.50 mL, 20.5 mmol) and then it was cooled to ꢁ40 ꢂC, which
caused some precipitation. CuBr$Me2S complex (206 mg,
1.00 mmol) was added under a flow of argon and the heteroge-
neous solution became mustard-yellow. After 10 min at ꢁ40 ꢂC the
monocuprate was allowed to warm to ꢁ15 ꢂC and oxazolidinone 1
(259 mg, 1.00 mmol) in dry THF (1.00 mL) was added dropwise. The
solution instantly became homogeneous and turned bright orange
in color. TLC analysis revealed that the starting material had been
consumed. The reaction was quenched with saturated aqueous
CDCl3)
d 174.4, 172.0, 153.1, 152.7, 147.6, 136.5, 136.3, 128.7, 128.6,
128.28, 128.26, 126.4, 126.1, 111.5, 81.9, 81.6, 67.0, 66.7, 48.3, 41.0,
38.6, 29.5, 28.7, 28.5, 23.5, 23.1, 19.8, 17.8, 15.9. HRMS (LSIMS): calcd
for C33H41N2O6 561.2965 (MþH), found 561.2965.
4.2.8. 2-((S)-But-3-en-2-yl)-1,5-bis((S)-5,5-dimethyl-2-oxo-4-
phenyloxazolidin-3-yl)-3-methylpentane-1,5-dione (6) and (11).
A dry two-necked round-bottomed flask was filled with an argon
atmosphere. A magnetic stirrer bar was added to the flask fol-
lowed by vinylmagnesium bromide (2.50 mL, 1 M solution in
THF). The Grignard was diluted with dry THF (1.00 mL) and dry

A.B. Hughes et al. / Tetrahedron 68 (2012) 1979e1987
1985
Me2S (1.50 mL, 20.5 mmol) then cooled to ꢁ40 ꢂC, which caused
some precipitation. CuBr$Me2S complex (257 mg, 1.25 mmol)
was added under a flow of argon and the heterogeneous solution
became dark green/black. After 10 min at ꢁ40 ꢂC the mono-
cuprate was allowed to warm to ꢁ15 ꢂC and oxazolidinone 1
(259 mg, 1.00 mmol) in dry THF (1.00 mL) was added as rapidly
as possible. The solution instantly became homogeneous but
remained black in color. TLC analysis revealed that the starting
material had been consumed. The reaction was quenched with
saturated aqueous ammonium chloride (5.00 mL) and 30% am-
monium hydroxide solution (5.00 mL). After stirring for 30 min
at room temperature the blue solution was diluted with brine
and the aqueous phase was extracted with ether. The combined
ethereal extracts were washed with brine then dried (MgSO4),
filtered, and concentrated to afford a white solid. The solid was
a mixture of two diastereoisomers, which were separated by
column chromatography. Elution with 15% ethyl acetate/hexane
afforded 6 (100 mg, 37% conversion) and 11 (67.0 mg, 24% con-
(KBr) 2973, 1770, 1711, 1697, 1390, 1373, 1334, 1269, 1224 cmꢁ1; 1H
NMR (300 MHz, CDCl3) 7.36e7.05 (10H, m), 5.82e5.68 (1H, m),
d
5.06 (1H, s), 5.03e4.99 (2H, m), 4.94 (1H, s), 4.12 (1H, apparent t, J
7.8 Hz), 2.99 (1H, dd, J 10.7, 17.9 Hz), 2.75 (1H, dd, J 2.2, 17.9 Hz),
2.54e2.41 (1H, m), 2.37e2.26 (1H, m), 2.05e1.90 (1H, m), 1.90e1.75
(1H, m), 1.55 (3H, s), 1.50 (3H, s), 0.97 (3H, s), 0.94 (3H, s), 0.91 (3H,
d, J 6.6 Hz), 0.83 (3H, d, J 6.6 Hz); 13C NMR (75 MHz, CDCl3)
d 174.9,
171.8, 153.1, 152.8, 136.5, 136.3, 136.2, 128.8, 128.7(2), 128.4, 126.6,
126.1, 116.5, 82.0, 81.6, 67.3, 66.9, 50.1, 39.3, 38.6, 33.2, 29.5, 28.9,
23.6, 23.2, 17.7, 15.0; HRMS (LSIMS): calcd for C33H41N2O6 561.2965
(MþH), found 561.2965. Compound 12 mp 62e65 ꢂC; Rf 0.37 (25%
EtOAc/hexane); nmax (KBr) 2976, 1775, 1700, 1458, 1326, 1161,
1102 cmꢁ1
; d 7.40e7.11 (10H, m),
1H NMR (300 MHz, CDCl3)
5.80e5.66 (1H, m), 5.04e4.97 (4H, m), 4.05 (1H, dd, J 6.5, 8.2 Hz),
3.21 (1H, dd, J 3.2, 16.9 Hz), 2.76 (1H, dd, J 10.1, 16.9 Hz), 2.62e2.53
(1H, m), 2.34e2.23 (1H, m), 2.04e1.90 (1H, m), 1.89e1.76 (1H, m),
1.57e1.55 (6H, m), 0.98e0.97 (6H, m), 0.88 (3H, d, J 6.6 Hz), 0.80
(3H, d, J 6.6 Hz); 13C NMR (75 MHz, CDCl3)
d 174.7, 171.7, 153.3,
version) both as colorless solids. Compound 6 mp 169 ꢂC; ½a D29
ꢃ
153.0, 136.5, 136.3, 136.1,128.94, 128.86(2), 128.6, 128.5, 126.4, 116.7,
82.3, 81.8, 67.7, 67.2, 50.1, 40.4, 38.2, 33.4, 29.4, 29.0, 23.7, 23.4, 16.2,
15.6; HRMS (LSIMS): calcd for C33H41N2O6 561.2965 (MþH), found
561.2965.
þ33.2 (c 1, CHCl3); Rf 0.24 (25% EtOAc/hexane); nmax (KBr) 2977,
1774, 1701, 1458, 1392, 1325, 1268 cmꢁ1
;
1H NMR (300 MHz,
CDCl3) 7.36e7.04 (10H, m), 5.92e5.81 (1H, m), 5.07e5.00 (3H,
d
m), 4.94, (1H, s), 4.19 (1H, apparent t, J 7.5 Hz), 2.95 (1H, dd, J
10.6, 18.1 Hz), 2.76 (1H, dd, J 2.1, 18.1 Hz), 2.65 (1H, quintet, J
7.5 Hz), 2.49e2.35 (1H, m), 1.53 (3H, s), 1.49 (3H, s), 1.01 (3H, d, J
7.5 Hz), 0.95 (3H, s), 0.94 (3H, s), 0.84 (3H, d, J 6.7 Hz); 13C NMR
4.2.10. 1,5-Bis((S)-5,5-dimethyl-2-oxo-4-phenyloxazolidin-3-yl)-3-
methyl-2-((S)-3-methylbutan-2-yl)pentane-1,5-dione (8) and (13). A
dry two-necked round-bottomed flask was filled with an argon
atmosphere. A magnetic stirrer bar was added to the flask followed
by isopropylmagnesium bromide (2.25 mL of a 1 M solution in
THF). The Grignard was diluted with dry THF (1.25 mL) and dry
Me2S (1.50 mL, 20.5 mmol) it was then cooled to ꢁ40 ꢂC, which
caused some precipitation. CuBr$Me2S complex (231 mg,
1.12 mmol) was added under a flow of argon and the heterogeneous
solution became satin-blue. After 10 min at ꢁ40 ꢂC the mono-
cuprate was allowed to warm to ꢁ15 ꢂC and oxazolidinone 1
(259 mg, 1.00 mmol) in dry THF (1.00 mL) was added as rapidly as
possible. The solution instantly became homogeneous and turned
black in color. TLC analysis revealed that the starting material had
been consumed. The reaction was quenched with saturated aque-
ous ammonium chloride (5.00 mL) and 30% ammonium hydroxide
solution (5.00 mL). After stirring for 30 min at room temperature
the blue solution was diluted with brine and the aqueous phase was
extracted with ether. The combined ethereal extracts were washed
with brine then dried (MgSO4), filtered, and concentrated in vacuo
to afford a white solid. The solid was a mixture of two di-
astereoisomers, which were separated by column chromatography.
Elution with 15% ethyl acetate/hexane afforded 8 (245 mg, 87%
conversion) and 13 (12.0 mg, 4% conversion) both as colorless
(75 MHz, CDCl3)
d 174.4, 172.0, 153.1, 152.8, 141.3, 136.5, 136.4,
128.8, 128.7(2), 128.4, 126.5, 126.2, 114.6, 82.0, 81.8, 67.2, 66.9,
50.5, 39.5, 37.4, 29.8, 28.9, 28.8, 23.6, 23.3, 17.4, 15.1; HRMS
(LSIMS): calcd for C32H39N2O6 547.2808 (MþH), found 547.2808.
Compound 11 mp 128 ꢂC; ½a D23
þ50.9 (c 0.79, CHCl3); Rf 0.30 (25%
ꢃ
EtOAc/hexane); nmax (KBr) 2973, 1777, 1714, 1697, 1457, 1333,
1161, 1103, 733 cmꢁ1 1H NMR (CDCl3)
; d 7.38e7.11 (10H, m),
5.76e5.64 (1H, m), 5.07e4.96 (4H, m), 4.09 (1H, dd, J 5.7, 9.2 Hz),
3.24 (1H, dd, J 3.6, 17.1 Hz), 2.77 (1H, dd, J 10.0, 17.1 Hz),
2.64e2.47 (2H, m), 1.56 (3H, s), 1.54 (3H, s), 0.98e0.96 (9H, m),
0.75 (3H, d, J 6.7 Hz); 13C NMR (75 MHz, CDCl3)
d 174.0, 171.6,
153.3, 153.0, 141.2, 136.4, 136.3, 128.9, 128.8(2), 128.52, 128.47,
126.4, 115.1, 82.3, 81.8, 67.5, 67.1, 50.3, 40.4, 38.7, 30.1, 29.0(2),
23.7, 23.4, 17.6, 15.4; HRMS (LSIMS): calcd for C32H39N2O6
547.2808 (MþH), found 547.2793.
4.2.9. 1,5-Bis((S)-5,5-dimethyl-2-oxo-4-phenyloxazolidin-3-yl)-3-
methyl-2-((S)-pent-4-en-2-yl)pentane-1,5-dione (7) and (12). A dry
two-necked round-bottomed flask was filled with an argon atmo-
sphere. A magnetic stirrer bar was added to the flask followed by
allylmagnesium bromide (2.00 mL, of a 1 M solution in Et2O). The
Grignard was diluted with dry THF (1.00 mL) and dry Me2S
(1.50 mL, 20.5 mmol) then cooled to ꢁ40 ꢂC, which caused some
precipitation. CuBr$Me2S complex (206 mg, 1.00 mmol) was added
under a flow of argon. The thick brown cuprate, which was allowed
to form over the next 10 min was not soluble until the temperature
was allowed to reach ꢁ15 ꢂC. At this point the oxazolidinone 1
(259 mg, 1.00 mmol) in dry THF (1.50 mL) was added as rapidly as
possible. TLC analysis revealed that the starting material had been
consumed. The reaction was quenched with saturated aqueous
ammonium chloride (5.00 mL) and 30% ammonium hydroxide so-
lution (5.00 mL). After stirring for 30 min at room temperature, the
blue solution was diluted with brine and the aqueous phase was
extracted with ether. The combined ethereal extracts were washed
with brine then dried (MgSO4), filtered, and concentrated to afford
a white solid. The solid was a mixture of two diastereoisomers,
which were separated by column chromatography. Elution with
15% ethyl acetate/hexane afforded 7 (135 mg, 48% conversion) and
12 (16.0 mg, 6% conversion), both as colorless solids. Compound 7
solids. Compound 8 mp 166e167 ꢂC. ½a D28
þ60.1 (c 2, CHCl3). Rf 0.34
ꢃ
(25% EtOAc/hexane); nmax (KBr) 2964, 2927, 1774, 1701, 1391, 1368,
1324,1268,1224 cmꢁ1; 1H NMR (300 MHz, CDCl3)
d 7.35e7.04 (10H,
m), 5.04 (1H, s), 5.00 (1H, s), 4.20 (1H, apparent t, J 6.7 Hz),
2.98e2.90 (2H, m), 2.51e2.42 (1H, m), 1.82e1.73 (2H, m), 1.53 (3H,
s), 1.51 (3H, s), 0.95e0.88 (9H, m), 0.81e0.78 (9H, m); 13C NMR
(75 MHz, CDCl3)
d 175.5, 172.5, 153.2, 152.8, 136.5, 136.3, 128.7,
128.6, 128.4, 128.3, 126.6, 126.1, 81.9, 81.6, 67.2, 66.9, 48.5, 38.7, 38.1,
29.3, 28.8(2), 28.7, 28.1, 23.6, 23.1, 21.5, 18.0, 16.2, 11.0; HRMS
(LSIMS): calcd for C33H43N2O6 563.3121 (MþH), found 563.3113.
Compound 13 nmax (KBr) 2961, 2924, 1775, 1701, 1326, 1268, 1224,
1162, 1100 cmꢁ1 1H NMR (300 MHz, CDCl3)
; d 7.44e7.22 (8H, m),
7.18e7.11 (2H, m), 5.02 (1H, s), 5.01 (1H, s), 4.12 (1H, dd, J 4.9,
9.4 Hz), 3.21 (1H, dd, J 3.1, 17.0 Hz), 2.70 (1H, dd, J 10.3, 17.0 Hz),
2.61e2.49 (1H, m), 1.89e1.76 (2H, m), 1.61e1.48 (6H, m), 1.00e0.96
(6H, m), 0.89 (3H, d, J 6.5 Hz), 0.83 (3H, d, J 6.7 Hz), 0.80e0.72 (6H,
m); 13C NMR (75 MHz, CDCl3) (rotamers)
d 175.4, 175.1, 171.9, 171.7,
153.4, 152.9, 136.5, 136.3, 129.0, 128.9, 128.5, 128.4, 126.7, 126.4,
82.2(2), 81.9, 81.8, 67.8(2), 67.3, 67.2, 48.9, 48.3, 40.8, 39.3, 38.7,
mp 186 ꢂC; ½a 2D8
þ55.8 (c 1, CHCl3). Rf 0.33 (25% EtOAc/hexane); nmax
ꢃ

1986
A.B. Hughes et al. / Tetrahedron 68 (2012) 1979e1987
30.2, 29.0(2), 28.8, 27.3, 23.8, 23.7, 23.5, 23.4, 22.1, 21.6, 15.6, 15.5,
14.7, 13.9, 11.3, 10.0. HRMS (LSIMS): calcd for C33H43N2O6 563.3121
(MþH), found 563.3119.
saturated aqueous ammonium chloride (5.00 mL) and 30% am-
monium hydroxide solution (5.00 mL). After stirring for 30 min at
room temperature the blue solution was diluted with brine and the
aqueous phase was extracted with ether. The combined ethereal
extracts were washed with brine then dried (MgSO4), filtered, and
concentrated to afford a white solid. The solid was a mixture of two
diastereoisomers, which were separated by column chromatogra-
phy. Elution with 15% ethyl acetate/hexane afforded 10 (88.0 mg,
30% conversion) and 15 (5.00 mg, 2% conversion) both as colorless
4.2.11. 1,5-Bis((S)-5,5-dimethyl-2-oxo-4-phenyloxazolidin-3-yl)-2-
isopropyl-3-methylpentane-1,5-dione (9) and (14). A dry two-
necked round-bottomed flask was filled with an argon atmo-
sphere. A magnetic stirrer bar was added to the flask followed by
methylmagnesium bromide (0.50 mL of a 3 M solution in Et2O). The
Grignard was diluted with dry THF (3.00 mL) and dry Me2S
(1.50 mL, 20.5 mmol) then cooled to ꢁ40 ꢂC. No precipitation was
observed. CuBr$Me2S complex (155 mg, 0.75 mmol) was added
under a flow of argon and the heterogeneous mixture became
yellow. After 10 min at ꢁ40 ꢂC the monocuprate was allowed to
warm to ꢁ15 ꢂC and oxazolidinone 1 (259 mg, 1.00 mmol) in dry
THF (1.00 mL) was added as rapidly as possible. TLC analysis
revealed that the starting material had been consumed. The re-
action was quenched with saturated aqueous ammonium chloride
(5.00 mL) and 30% ammonium hydroxide solution (5.00 mL). After
stirring for 30 min at room temperature the blue solution was di-
luted with brine and the aqueous phase was extracted with ether.
The combined ethereal extracts were washed with brine then dried
(MgSO4), filtered, and concentrated at reduce pressure to afford
a white solid. The solid was a mixture of two diastereoisomers,
which were separated by column chromatography. Elution with
15% ethyl acetate/hexane afforded 9 (115 mg, 43% conversion) and
14 (62.0 mg, 23% conversion) both as colorless solids. Compound 9
solids. Compound 10 mp 97e100 ꢂC; ½a D29
þ56.5 (c 1, CHCl3); Rf 0.29
ꢃ
(25% EtOAc/hexane); nmax (KBr) 3032, 2974, 1774, 1701, 1392, 1367,
1324, 1267, 1223 cmꢁ1; 1H NMR (300 MHz, CDCl3)
d 7.33e7.03 (15H,
m), 4.91 (1H, s), 4.86 (1H, s), 4.55 (1H, apparent t, J 7.9 Hz), 3.20 (1H,
quintet, J 7.4 Hz), 2.92 (1H, dd, J 10.7, 18.2 Hz), 2.75 (1H, dd, J 2.2,
18.2 Hz), 2.34e2.20 (1H, m), 1.50 (3H, s), 1.31 (3H, d, J 7.0 Hz), 1.19
(3H, s), 0.93 (3H, s), 0.88e0.86 (6H, m); 13C NMR (75 MHz, CDCl3)
d
174.7, 171.7, 152.9(2), 144.0, 136.7, 136.4, 128.8(2), 128.7, 128.5(2),
128.4, 127.7, 126.5, 126.2, 82.0, 81.5, 67.2, 66.9, 51.7, 39.5, 39.3, 30.3,
28.9, 28.4, 23.7, 23.3,17.8,16.7; HRMS (LSIMS): calcd for C36H41N2O6
597.2965 (MþH), found 597.2957. Compound 15 mp 161 ꢂC; ½a D28:5
ꢃ
þ53.8 (c 0.8, CHCl3); nmax (KBr) 2972, 1772, 1709, 1691, 1457, 1323,
1162, 1103, 701 cmꢁ1; 1H NMR (300 MHz, CDCl3)
d 7.38e7.05 (15H,
m), 4.98 (1H, s), 4.96 (1H, s), 4.56 (1H, dd, J 5.8, 9.5 Hz), 3.24e3.13
(2H, m), 2.71 (1H, dd, J 10.2, 16.7 Hz), 2.25e2.12 (1H, m), 1.53 (3H, s),
1.39 (3H, s), 1.24 (3H, d, J 6.9 Hz), 0.95 (3H, s), 0.94 (3H, s), 0.73 (3H,
d, J 6.7 Hz); 13C NMR (75 MHz, CDCl3)
d 174.5, 171.3, 153.2, 152.9,
143.9, 136.4, 136.3, 128.9(2), 128.8, 128.53(2), 128.47, 127.6(2), 126.6,
82.2, 81.7, 67.5, 67.0, 51.2, 40.42, 40.37, 30.4, 28.9, 28.7, 23.6, 23.5,
19.3, 15.4; HRMS (LSIMS): calcd for C36H41N2O6 597.2965 (MþH),
found 597.2962.
mp 61e63 ꢂC; ½a 3D0:5
þ38.7 (c 1, CHCl3); Rf 0.26 (25% EtOAc/hexane);
ꢃ
nmax (KBr) 3034, 2974, 2876, 1767, 1711, 1698, 1390, 1365, 1266,
1231 cmꢁ1 1H NMR (300 MHz, CDCl3)
; d 7.37e7.06 (10H, m), 5.07
(1H, s), 5.00 (1H, s), 4.02 (1H, apparent t, J 7.5 Hz), 2.96 (1H, dd, J
10.7, 17.6 Hz), 2.75 (1H, apparent d, J 17.6 Hz), 2.49e2.40 (1H, m),
2.13e2.00 (1H, m),1.55 (3H, s),1.50 (3H, s), 1.00e0.91 (12H, m), 0.82
4.3. X-ray crystallography
(3H, d, J 6.5 Hz); 13C NMR (CDCl3)
d
(rotamers) 175.0, 174.5, 171.9,
The temperature during data collection was maintained at
130.0(1) using an Oxford Cryostream cooling device. Intensity data
were collected with a Bruker SMART Apex CCD detector using Mo
171.4, 153.1,152.7,152.8, 152.3, 136.5, 136.1, 136.3, 135.8,128.8, 128.7,
128.3, 128.2, 127.9,126.5, 126.1,125.7, 82.0, 81.5, 81.1, 67.1, 66.8, 66.8,
66.4, 51.6, 51.1, 39.3, 38.8, 29.6, 29.1, 28.8, 28.7, 28.3, 27.8, 23.6, 23.2,
22.7, 20.5, 20.0, 18.6, 18.1, 17.6, 17.1; HRMS (LSIMS): calcd for
C31H39N2O6 535.2808 (MþH), found 535.2814. Compound 14 mp
Ka
radiation (graphite crystal monochromator
l¼0.71073). Data
were reduced using the program SAINT.26
The structure was solved by direct methods and difference
Fourier synthesis. Thermal ellipsoid plots were generated using the
program ORTEP-327 integrated within the WINGX28 suite of
programs.
163e164 ꢂC; ½a 2D6:5
ꢃ
þ42.2 (c 1, CHCl3). Rf 0.34 (25% EtOAc/hexane);
1H NMR
d 7.40e7.12 (10H, m), 5.05 (1H, s), 5.02 (1H, s),
nmax (KBr) 2962, 1777, 1700, 1366, 1264, 1227 cmꢁ1
;
(300 MHz, CDCl3)
3.92 (1H, dd, J 6.1, 8.8 Hz), 3.22 (1H, dd, J 3.2, 17.1 Hz), 2.76 (1H, dd, J
10.2, 17.1 Hz), 2.57e2.50 (1H, m), 2.06e1.97 (1H, m), 1.57 (3H, s),
1.55 (3H, s), 0.98 (3H, s), 0.97 (3H, s), 0.95 (3H, d, J 6.9 Hz), 0.90 (3H,
Crystallographic data for 4a, 4e, 5e9, 14, and 15 have been de-
posited in the Cambridge Crystallographic Data Centre (CCDC) as
supplementary publication numbers CCDC 805090e805098. These
data can be freely obtained from the CCDC by sending an applica-
tion by email to deposit@ccdc.cam.ac.uk.
d, J 6.6 Hz), 0.79 (3H, d, J 6.7 Hz); 13C NMR (75 MHz, CDCl3)
d 174.9,
171.7, 153.4, 153.0, 136.5, 136.3, 128.9(2), 128.8, 128.5, 128.4, 126.3,
82.2, 81.7, 67.6, 67.1, 51.8, 40.5, 29.6, 29.0(2), 28.8, 23.7, 23.4, 20.3,
20.0, 15.4; HRMS (LSIMS): calcd for C31H39N2O6 535.2808 (MþH),
found 535.2793.
4.3.1. Crystal data for 4a. C18H23NO3, M¼301.37, T¼130.0(2) K,
l
¼0.71069, orthorhombic, space group P2(1)2(1)2(1) a¼6.2884 (8),
3
ꢀ ꢀ
b¼13.132
(2),
c¼19.682
(Mo K
(2) A,
V¼1625.3(3) A ,
Z¼4,
4.2.12. 1,5-Bis((S)-5,5-dimethyl-2-oxo-4-phenyloxazolidin-3-yl)-3-
methyl-2-((R)-1-phenylethyl)pentane-1,5-dione (10) and (15). A dry
two-necked round-bottomed flask was filled with an argon atmo-
sphere. A magnetic stirrer bar was added to the flask followed by
phenylmagnesium bromide (1.50 mL of a 1 M solution in THF). The
Grignard was diluted with dry THF (2.00 mL) and dry Me2S
(1.50 mL, 20.5 mmol) and then it was cooled to ꢁ40 ꢂC, which
caused some precipitation. CuBr$Me2S complex (155 mg,
0.75 mmol) was added under a flow of argon and the heteroge-
neous solution became mustard-yellow. After 10 min at ꢁ40 ꢂC the
monocuprate was allowed to warm to ꢁ15 ꢂC and oxazolidinone 1
(259 mg, 1.00 mmol) in dry THF (1.00 mL) was added as rapidly as
possible. The solution instantly became homogeneous and turned
bright orange in color. TLC analysis revealed that the starting ma-
terial had been consumed. The reaction was quenched with
Dc¼1.232 mg Mꢁ3
,
m
a
)¼0.083 mmꢁ1, F(000)¼648, crystal
size 0.4ꢄ0.3ꢄ0.03 mm. 10,249 Reflections measured, 3630 in-
dependent reflections (Rint¼0.067) the final R was 0.0486 [I>2
s(I)]
and wR(F2) was 0.0795 (all data).
4.3.2. Crystal data for 4e. C16H21NO3, M¼275.34, T¼130.0(2) K,
l
¼0.71069, monoclinic, space group P2(1) a¼5.400 (1), b¼18.884
3
ꢀ ꢀ
(4), c¼7.778(2) A,
b
¼110.208 (3)ꢂ, V¼744.3(3) A , Z¼2,
Dc¼1.229 mg Mꢁ3
,
m(Mo K
a
)¼0.084 mmꢁ1, F(000)¼296, crystal
size 0.4ꢄ0.3ꢄ0.20 mm. 2810 Reflections measured, 2286 in-
dependent reflections (Rint¼0.039) the final R was 0.0478 [I>2
s(I)]
and wR(F2) was 0.1025 (all data).
4.3.3. Crystal data for 5. C33H40N2O6, M¼560.67, T¼130.0(2) K,
¼0.71069, monoclinic, space group P2(1), a¼12.125(1),
l

A.B. Hughes et al. / Tetrahedron 68 (2012) 1979e1987
1987
3
ꢂ
ꢀ
ꢀ
b¼10.380(1), c¼13.054(1) A,
b
¼104.206(2) , V¼1592.8(3) A , Z¼2,
4.3.9. Crystal data for 15. C37H42N2O6Cl2, M¼681.63, T¼130.0(2) K,
Dc¼1.169 mg Mꢁ3
,
m
(Mo K
a
)¼0.080 mmꢁ1, F(000)¼600, crystal size
l
¼0.71069, monoclinic, space group P2(1) a¼9.715 (1), b¼10.105
3
ꢀ ꢀ
0.45ꢄ0.25ꢄ0.20 mm. 8420 Reflections measured, 5360 in-
(1), c¼17.719 (2) A,
b
¼92.779 (2)ꢂ, V¼1737.4(3) A , Z¼2,
dependent reflections (Rint¼0.031) the final R was 0.0465 [I>2
s
(I)]
Dc¼1.303 mg Mꢁ3
,
m
(Mo K
a
)¼0.235 mmꢁ1, F(000)¼720, crystal size
and wR(F2) was 0.0976 (all data).
0.2ꢄ0.15ꢄ0.10 mm. 8368 Reflections measured, 5744 independent
reflections (Rint¼0.0498) the final R was 0.0786 [I>2
s(I)] and
wR(F2) was 0.2038 (all data).
4.3.4. Crystal data for 6. C32H38N2O6, M¼546.64 T¼130.0(2) K,
¼0.71069, monoclinic, space group P2(1), a¼12.354(1),
l
3
ꢀ
ꢂ
ꢀ
Supplementary data
b¼12.745(1), c¼19.062(2) A, ¼96.179(2) , V¼2983.9 (4) A , Z¼4,
b
Dc¼1.216 mg Mꢁ3
,
m
(Mo K
a
)¼0.084 mmꢁ1, F(000)¼1170, crystal
Supplementary data related to this article can be found online at
doi:10.1016/j.tet.2011.12.046.
size 0.45ꢄ0.35ꢄ0.20 mm. 18,906 Reflections measured, 12,891 in-
dependent reflections (Rint¼0.0397) the final R was 0.0559 [I>2
s(I)]
and wR(F2) was 0.1320 (all data).
References and notes
4.3.5. Crystal data for 7. C33H40N2O6, M¼560.67, T¼130.0(2) K,
¼0.71069, monoclinic, space group P2(1), a¼10.484 (2),
1. Komnenos, T. Liebigs Ann. Chem. 1883, 218, 145.
l
2. Conjugate Addition Reactions in Organic Synthesis, Tetrahedron Organic Chemistry
Series; Perlmutter, P., Ed.; Pergamon: Oxford, 1992; Vol. 9.
3. Organocopper Reagentsa Practical Approach; Taylor, R. J. K., Ed.; Oxford University:
Oxford, 1994.
4. Kharasch, M. S.; Tawney, P. O. J. Am. Chem. Soc. 1941, 63, 2308.
5. Oppolzer, W.; Moretti, R.; Godel, T.; Meunier, A.; Loher, H. Tetrahedron Lett.
1983, 24, 4971; Oppolzer, W.; Stevenson, T. Tetrahedron Lett. 1986, 27, 1139.
6. Helmchen, G.; Wegner, G. Tetrahedron Lett. 1985, 26, 6051.
7. Ahn, K.-H.; Klassen, R. B.; Lippard, S. J. Organometallics 1990, 9, 3178.
8. Alexakis, A.; Mutti, S.; Normant, J. F. J. Am. Chem. Soc. 1991, 113, 6332.
9. Kretchmer, R. A. J. Org. Chem. 1972, 37, 2744.
3
ꢀ
ꢂ
ꢀ
b¼10.043(2), c¼15.826(3) A, ¼108.804(3) , V¼1577.2(3) A , Z¼4,
b
Dc¼1.181 mg Mꢁ3
,
m
(Mo K
a
)¼0.081 mmꢁ1, F(000)¼600, crystal size
0.5ꢄ0.4ꢄ0.30 mm. 7521 Reflections measured, 4152 independent
reflections (Rint¼0.056) the final R was 0.0391 [I>2
s
(I)] and wR(F2)
was 0.1064 (all data).
4.3.6. Crystal data for 8. C33H42N2O6, M¼562.69, T¼130.0(2)
K,
¼0.71069, orthorhombic, space group P2(1)2(1)2(1), a¼12.325
l
10. Langer, W.; Seebach, D. Helv. Chim. Acta 1979, 62, 1710.
11. Leyendecker, F.; Laucher, D. New J. Chem. 1985, 9, 13.
3
ꢀ
ꢀ
(1), b¼14.190 (1), c¼17.819 (1) A, V¼3116.5(4) A , Z¼4,
Dc¼1.199 mg Mꢁ3
,
m
(Mo K
a
)¼0.082 mmꢁ1, F(000)¼1208, crystal
12. Nicolas, E.; Russell, K. C.; Hruby, V. J. J. Org. Chem. 1993, 58, 766.
13. Nicolas, E.; Russell, K. C.; Knollenberg, J.; Hruby, V. J. J. Org. Chem. 1993, 58, 7565.
14. Bull, S. D.; Davies, S. G.; Jones, S.; Sanganee, H. J. J. Chem. Soc., Perkin Trans. 11999,
387; Davies, S. G.; Sanganee, H. J.; Szolcsanyi, P. Tetrahedron 1999, 55, 3337.
15. Ley, S. V.; Dixon, D. J.; Guy, R. T.; Rodrıguez, F.; Sheppard, T. D. Org. Biomol. Chem.
2005, 3, 4095.
size 0.4ꢄ0.4ꢄ0.30 mm. 16,224 Reflections measured, 5477 in-
dependent reflections (Rint¼0.072) the final R was 0.0375 [I>2
s(I)]
and wR(F2) was 0.0861 (all data).
16. Posner, G. H.; Canella, K. A.; Silversmith, E. F. Proc. -Indian Acad. Sci., Chem. Sci.
1988, 100, 81; See also Suzuki, M.; Noyori, R. In Organocopper Reagents a Prac-
tical Approach; Taylor, R. J. K., Ed.; Oxford University: Oxford, 1994; p 201.
17. Spitzner, D. Tetrahedron Lett. 1978, 3349; Spitzner, D.; Wagner, P.; Simon, A.;
Peters, K. Tetrahedron Lett. 1989, 30, 547; Posner, G. H.; Mallamo, J. P.; Black, A. Y.
Tetrahedron 1981, 37, 3921.
18. Hanessian, S.; Gomtsyan, A. Tetrahedron Lett. 1994, 35, 7509.
19. Davies, S. G.; Smith, A. D.; Cowley, A. R. Synlett 2004, 1957.
20. Daviaud, G.; Miginiac, P. Tetrahedron Lett. 1973, 3345.
21. Munch-Petersen, J. J. Org. Chem. 1957, 22, 170.
4.3.7. Crystal data for 9. C31H38N2O8, M¼534.63, T¼130.0(2) K,
l
¼0.71069, monoclinic, space group P2(1) a¼12.285 (1), b¼12.391
3
ꢀ ꢀ
(1),
c¼19.210(2) A,
b
¼95.052(1)ꢂ,
V¼2912.9(5) A ,
Z¼4,
Dc¼1.219 mg Mꢁ3
,
m
(Mo K
a
)¼0.084 mmꢁ1, F(000)¼1144, crystal
size 0.3ꢄ0.2ꢄ0.30 mm. 18,539 Reflections measured, 12,497 in-
dependent reflections (Rint¼0.061) the final R was 0.053 [I>2
s(I)]
and wR(F2) was 0.1095 (all data).
22. Lou, B.-S.; Li, G.; Lung, F.-D.; Hruby, V. J. J. Org. Chem. 1995, 60, 5509.
23. Bull, S. D.; Davies, S. G.; Nicholson, R. L.; Sanganee, H. J.; Smith, A. D. Org. Biomol.
Chem. 2003, 1, 2886.
24. Still, W. C.; Kahn, M.; Mitra, A. J. Org. Chem. 1978, 43, 2923.
25. Armarego, W. L. F.; Perrin, D. D. Purification of Laboratory Chemicals, 3rd ed.;
Pergamon: Oxford, 1988.
26. Siemens. SMART, SAINT, SADABS; Siemens Analytical X-ray Instruments: Madison,
Wisconsin, USA, 1999.
27. Farrugia, L. J. J. Appl. Crystallogr. 1997, 30, 565.
4.3.8. Crystal data for 14. [C32H38N2O6]2.CH2Cl2, M¼1154.19,
T¼130.0(2) K, ¼0.71069, monoclinic, space group C2 a¼31.261 (2),
l
3
ꢀ
ꢂ
ꢀ
b¼7.8316 (4), c¼24.540(3) A, ¼91.469(1) , V¼6006.0(5) A , Z¼4,
b
Dc¼1.276 mg Mꢁ3
,
m
(Mo K
a
)¼0.271 mmꢁ1, F(000)¼2456, crystal
size 0.4ꢄ0.35ꢄ0.30 mm. 15,996 Reflections measured, 8189 in-
dependent reflections (Rint¼0.030) the final R was 0.0405 [I>2
s(I)]
and wR(F2) was 0.0991 (all data).
28. Farrugia, L. J. J. Appl. Crystallogr. 1999, 32, 837.
́