Alkynes to (E)-enolates using tandem catalysis: Stereoselective anti-aldol and syn-[3,3]-rearrangement reactions

Article abstract of DOI:10.1016/j.tet.2010.05.045

A new tandem catalysis strategy that transforms alkyne derivatives to (E)-enol-equivalents followed by stereoselective anti-selective aldol coupling or syn-selective [3,3]-rearrangement transformations is reported. The mechanism is thought to proceed through an interchanging series of Lewis acid and Bronsted acid catalyzed reactions via the intermediacy of a ketiminum ion species.

Full text of DOI:10.1016/j.tet.2010.05.045

Tetrahedron 66 (2010) 6429e6436
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Alkynes to (E)-enolates using tandem catalysis: stereoselective anti-aldol and syn-
[3,3]-rearrangement reactions
Neil P. Grimster a, Donna A.A. Wilton a, Louis K.M. Chan a, Christopher R.A. Godfrey b, Clive Green c,
,
Dafydd R. Owen d, Matthew J. Gaunt a
*
a Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, United Kingdom
b Syngenta Crop Protection, Münchwilen AG, Schaffhauserstrasse, WT-810.3.18, CH-4332 Stein, Switzerland
c AstraZeneca, Alderley Park, Macclesfield, Cheshire SK10 4TF, United Kingdom
d Pfizer Global Research and Development, Sandwich, Kent CT13 9NJ, United Kingdom
a r t i c l e i n f o
a b s t r a c t
Article history:
A new tandem catalysis strategy that transforms alkyne derivatives to (E)-enol-equivalents followed by
stereoselective anti-selective aldol coupling or syn-selective [3,3]-rearrangement transformations is
reported. The mechanism is thought to proceed through an interchanging series of Lewis acid and
Brønsted acid catalyzed reactions via the intermediacy of a ketiminum ion species.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 4 January 2010
Received in revised form 8 May 2010
Accepted 13 May 2010
Available online 20 May 2010
Keywords:
Tandem catalysis
Enolate
Alkyne
Stereoselective aldol
Stereoselective Sigmatropic rearrangement
1. Introduction
multi-catalysis system can also catalyze further transformations,
and here we detail the development of catalytic stereoselective
The enolate and its derivatives represent the most important
reactive intermediate in synthetic organic chemistry.1 The classical
formation of enolates or enols is realized directly from the corre-
sponding carbonyl compound via base mediated deprotonation or
acid induced enolization, respectively (Eq. 1); this can often be
controlled to form (E) or (Z) geometric isomers, depending on the
nature of the carbonyl, or the conditions employed. The enolization
event is controlled through a mix of steric and electronic factors
that requires careful selection of reaction conditions. Recent
advances have focused on the development of catalytic and
asymmetric enolate chemistry, and have led to a number of
important advances in this field.2 A particular challenge for enolate
chemistry is the generation and direct transformation of (E)-eno-
lates derived from amides. A solution to this problem would have
significant utility in synthesis. Herein, we disclose our initial
studies towards the catalytic and stereoselective formation and
reaction of (E)-enolate equivalents from alkynes (Eq. 2). This
strategy uses an interchanging series of Lewis and Brønsted acid
catalyzed processes (Eq. 3), and facilitates the syn-addition of an
alcohol across an ynamide to form the (E)-enolate equivalent. This
anti-aldol process and the demonstration of a syn-selective [3,3]-
sigmatropic rearrangement reaction (Eq. 4).3
Conventional enolate formation: carbonyls to enolates
O–
O
O–
base
(E)
R2
or
R1
R2
R1
(1)
R1
R2
(Z)
New strategy for catalytic enol formation: alkynes to enolates
R3
R1
R3
O
R3O–H
catalyst
O
O
R1
H
R1
(2)
(3)
R2
R2
R1
R2
Tandem catalysis concept
R1
E
E(+)
R3O–H
LA
BA
LA
R2
R2
tandem catalysis
LA = Lewis Acid; BA = Brønsted Acid
Applications of tandem catalysis strategy - this study
O
R2
NR2
R2
OH
SiR3
R3
R3Si–OH, R3CHO
O
O
(4)
R2N
R2N
cat. M(OTf)n
[3,3]-rearrangement
cat. M(OTf)n
R1
R1
R1
* Corresponding author. Tel.: þ44 (0)1223 336 318; fax: þ44 (0)1223 336 362;
anti-aldol reaction
e-mail address: mjg32@cam.ac.uk (M.J. Gaunt).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.05.045

6430
N.P. Grimster et al. / Tetrahedron 66 (2010) 6429e6436
Table 1
2. Results and discussion
Optimization of the anti-aldol reaction
R3Si
Ph
O
O
O
O
Central to our hypothesis for the ‘enolization’ of alkynes was the
realization that ynamides possess the same overall oxidation state
as an enol-aminal, and that the addition of an OeH group across the
triple bond would reveal the enol functionality (Eq. 2). The cata-
lyzed hydration of alkynes to ketones is a relatively well-known
transformation4 and yet, there are few examples of the direct in-
termolecular interception of the enol intermediate to facilitate
further reactions.5 Our first task was to design a system that would
catalyze (a) the (E)-selective hydroalkoxylation of an ynamide, and
(b) subsequent transformation of the enol derivative.6 Guided by
the ynamide 1 reactivity,7 we speculated that the combination of
a Lewis acid and protic nucleophile would generate a highly acidic
species that could protonate the ynamide under mild conditions.8
To test this hypothesis, we treated ynamide 1a with i-PrOH in
the presence of Zn(OTf)2 in CH2Cl2 at room temperature. Un-
fortunately, the only product observed was the amide resulting
from hydrolysis of ynamide. However, on use of a larger oxazoli-
dinone 1b, we could observe the enol-aminal (int-1b). Importantly,
NOE correlation revealed that the enol was of (E)-geometry, con-
firming the syn-addition process outlined in our enolization blue-
print (Fig. 1).
O
5 mol% Sc(OTf)3
N
O
N
R3SiOH
+
PhCHO (3a), additive
Ph
Me
Me
Me
Ph
DCE, temperature, 24h
Me
2
1c
4a-b
Entry
Silanol 2
Additive
Temp ꢀC
Yield %
dr (anti/syn)
1
2
3
4
Ph3SiOH 2a
Ph3SiOH 2a
Ph3SiOH 2a
d
rt
rt
51
73
80
65
67:33
67:33
67:33
80:20
NaOTf
NaOTf
NaOTf
50 ꢀ
50 ꢀ
C
C
i-Pr3SiOH 2b
formation of TfOH (essentially buffering the reaction and mini-
mizing the TfOH catalyzed decomposition). The diastereomeric
ratio (dr) of the reaction could be improved by changing the nature
of the silanol, with i-Pr3SieOH giving the highest selectivity for the
reaction between ynamide 1c and benzaldehyde 3a (entry 4). In our
initial assessment of the reaction scope we found that a range of
substrates were suitable for this process (Table 2). Pleasingly, alkyl
ynamide (R2¼Me 1d) afforded anti-propionate aldol product 4c
with benzaldehyde in 54% yield (Table 2, entry 1).
Table 2
O
O
O
O
Scope of the anti-aldol reaction
i-PrOH
c-hex
N
O
N
O
Zn(OTf)2
O
Ph3SiO
R1
O
O
O
c-hex
c-hex
5 mol% Sc(OTf)3
hydrolysis of ynamide
N
1a
N
O
R1
Me
R2
R2
Me
1c-e
Ph3SiOH (2a), NaOTf
attack
O
Me
4c-i
DCE, 50oC, 24h
Me Me
Me
over C–H
O
3
is favoured
O
H
H
O
O
O
i-PrOH
N
•
N
H
N
Entry
R1
R2
Yield %
54 (4c)
dr (anti/syn)
O
5%
Zn(OTf)2
Me
R
nOe
R
Me
c-hex
c-hex
hindered
attack
1
2
3
4
5
6
7
Ph
Ph
Me
67:33
80:20b
83:17
Me
Me
n-C6H13
n-C6H13
Ph
Ph
Ph
62 (4d)
66 (4e)
57 (4f)
80 (4a)
73 (4g)
72 (4h)
2,6-(OMe)2C6H3
n-C3H7
Ph
i-C3H7
c-C6H11
1b
int-1b
86:14b
67:33
Figure 1. Initial investigation into the catalytic formation of (E)-enol-equivalents from
ynamide 1.
>95:5
>95:5
Ph
Ph
( )
>95:5a,b
To rationalize this event, we propose that trifluoromethan-
sulfonic acid (TfOH) is generated as a result of combining Zn(OTf)2 in
i-PrOH. This acid protonates the ynamide forming a ketimium
species that undergoes selective attack over the CeH bond to form
the (E)-enol derivative.9 In monitoring this reaction by 19F NMR
spectroscopy weare able todetecttheformation ofTfOH, supporting
our hypothesis for a multi-catalysis system.3,8,10 To exploit the
catalytic formation of this (E)-enol-equivalent, we considered its
combination with an aldol-type transformation. Such a process
would potentially enable a catalytic anti-aldol reaction, whose
asymmetric variant would represent an important advance in this
area.1a,11 We selected Ph3SieOH 2a as the protic nucleophile for the
activation strategy as this would generate the corresponding
enol-silane on reaction with the ynamide 1. Subsequent tandem
aldol reaction, through a Lewis acid mediated Mukaiyama-type
mechanism, would potentially form the anti-aldol product 4.
Our optimization with Ph3SieOH 2a, phenyl-ynamide 1c and
benzaldehyde 3a revealed that Sc(OTf)3 was the best catalyst for
this process, and that 1,2-dichloroethane (DCE) was the optimal
solvent, delivering the aldol product in favour of the anti-isomer 4a
(Table 1, entry 1).
8
Ph
43 (4i)
Me
a
FelkineAhn/anti-FelkineAhn (3:1) isomers observed by 1H NMR spectroscopy
of the crude reaction mixture.
Relative stereo-configuration of the anti-aldol products were confirmed by X-
ray crystallography analysis (see Experimental for details).
b
An improved dr was observed in cases when n-hexyl ynamide
(R2¼n-Hex 1e) was employed (entries 2 and 3). Unbranched alkyl
aldehydes, such as butanal, gave the desired anti-aldol product 4f in
reasonable yield with 86:14 dr (entry 4). Reactions with a-branched
aldehydes delivered the anti-aldol products 4gei in excellent dr
(>95:5) and good yields (entries 6e8). It is notable that the silyl
group is transferred to the hydroxyl during the reaction, providing
a convenient concomitant hydroxyl protection feature. When
a-
phenylpropionaldehyde was employed, the reaction afforded a rea-
sonableyield of 4i (>95:5 anti/syn) as a 3:1 mixture of FelkineAhn to
anti-FelkineAhn isomers (entry 8). In most cases, the anti-aldol
isomer was crystalline, thereby providing a convenient method of
separation and also providing proof of stereochemistry.
An increase in yield was observed upon addition of 1 equiv of
NaOTf, resulting in an isolated yield of 73% (entry 2); further im-
provements were observed when the temperature of the reaction
was increased to 50 ꢀC, affording 80% of the desired aldol product
(entry 3). It is possible that the NaOTf additive moderates the
We next turned our attention to the investigation of an asym-
metric process, and in particular to the auxiliary controlled anti-
aldol reaction. Evans and co-workers have demonstrated that
a Lewis acid catalyzed process can afford high dr using aromatic
aldehydes.11a,b Interestingly, this reaction is proposed to occur

N.P. Grimster et al. / Tetrahedron 66 (2010) 6429e6436
6431
Table 4
through a (Z)-enolate equivalent and boat-type transition state.
Scope of catalytic [3,3]-rearrangment reaction
Kobayashi et al. have also shown that diastereoselective aldol
reactions with N-Boc amides proceed with excellent selectivity
and yield.11c
R2
O
O
O
O
catalyst
N
R2
OH
N
O
In considering an asymmetric process, we found that the anti-
aldol reaction between chiral ynamide 1f (derived from (S)-tert-
leucine), 2a and iso-butanal proceeded in 44% yield and 94:6 dr
(anti/sum of all other isomers, 4j), under the optimal conditions
(Table 3). However, whenwe changed the protic nucleophile to (p-F-
C6H4)3SieOH 2c, we found that the aldol reactions proceeded with
excellent selectivity (>95:5 dr) in favour of the anti-diastereoisomer
with both branched and unbranched alkyl aldehydes (4k-n). In
contrast to Ph3SieOH, the use of (p-F-Ph)3SieOH 2c results in
cleavage of the silyl ether under the reaction conditions employed.
additive
R1
R1
r.t., DCE
Me
Me
6a-g
Me
Me
5
1
Ph
O
Ph
O
Ph
O
Ph
O
NR2
NR2
NR2
NR2
Ph
Me
S
10 mol% Zn(OTf)2
50% t-BuCO2H
6a, 88%, dr >95:5
10 mol% Zn(OTf)2
10 mol% Zn(OTf)2
40°C
3AMS
10 mol% Zn(OTf)2
6d, 66%, dr >95:5
6b, 97%, dr 90:10
6c, 88%, dr >95:5
CF3
Me
Table 3
Asymmetric anti-aldol reaction with aliphatic aldehydes
Me
O
O
O
X
Sc
NR2
NR2
X
X
SiAr3
O
NR2
RO
R1
O
O
O
Ph
Ph
5 mol% Sc(OTf)3
R1CHO
O
Ph
O
10 mol% Sc(OTf)3
50% t-BuCO2H
6e, 76%, dr >95:5
1 mol% Zn(OTf)2
50% t-BuCO2H
6f, 59%, dr >95:5
O
N
O
N
3 mol% Zn(OTf)2
6g, 54%, dr >95:5
Ph
Me3C
R1
N
O
DCE, 50ÞC,48h
Ar3SiOH (2a,c)
CMe3
Ph
Ph
Me3C
possible
1f
4j-n
Me
O
O
O
OH
Me
O
10 mol % Zn(OTf)2
Me
N
O
transition state
N
Me
Ph
Me
50 mol % t-BuCO2H
r.t. DCE
Me
1c
Me
Ph
Me
Entry
R1
Ar
R
Yield %
dr (anti/syn)
(
)-5
(
)-6h, 63%, dr >95:5
1
2
3
4
5
i-C3H7
i-C3H7
c-C6H11
n-C3H7
(CH2)2Ph
Ph (2a)
p-F-Ph (2c)
(2c)
(2c)
(2c)
Ph3Si
H
H
H
H
44 (4j)
52 (4k)
50 (4l)
50 (4m)
61 (4n)
94:6
>95:5a
>95:5
>95:5
>95:5
a
Absolute stereo-configuration of the anti-aldol product was confirmed by X-ray
(TfO) SPch
O
Me
O
3
Ar
O
(a)
10 mol % Sc(OTf)3
DCE, 24h
O
δ+
crystallography analysis (see Experimental for details).
Me3C
Ar
Me
Me
X
N
possible
N
OH
Ph
Me
Me
transition state
Ph
Me
1c
Ph
Ar
Me
O
O
(+)-6i, 60%, 90% ee
(+)-5f, 95% ee
In order to further explore the capacity of the catalytic ynamide-
to-enol transformation, we also investigated a [3,3]-sigmatropic
process, based on the Ficini modification of the Claisen rearrange-
ment.12 The transformation involves the union of an ynamine and
an allylic alcohol, followed by thermal rearrangement. Hsung re-
cently reported that a sulfonic acid catalyzed rearrangement can be
effected under thermal conditions at temperatures >80 ꢀC.13 In line
with our hypothesis, we envisaged that both ‘enol’ formation and
the rearrangement could be facilitated at ambient temperature.14
A similar screen of conditions to that of the aldol process
identified optimal parameters comprising reaction of 5 (R2¼Ph)
and 1c in the presence of 1 mol % Zn(OTf)2 and 50 mol % PivOH as
the additive, resulting in 88% yield of 6a (>95:5 dr) after 24 h at
room temperature (Table 4). We also found that 1 mol % of Sc(OTf)3
catalyzes the reaction with similar outcome.
>95:5 dr
Ar = 4-(CF3)C6H4
possible
transition states
(b)
Zn(OTf)2
O
Ph
R1
O
O
N
δ+
O
10 mol % Zn(OTf)2
Ph
CMe3
R1
N
Xc
50 mol % t-BuCO2H
r.t. DCE, 5a
R1
CMe3
O
O
1f
1g
R
1 = Ph, gives (+)-6j, 79%, dr 90:10 (syn only)
R1 = n-C6H13, gives (+)-6k, 79%, dr 91:9 (syn only)
Scheme 1. Asymmetric [3,3]-sigmatropic rearrangement.
In summary, we have developed a new tandem catalysis strat-
egy that transforms alkyne derivatives to (E)-enol-equivalents.
Furthermore, catalytic stereoselective anti-selective aldol couplings
and syn-selective [3,3]-rearrangement transformations can be
effected through this tandem process. The mechanism is thought to
proceed through an interchanging series of Lewis acid and Brønsted
acid catalyzed reactions via the intermediacy of a ketiminum ion
species. Further investigations into a catalytic enantioselective
transformation are ongoing.
We tested a range of substituted 1ꢀ and 2ꢀ allylic alcohols 5 and
ynamides 1 under our optimized reaction conditions (Table 4) and
showed that aryl (R1, R2), heteroaryl (R1), alkenyl (R2) and alkyl (R1,
R2) substituents could be accommodated on both the ynamide (R1)
and allylic alcohol (R2) portions of the molecule. In most cases
diastereoselectivities (in favour of the syn-isomer) were excellent.
When enantioenriched (þ)-5f was subjected to our standard
reaction conditions, we found that the rearrangement took place
with transposition of chirality from the allylic alcohol (þ)-5f to the
product (þ)-6i (Scheme 1a). Using the ynamides 1feg, we found
that rearrangement proceeded with good stereocontrol to afford
only the syn products 6jek with good dr (Scheme 1b).15 While we
cannot fully rationalize the origin of stereoinductions, the observed
outcome is consistent with a chair transition state and non-che-
lated auxiliary.
3. Experimental section
3.1. General experimental
All reagents were purchased at the highest commercial quality.
Ynamides were synthesized according to literature procedure.16
Reactions were carried out using oven dried glassware and under

6432
N.P. Grimster et al. / Tetrahedron 66 (2010) 6429e6436
an atmosphere of nitrogen unless otherwise stated. 1,2-Di-
chloroethane was freshly distilled over calcium hydride before use.
All reactions were monitored by TLC carried out on glass precoated
(0.25 mm) with Merck silica gel 60 F254 or from 1H NMR spectra
taken from reaction samples. Flash column chromatography was
performed with Merck silica gel 60 (230e400 mesh).
silanol (2.0 equiv) were added and reaction vessel was sealed with
a septum. The reaction vessel was evacuated and back-filled with
nitrogen three more times before freshly distilled 1,2-di-
chloroethane (0.1 M w.r.t. aldehyde) and freshly distilled aldehyde
(1.0 equiv) were added. The reaction mixture was stirred at 50 ꢀC
for 24e48 h. Once completed, as shown by TLC analysis, the re-
action mixture was filtered through a pad of silica, eluted with
EtOAc. The solvent was removed under reduced pressure and di-
astereomeric ratio was obtained by 1H NMR spectroscopy of the
crude mixture. Product was purified by flash column chromatog-
raphy on silica gel to afford the aldol product.
1H NMR, 13C NMR and 19F NMR spectra were determined on
a Bruker DPX 400 MHz spectrometer operating at 400, 100 and
376 MHz, respectively. Chemical shifts (d
) for 1H NMR, 13C NMR are
quoted relative to residual solvent (chloroform,
d
¼7.26 ppm for 1H
and
d
¼77.0 for 13C of chloroform-d1) and chemical shifts (
d F
) for 19
NMR are quoted relative to fluorobenzene (
d
¼0.0). Coupling con-
stants (J) are corrected and quoted to the nearest 0.1 Hz. DEPT135
and 2-dimensional experiments (COSY, HMBC and HMQC) were
used to support assignments were appropriate, but are not in-
cluded. IR spectra were recorded as a film on a Perkin Elmer
Spectrum One-FT-IR spectrometer fitted with an ATR sampling
accessory. Optical rotations were measured in chloroform on
3.4.1. rac-3-((2RS,3SR)-2,3-Diphenyl-3-(triphenylsilyloxy)prop-
anoyl)-4,4-dimethyloxazolidin-2-one, 4a. General procedure A per-
formed on a 0.25 mmol scale. The crude product (67:33 anti/syn as
determined by 1H NMR analysis) was purified by column chroma-
tography (1:4 Et2O/hexanes) to afford 4a (113 mg, 80%) as a pale
yellow solid (Recrystallization by dissolving in a minimum amount
of dichloromethane with slow addition of hexane at 0 ꢀC afforded
anti-4a as a white solid.). Rf¼0.20 (1:4 Et2O/hexane); mp 160 ꢀC; 1H
a Perkin Elmer 343 Polarimeter; [
a
]
values are reported in
D
10ꢁ1 degrees cm2 gꢁ1 at 589 nm. Melting points were recorded
using a Reichert hot stage apparatus and are reported uncorrected.
HRMS were measured on a Micromass Q-TOPF spectrometer by
electrospray ionization (ESI) or electron impact (EI) techniques at
the EPSRC Mass Spectrometry Service at the University of Swansea.
NMR (400 MHz, chloroform-d1)
d 7.48 (m, 6H, ArH), 7.41e7.35 (m,
3H, ArH), 7.33e7.26 (m, 6H, ArH), 7.13e7.08 (m, 2H, ArH), 7.08e7.03
(m, 3H, ArH), 7.01e6.97 (m, 1H, ArH), 6.96e6.86 (m, 4H, ArH), 5.75
(d, 1H, J¼9.9 Hz, (Ph3SiO)CH), 5.51 (d, 1H, J¼9.9 Hz, PhCH), 3.85 (s,
2H, OCH2), 1.40 (s, 3H, NCMeMe0), 1.32 (s, 3H, NCMeMe0); 13C NMR
3.2. 19F NMR experiment for the observation of the formation
of trifluoromethanesulfonic acid formation
(100 MHz, chloroform-d1)
d 173.9, 140.8, 136.1, 135.2, 134.8, 130.0,
129.9, 128.4, 128.2, 127.9, 127.9, 127.8, 127.5, 79.7, 75.2, 61.0, 58.9,
25.2, 24.9; nmax (film)/cmꢁ1 1772, 1701, 1370, 1304, 1174, 1116, 1087,
909, 737, 710; HRMS (ESþ) calcd for C38H35NO4Si [MþNH4]þ
615.2674, found 615.2669.
A solution of isopropanol (9.1 mL, 0.12 mmol) and 3-(cyclo-
hexylethynyl)-4,4-dimethyloxazolidin-2-one (39.6 mg, 0.18 mmol)
in chloroform-d1 (1.2 mL) was added to a sealed reaction vessel
3.4.2. rac-3-((2RS,3SR)-2,3-Diphenyl-3-(triisopropylsilyloxy)prop-
anoyl)-4,4-dimethyloxazolidin-2-one, 4b. General procedure A was
performed on a 0.25 mmol scale. The crude product (80:20 anti/syn
as determined by 1H NMR analysis) was purified by column chro-
matography (1:4 Et2O/hexanes) to afford 4b (80 mg, 65%) as a yel-
low oil. Rf¼0.20 (1:4 Et2O/hexane); 1H NMR (400 MHz, chloroform-
containing zinc triflate (3.3 mg, 1.3 mmol) and fluorobenzene (in-
ternal standard, 2.8 mg, 0.03 mmol). 19F NMR experiments were
then measured at 20 min intervals over a period of 15 h in order to
observe the formation of TfOH. 19F NMR (376 MHz, chloroform-d1)
d
37.3 (TfOH), 35.0 (Zn(OTf)2), 0.0 (FPh).
d1)
d
7.10 (s, 5H, ArH), 7.07(s, 5H, ArH), 5.49 (d, 1H, J¼9.6 Hz, (i-
3.3. (E)-3-(2-Cyclohexyl-1-isopropoxyvinyl)oxazolidin-2-one,
int-1b
Pr)3SiOCH), 5.44 (d, 1H, J¼9.6 Hz, PhCH), 3.98 (d, 1H, J¼8.3 Hz,
OCHH0), 3.87 (d, 1H, J¼8.3 Hz, OCHH0), 1.69 (s, 3H, NCMeMe0), 1.44
(s, 3H, NCMeMe0), 1.03e0.97 (m, 21H, (i-Pr)3Si); 13C NMR (100 MHz,
A solution of isopropanol (9.6 mL, 0.13 mmol) and 3-(cyclo-
hexylethynyl)-4,4-dimethyloxazolidin-2-one (41.7 mg, 0.19 mmol)
in 1,2-dichloromethane (1.3 mL) was added to a sealed reaction
chloroform-d1)
d 171.6, 151.8, 140.2, 133.2, 127.6, 126.2, 125.8, 125.7,
125.5, 125.2, 76.2, 73.0, 58.8, 57.7, 23.6, 22.5, 16.3, 16.1, 15.9, 10.8;
nmax (film)/cmꢁ11775, 1703, 1455, 1369, 1314, 1304, 1216, 1173, 1088,
1065, 1038, 882, 806, 697, 679; HRMS (ESþ) calcd for C29H41NO4Si
[MþH]þ 496.2878, found 496.2871.
vessel containing zinc triflate (3.5 mg, 1.3 mmol). The solution was
stirred under a positive pressure of nitrogen for 24 h at room
temperature. Upon completion, the reaction mixture was filtered
through a pad of silica, washed with dichloromethane and evapo-
rated to dryness under reduced pressure. The crude product was
purified by column chromatography (50% diethyl ether in hexanes)
to afford the enol int-1b (29 mg, 82%) as a colourless oil. Rf 0.37 (50%
3.4.3. rac-4,4-Dimethyl-3-((2R,3S)-2-methyl-3-phenyl-3-(triphe-
nylsilyloxy)propanoyl)oxazolidin-2-one, 4c. General procedure
A
was performed 0.25 mmol scale. The crude product (67:33 anti/syn
as determined by 1H NMR analysis) was purified by column chro-
matography (1:3 Et2O/hexanes) to afford 4c (72 mg, 54%) as a col-
ourless oil. Diastereomers were inseparable by recrystallization.
Rf¼0.23 (1:3 Et2O/hexane); 1H NMR (400 MHz, chloroform-d1)
diethyl ether in hexanes); 1H NMR (400 MHz, chloroform-d1)
d 4.68
(d, 1H, J¼10.3 Hz, C]CHCy), 4.13 (q, 1H, J¼6.1 Hz, OCH(Me)2), 4.04
(s, 2H, OCH2), 1.90e1.87 (m, 1H, Cy), 1.69e1.60 (m, 10H, Cy), 1.36 (s,
6H, NCMe2), 1.23 (d, 6H, J¼6.1 Hz, OCH(Me)2); 13C NMR (100 MHz,
chloroform-d1) d 155.7, 139.1, 114.0, 75.8, 69.5, 59.1, 36.6, 33.0, 27.5,
d
7.49e7.09 (m, 40H, majorþminor ArH), 5.04 (d, 1H, J¼9.6 Hz,
26.2, 25.9, 21.9; nmax (film)/cmꢁ1 2923, 1757, 1671, 1449, 1372, 1181,
1043; HRMS (ESþ) mass calcd for C16H27NO3 [(MþH)þ]: 282.2064;
found: 282.2065.
major Ph3SiOCH), 4.95 (d, 1H, J¼8.3 Hz, minor Ph3SiOCH), 4.50 (m,
1H, major MeCH), 4.32 (m, 1H, minor MeCH), 3.90 (d, 1H, J¼8.3 Hz,
major OCHH0), 3.77e3.73 (m, 2H, major OCHH0þminor OCHH0), 3.48
(d,1H, J¼8.3 Hz, minor OCHH0), 1.50 (s, 3H, major NCMeMe0), 1.37 (s,
3H, minor NCMeMe0), 1.32 (d, 3H, J¼6.8 Hz, minor CHMe), 1.18 (s,
3H, major NCMeMe0), 0.84 (s, 3H, minor NCMeMe0), 0.80 (d, 3H,
3.4. General procedure A: anti-aldol reactions
J¼6.8 Hz, CHMe); 13C NMR (100 MHz, chloroform-d1)
d 177.5, 176.3,
Scandium triflate (5 mol %) and sodium triflate (if stated,
1.0 equiv) were added to the reaction vessel with magnetic stirrer
and were dried using a heat gun (>230 ꢀC) for 1 min under high
vacuum. After back-filling with nitrogen, ynamide (2.0 equiv) and
154.5, 142.2, 141.4, 136.0, 134.7, 134.6, 130.3, 130.1, 128.5, 128.4,
128.3, 128.3, 128.1, 127.9, 80.1, 78.9, 75.2, 47.9, 46.9, 25.3, 25.1, 24.7,
23.9, 15.0, 14.9; nmax (film)/cmꢁ1 1772, 1700, 1429, 1378, 1305, 1217,

N.P. Grimster et al. / Tetrahedron 66 (2010) 6429e6436
6433
1175, 1115, 1105, 1085, 1064, 1028, 882, 766, 738, 709, 699; HRMS
[MþNa]þ 586.2384, found 586.2374. X-ray crystallography de-
(ESþ) calcd for C33H33NO4Si [MþH]þ 536.2257, found 536.2245.
position number: CCDC 679323.
3.4.4. rac-4,4-Dimethyl-3-((RS)-2-((SR)-phenyl(triphenylsilyloxy)
methyl)octanoyl) oxazolidin-2-one, 4d. General procedure A was
performed on a 0.25 mmol scale. The crude product (80:20
anti/syn as determined by 1H NMR analysis) was purified by
column chromatography (1:5 Et2O/hexanes) to afford 4d (75 mg,
62%) as a white solid (Recrystallization by dissolving in a mini-
mum amount of dichloromethane with slow addition of hexane at
0 ꢀC afforded anti-4d as a white solid.). Rf¼0.19 (1:5 Et2O/hexane);
3.4.7. rac-4,4-Dimethyl-3-((2RS,3RS)-4-methyl-2-phenyl-3-(triphe-
nylsilyloxy)pentanoyl)oxazolidin-2-one, 4g. General procedure
A
was performed on a 0.27 mmol scale. The crude product (>95:5
anti/syn as determined by 1H NMR analysis) was purified by column
chromatography (1:4 Et2O/hexanes) to afford 4g (108 mg, 73%) as
a white solid. Rf¼0.38 (1:2 Et2O/hexane); mp 146 ꢀC; 1H NMR
(400 MHz, chloroform-d1)
d 7.76 (m, 6H, ArH), 7.44e7.38 (m, 9H,
ArH), 7.30e7.21 (m, 5H, ArH), 5.62 (d, 1H, J¼9.7 Hz, PhCH), 4.62 (dd,
1H, J¼9.8, 1.4 Hz, Ph3SiOCH), 3.67 (ABq, 2H, J¼15.0, 8.2 Hz, OCH2),
1.29 (m, 1H, CH(Me)2), 1.05 (s, 3H, NCMeMe0), 0.99 (d, 3H, J¼6.8 Hz,
CH(Me)(Me0)), 0.83 (s, 3H, NCMeMe0), 0.73 (d, 3H, J¼6.9 Hz, CH(Me)
mp 100 ꢀC; 1H NMR (400 MHz, chloroform-d1)
d 7.57e7.49 (m, 1H,
ArH), 7.36e7.30 (m, 2H, ArH), 7.28e7.24 (m, 6H, ArH), 7.19e7.14
(m, 6H, ArH), 7.11e7.69 (m, 5H, ArH), 4.89 (d, 1H, J¼9.6 Hz, PhCH),
4.68 (dt, 1H, J¼10.8, 3.6 Hz, (C6H13)CH), 3.79 (d, 1H, J¼8.4 Hz,
OCHH0), 3.57 (d, 1H, J¼8.4 Hz, OCHH0), 1.58 (s, 3H, NCMeMe0),
1.11e1.06 (m, 3H, (CH2)5CH3), 1.02 (s, 3H, NCMeMe0), 1.05e0.92 (m,
6H, (CH2)5CH3), 0.90e0.80 (m, 1H, (CH2)5CH3), 0.72 (t, 3H,
(Me0)); 13C NMR (100 MHz, chloroform-d1)
d 173.9, 154.1, 136.5,
136.1, 135.9, 130.5, 129.6, 128.9, 127.8, 127.7, 78.9, 75.0, 60.7, 56.0,
30.4, 30.1, 24.8, 24.2, 20.9, 15.0; nmax (film)/cmꢁ1 1771, 1702, 1429,
1375, 1305, 1177, 1114, 1088, 1051, 909, 735; HRMS (ESþ) calcd for
C35H38NO4Si [MþH]þ 564.2570, found 564.2584.
J¼7.1 Hz, (CH2)5CH3); 13C NMR (100 MHz, chloroform-d1)
d 177.5,
154.5, 141.7, 135.9, 135.3, 134.6, 130.5, 130.0, 128.4, 128.3, 128.3,
127.9, 80.2, 74.9, 61.0, 51.8, 31.9, 30.1, 29.5, 27.1, 25.4, 24.8, 22.8,
14.3; nmax (film)/cmꢁ1 1773, 1697, 1429, 1383, 1305, 1173, 1116,
1086, 1071, 710, 698; HRMS (ESþ) calcd for C38H43NO4Si [MþNH4]þ
623.3300, found 623.3301. X-ray crystallography deposition
number: CCDC 679324.
3.4.8. rac-3-((2RS,3RS)-3-Cyclohexyl-2-phenyl-3-(triphenylsilyloxy)
propanoyl)-4,4-dimethyloxazolidin-2-one, 4h. General procedure A
was performed on a 0.41 mmol scale. The crude product (>95:5
anti/syn as determined by 1H NMR analysis) was purified by column
chromatography (1:3 Et2O/hexanes) to afford 4h (178 mg, 72%) as
a white amorphous solid. Rf¼0.21 (1:3 Et2O/hexane); 1H NMR
(400 MHz, chloroform-d1)
d 7.72 (m, 6H, ArH), 7.44e7.33 (m, 9H,
3.4.5. rac-3-((RS)-2-((SR)-(2,6-Dimethoxyphenyl)(triphenylsilyloxy)
methyl)octanoyl)-4,4-dimethyloxazolidin-2-one, 4e. General pro-
cedure A was performed on a 0.30 mmol scale. The crude product
(83:17 anti/syn as determined by 1H NMR analysis) was purified by
column chromatography (1:4 Et2O/hexanes) to afford 4e (131 mg,
66%) as a clear oil (Recrystallization by dissolving in a minimum
amount of dichloromethane with slow addition of Hex at 0 ꢀC
afforded anti-4e as a white solid.). Rf¼0.20 (1:4 Et2O/hexane); mp
ArH), 7.28e7.18 (m, 5H, ArH), 5.65 (d, 1H, J¼9.8 Hz, PhCH), 4.56
(appt. d, 1H, J¼9.8 Hz, Ph3SiOCH), 3.63 (ABq, 2H, J¼10.7, 8.4 Hz,
OCH2), 1.74e1.61 (m, 2H, CyH), 1.52e1.28 (m, 5H, CyH), 1.12e1.06
(m,1H, CyH),1.03 (s, 3H, NCMeMe0), 0.99e0.85 (m, 2H, CyH), 0.82 (s,
3H, NCMeMe0), 0.85e0.75 (m, 1H, CyH); 13C NMR (100 MHz, chlo-
roform-d1)
d 174.1, 145.1, 136.5, 136.2, 136.0, 135.4, 130.0, 129.6,
128.9, 128.3, 127.9, 127.8, 79.1, 75.0, 60.7, 55.1, 40.9, 30.5, 26.8, 26.8,
26.6, 25.8, 24.9, 24.3; nmax (film)/cmꢁ1 1773, 1702, 1429, 1377, 1315,
1303, 1175, 1113, 1086, 908, 734, 708, 700; HRMS (ESþ) calcd for
C38H41NO4Si [MþNa]þ 626.2703, found 626.2707.
106e108 ꢀC; 1H NMR (400 MHz, chloroform-d1)
d 7.38e7.35 (m, 6H,
ArH), 7.26e7.31 (m, 3H, ArH), 7.23e7.19 (m, 6H, ArH), 6.92 (t, 1H,
J¼8.3 Hz, ArH), 6.18 (d, 1H, J¼8.2 Hz, ArH), 6.10 (d, 1H, J¼8.3 Hz,
ArH), 5.98 (d, 1H, J¼10.1 Hz, Ph3SiOCH), 5.45 (dt, 1H, J¼10.5, 3.9 Hz,
(C6H13)CH), 3.83 (d, 1H, J¼8.2 Hz, OCHH0), 3.59 (m, 4H,
OCHH0þOMe), 3.37 (s, 3H, OMe0), 1.50 (s, 3H, NCMeMe0), 1.22 (s, 3H,
NCMeMe0), 1.2e0.9 (m, 10H, (CH2)5CH3), 0.84 (t, 3H, J¼7.1 Hz,
3.4.9. rac-3-((2RS,3RS,4SR)-2,4-Diphenyl-3-(triphenylsilyloxy)penta-
noyl)-4,4-dimethyloxazolidin-2-one, 4i. General procedure A was
performed on a 0.37 mmol scale. The crude product (>95:5 antisyn
as determined by 1H NMR analysis, a 3:1 Felkin to anti-Felkin
product) was purified by column chromatography (1:4 EtOAc/
hexanes) to afford 4i (99 mg, 43%) as a white amorphous solid
(CH2)5CH3); 13C NMR (100 MHz, chloroform-d1)
d 178.8, 159.9,
158.1, 154.0, 135.4, 135.1, 129.2, 129.2, 127.2, 116.3, 104.3, 103.1, 74.4,
70.8, 55.4, 55.1, 47.6, 31.6, 29.4, 29.3, 26.8, 25.1, 24.3, 22.5, 14.0; nmax
(film)/cmꢁ1 2931, 1777, 1695, 1594, 1475, 1305, 1115, 1107, 1085, 710,
700; HRMS (ESþ) calcd for C40H47NO6Si [MþNa]þ 688.3070, found
688.3110.
(Recrystallization by dissolving in
a minimum amount of
dichloromethane with slow addition of Hex at 0 ꢀC afforded anti-4i
Felkin product as a white solid.). Rf¼0.29 (1:4 EtOAc/hexane); mp
215e216 ꢀC; 1H NMR (400 MHz, chloroform-d1)
d 7.39e7.23 (m,
20H, ArH), 7.07 (t, 1H, J¼7.3 Hz, ArH), 6.50 (t, 2H, J¼7.8 Hz, ArH),
6.78 (d, 2H, J¼7.3 Hz, ArH), 5.72 (d, 1H, J¼9.7 Hz, PhCH), 4.80 (dd,
1H, J¼9.7, 1.3 Hz, Ph3SiOCH), 3.67 (ABq, 2H, J¼8.2, 12.1 Hz, OCH2),
2.44 (q, 1H, J¼6.97 Hz, MeCH), 1.43 (d, 3H, J¼7.0 Hz, MeCH), 1.02 (s,
3H, NCMeMe0), 0.77 (s, 3H, NCMeMe0); 13C NMR (100 MHz, chlo-
3.4.6. rac-4,4-Dimethyl-3-((2RS,3RS)-2-phenyl-3-(triphenylsilyloxy)
hexanoyl)oxazolidin-2-one, 4f. General procedure A was performed
on a 0.22 mmol scale. The crude product (86:14 anti/syn as de-
termined by 1H NMR analysis) was purified by column chroma-
tography (1:4 Et2O/hexanes) to afford 4f (141 mg, 57%) as a white
solid (Recrystallization by dissolving in a minimum amount of
dichloromethane with slow addition of Hex at 0 ꢀC afforded anti-4f
as a white solid.). Rf¼0.18 (1:4 Et2O/hexane); mp 106 ꢀC; 1H NMR
roform-d1)
d 173.3, 154.1, 144.7, 136.6, 135.8, 135.6, 129.7, 129.4,
129.2, 128.8, 128.1, 127.8, 126.1, 79.9, 75.0, 60.7, 56.6, 40.5, 24.7, 24.3,
11.3; nmax (film)/cmꢁ1 1771, 1702, 1312, 1115, 1088, 908, 732, 698;
HRMS (ESþ) calcd for C40H39NO4Si [MþNH4]þ 643.2987, found
643.2984. X-ray crystallography deposition number: 679325.
(400 MHz, chloroform-d1)
d 7.75e7.71 (m, 6H, ArH), 7.47e7.36 (m,
11H, ArH), 7.31e7.24 (m, 3H, ArH), 5.55 (d, 1H, J¼9.7 Hz, PhCH), 4.83
(dt, 1H, J¼9.7, 5.1 Hz, Ph3SiOCH), 3.74 (ABq, 2H, J¼8.3 Hz, OCH2),
1.35e1.30 (m, 2H, Ph3SiOCHCH2), 1.29 (s, 3H, NCMeMe0), 1.24e1.15
(m, 2H, CH3CH2), 1.07 (s, 3H, NCMeMe0), 0.46 (t, 3H, J¼6.8 Hz,
3.4.10. (S)-4-tert-Butyl-3-((2R,3R)-4-methyl-2-phenyl-3-(triphe-
nylsilyloxy)pentanoyl)oxazolidin-2-one, 4j. General procedure
A
was performed on a 0.17 mmol scale. The crude product (94:6 anti/
syn as determined by 1H NMR analysis) was purified by column
chromatography (1:4 Et2O/hexanes) to afford 4j (44 mg, 44%) as
a colourless oil. Rf¼0.22 (1:4 Et2O/hexane); 1H NMR (400 MHz,
CH3CH2); 13C NMR (100 MHz, chloroform-d1)
d 174.3, 154.3, 136.5,
136.1, 135.5, 130.2, 129.7, 128.9, 128.1, 127.9, 75.7, 75.1, 60.9, 56.4,
36.3, 25.0, 24.7, 17.3, 14.0; nmax (film)/cmꢁ1 1769, 1703, 1428, 1317,
1303, 1114, 1104, 1091, 1037, 698; HRMS (ESþ) calcd for C35H37NO4Si
chloroform-d1)
d 7.73e7.72 (m, 6H, ArH), 7.41e7.35 (m, 11H, ArH),

6434
N.P. Grimster et al. / Tetrahedron 66 (2010) 6429e6436
7.25e7.19 (m, 3H, ArH), 5.63 (d, 1H, J¼10.0 Hz, PhCH), 4.73 (dd, 1H,
J¼10.0, 1.2 Hz, Ph3SiOCH), 3.94 (dd, 1H, J¼8.8, 1.6 Hz, NCH), 3.75 (t,
1H, J¼8.8 Hz, OCHH0), 3.62 (dd, 1H, J¼8.0, 1.6 Hz, OCHH0), 1.34 (m,
1H, CH(Me)(Me0)), 0.96 (d, 3H, J¼6.8 Hz, CH(Me)(Me0)), 0.63 (d, 3H,
J¼6.8 Hz, CH(Me)(Me0)), 0.48 (s, 9H, t-Bu); 13C NMR (100 MHz,
chromatography (1:4 EtOAc/hexanes grading to 1:2 EtOAc/hex-
anes) to afford 4n (48 mg, 61%) as a colourless oil. Rf¼0.10 (1:4
EtOAc/hexane); 1H NMR (400 MHz, chloroform-d1)
d 7.40e7.36
(m, 2H, ArH), 7.32e7.18 (m, 5H, ArH), 7.15e7.12 (m, 1H, ArH),
7.06e7.03 (m, 2H, ArH), 5.11 (d, 1H, J¼9.5 Hz, PhCH), 4.47 (dd, 1H,
J¼7.0, 2.3 Hz, NCH), 4.32 (br m, 1H, OHCH), 4.26e4.19 (m, 2H,
OCH2), 2.82 (m, 1H, PhCHH0), 2.58 (m, 1H, PhCHH0), 2.50 (br s, 1H,
OH), 1.63 (m, 2H, PhCH2CH2), 0.68 (s, 9H, t-Bu); 13C NMR
chloroform-d1) d 172.8, 154.3, 136.1, 135.8, 135.5, 129.5, 128.4, 127.5,
78.3, 77.2, 64.5, 60.0, 53.9, 35.8, 29.7, 25.1, 20.4, 14.9, 14.6 (2 aro-
matic carbon signals missing due to overlap); nmax (film)/cmꢁ1
2965, 1775, 1705, 1182, 1105, 1114, 1050, 710, 700; [
a
]
25 þ6.0 (c 0.1,
(100 MHz, chloroform-d1)
d 173.6, 154.0, 141.7, 135.4, 129.3, 128.6,
D
CHCl3); HRMS (ESþ) calcd for C37H41NO4Si [MþNH4]þ 609.3143,
128.4, 128.3, 127.8, 125.7, 72.8, 65.1, 60.7, 56.0, 36.0, 35.2, 31.6,
25
found 609.3136.
25.3; nmax (film)/cmꢁ1 3459, 2963, 1778, 1702, 1370; [
a
]
ꢁ7.5 (c
0.36, CHCl3); HRMS (ESþ) calcd for C24H29NO4 [MþNa]þD418.1994,
3.4.11. (3S)-3-tert-Butyl-2-((2R,3R)-3-hydroxy-4-methyl-2-phenyl-
pentanoyl)cyclopentanone, 4k. General procedure A was performed
on a 0.20 mmol scale. The crude product (>95:5 anti/sum of all
others as determined by 1H NMR analysis) was purified by column
chromatography (1:4 EtOAc/hexanes grading to 1:2 EtOAc/hex-
anes) to afford 4k (35 mg, 52%) as a white solid. Rf¼0.10 (1:4 EtOAc/
found 418.1992.
3.5. General procedure B: FicinieClaisen rearrangement
Metal triflate and additive were added to a reaction vessel,
which was sealed under a positive pressure of nitrogen with
magnetic stirring. Allyl alcohol (1.0 equiv) and ynamide (1.5 equiv)
were azeotroped with toluene (3ꢂ25 mL), and dried in vacuo, be-
fore being dissolved in 1,2-dichloroethane (0.1 M with respect to
the allyl alcohol) and added to the reaction vessel. The reaction
mixture was stirred at room temperature for 24 h, unless stated
otherwise. Once complete, the reaction mixture was filtered
through a pad of silica and washed with dichloromethane. The
reaction mixture was evaporated to dryness under reduced pres-
sure and the residue purified by column chromatography.
hexane); mp 106 ꢀC; 1H NMR (400 MHz, chloroform-d1)
d 7.39 (m,
2H, PhH), 7.26e7.17 (m, 3H, PhH), 5.23 (d, 1H, J¼9.6 Hz, PhCH), 4.42
(dd, 1H, J¼6.8, 2.9 Hz, NCH), 4.21e4.14 (m, 3H, OCH2þHOCH), 2.21
(d, 1H, J¼6H, OH), 1.41 (m, 1H, CH(Me)(Me0)), 0.85 (d, 3H, J¼7.2 Hz,
CH(Me)(Me0)), 0.81 (d, 3H, J¼6.8 Hz, CH(Me)(Me0)), 0.62 (s, 9H, t-
Bu); 13C NMR (100 MHz, chloroform-d1)
d 174.3, 154.7, 136.1, 129.7,
129.0, 128.1, 65.5, 61.1, 53.5, 36.4, 29.2, 25.7, 20.8, 14.6; nmax (film)/
cmꢁ1 3600e3300 (br), 2963, 1778, 1702, 1370, 1186, 723; [
a
]
25 þ18
D
(c 0.27, CHCl3); HRMS (ESþ) calcd for C19H27NO4 [MþH]þ 334.2013,
found 334.2013. X-ray crystallography deposition number: CCDC
679326.
3.5.1. rac-(2RS,3SR)-3-(2,3-Diphenyl-pent-4-enoyl)-4,4-dimethylox-
azolidin-2-one, 6a. General procedure B performed on a 0.13 mmol
scale. The crude product (>95:5 syn/anti as determined by 1H NMR
analysis) was purified by column chromatography (50% diethyl ether
in hexanes) to afford the amide 6a (38 mg, 88%) as a white solid. Rf
0.46 (50% diethyl ether in hexanes); 1H NMR (400 MHz, chloroform-
3.4.12. (S)-4-tert-Butyl-3-((2R,3R)-3-cyclohexyl-3-hydroxy-2-phenyl-
propanoyl)oxazolidin-2-one, 4l. General procedure A was performed
on a 0.20 mmol scale. The crude product (>95:5 anti/sum of all others
as determined by 1H NMR analysis) was purified by column chro-
matography (1:4 EtOAc/hexanes grading to 1:2 EtOAc/hexanes) to
afford 4l (37 mg, 50%) as a colourless oil. Rf¼0.15 (1:4 EtOAc/hexane);
d1)
d 7.21e7.19 (m, 2H, PhH), 7.12e7.06 (m, 5H, PhH), 7.05e7.00 (m,
3H, PhH), 6.13 (ddd, 1H, J¼17.4, 11.0, 8.0 Hz, CH2]CH), 5.56 (d, 1H,
1H NMR (400 MHz, chloroform-d1)
d 7.45e7.44 (m, 2H, PhH),
J¼11.3 Hz, C(O)CH), 5.20 (dd, 1H, J¼17.2, 1.1 Hz, CH]CHcisHtrans), 5.10
7.32e7.24 (m, 3H, PhH), 5.34 (d, 1H, J¼9.5 Hz, PhCH), 4.48 (dd, 1H,
J¼7.1, 2.3 Hz, NCH), 4.25e4.16 (m, 3H, OCH2þHOCH), 2.32 (br s, 1H,
OH), 1.76e1.06 (br m, 11H, CyH), 0.68 (s, 9H, t-Bu); 13C NMR
(dt, 1H, J¼10.3, 0.7 Hz, CH]CHcis
H
trans), 4.14 (dd, 1H, J¼12.4, 8.1 Hz,
CH2]CHCH), 3.97 (d, 1H, J¼8.4 Hz, OCHH0), 3.87 (d, 1H, J¼8.4 Hz,
OCHH0), 1.59 (s, 3H, NCMeMe0), 1.41 (s, 3H, NCMeMe0); 13C NMR
(100 MHz, chloroform-d1)
d
174.0, 157.2, 135.7, 129.3, 128.6, 127.6,
(100 MHz, chloroform-d1) d 173.4, 153.9, 140.6, 139.8, 136.5, 129.3,
65.1, 60.7, 52.2, 38.9, 36.0, 30.6, 26.4, 26.3, 26.0, 25.3, 25.0, 24.8; nm2a5x
128.5, 128.1, 128.1, 127.0, 115.8, 74.9, 60.8, 53.9, 53.8, 30.9, 25.0, 24.5;
nmax (film)/cmꢁ1 2972, 1772, 1701, 1320, 1271; HRMS (ESþ) mass
calcd for C22H23NO3 [(MþH)þ]: 350.1756; found: 350.1751.
(film)/cmꢁ1 3502, 2927, 1779, 1701, 1369, 1220, 1184, 1111, 724; [
a]
D
þ0.6 (c 0.57, CHCl3); HRMS (ESþ) calcd for C22H31NO4 [MþNa]þ
396.2151, found 396.2165.
3.5.2. rac-(2RS,3SR)-4,4-Dimethyl-3-[2-(1-phenylallyl)-octanyl]-ox-
azolidin-2-one, 6b. General procedure B performed on a 0.21 mmol
scale. The crude product (90:10 syn/anti as determined by 1H NMR
analysis) was purified by column chromatography (20% diethyl
ether in hexanes) to afford amide 6b (71 mg, 97%) as a colourless oil.
Rf 0.66 (50% diethyl ether in hexanes); 1H NMR (400 MHz, chloro-
3.4.13. (S)-4-tert-Butyl-3-((2R,3R)-3-hydroxy-2-phenylhexanoyl)ox-
azolidin-2-one, 4m. General procedure
A was performed on
a 0.20 mmol scale. The crude product (>95:5 anti/sum of all others
as determined by 1H NMR analysis) was purified by column chro-
matography (1:4 EtOAc/hexanes grading to 1:2 EtOAc/hexanes) to
afford 4m (33 mg, 50%) as a colourless oil. Rf¼0.10 (1:4 EtOAc/
form-d1)
d
7.31e7.18 (m, 5H, PhH), 6.01 (ddd, 1H, J¼17.0, 9.7, 7.3 Hz,
hexane); 1H NMR (400 MHz, chloroform-d1)
d
7.44e7.42 (m, 2H,
CH2]CH), 5.03 (dd, 1H, J¼17.0, 1.6 Hz, CH]CHtransHcis), 4.94 (dd,
PhH), 7.32e7.25 (m, 3H, PhH), 5.07 (d, 1H, J¼9.5 Hz, PhCH), 4.49 (dd,
1H, J¼7.2, 2.2 Hz, NCH), 4.28 (m,1H, HOCH), 4.22 (m, 2H, OCH2),1.25
(m, 4H, CH3CH2CH2), 0.82 (t, 3H, J¼7.0 Hz, CH3), 0.68 (s, 9H, t-Bu);
1H, J¼10.1, 1.7 Hz, CH]CHtrans
H
cis), 4.44 (td, 1H, J¼10.5, 3.5 Hz, C(O)
CH), 3.98 (AB q, 2H, J¼8.4 Hz, OCH2), 3.44 (t, 1H, J¼10.0 Hz, PhCH),
1.58 (s, 3H, NCMeMe0), 1.53 (s, 3H, NCMeMe0), 1.25e1.12 (m, 10H,
(CH2)5CH3), 0.81 (t, 3H, J¼7.2 Hz, (CH2)5CH3); 13C NMR (100 MHz,
13C NMR (100 MHz, chloroform-d1)
d 173.7,154.1,135.7,129.3, 128.6,
127.7, 73.2, 65.1, 60.7, 56.0, 36.0, 35.8, 25.3, 18.5, 13.8; nmax (film)/
chloroform-d1) d 177.1, 154.2, 141.9, 139.7, 128.6, 128.0, 126.6, 115.7,
cmꢁ1 3470, 2961, 2872, 1779, 1702,1370, 1121, 1188, 1117, 723, 700;
74.8, 60.9, 55.1, 47.8, 31.5, 31.4, 29.1, 27.1, 25.0, 24.7, 22.4, 13.9; nmax
(film)/cmꢁ1 2926, 1770, 1698, 1377, 1172, 1086; HRMS (ESþ) mass
calcd for C22H31NO3 [(MþH)þ]: 358.2377; found: 358.2377.
25
[
a]
þ4.9 (c 0.57, CHCl3); HRMS (ESþ) calcd for C19H27NO4
D
[MþNa]þ 356.1838, found 356.1846.
3.4.14. (S)-4-tert-Butyl-3-((2R,3R)-3-hydroxy-2-phenylhexanoyl)ox-
3.5.3. rac-(2RS,3RS)-4,4-Dimethyl-3-(3-phenyl-2-thiophen-3-yl-pent-
4-enoyl)-oxazolidin-2-one, 6c. General procedure B performed on
a 0.6 mmol scale. The crude product (>95:5 syn/anti as determined
by 1H NMR analysis) was purified by column chromatography (40%
azolidin-2-one, 4n. General procedure
A was performed on
a 0.20 mmol scale. The crude product (>95:5 anti/sum of all others
as determined by 1H NMR analysis) was purified by column

N.P. Grimster et al. / Tetrahedron 66 (2010) 6429e6436
6435
diethyl ether in hexanes) to afford amide 6c (160 mg, 78%) as
a white solid. Rf 0.56 (50% diethyl ether in hexanes); mp 68e70 ꢀC;
1700, 1300, 1173; HRMS (ESþ) mass calcd for C19H23NO3 [(MþH)þ]:
314.1756; found: 314.1757.
1H NMR (400 MHz, chloroform-d1)
d 7.16e7.02 (m, 6H, ArH), 6.97
(dd, 1H, J¼3.1, 1.4 Hz, ArH), 6.88 (dd, 1H, J¼4.9, 1.4 Hz, ArH), 6.10
(ddd, 1H, J¼17.8, 10.3, 8.0 Hz, CH2]CH), 5.67 (d, 1H, J¼11.2 Hz, C(O)
CH), 5.18 (dt, 1H, J¼17.8, 1.2 Hz, CH]CHtransHcis), 5.09 (dq, 1H,
3.5.7. rac-(2RS,3RS)-4,4-Dimethyl-3-(2-phenyl-3-ethyl-pent-4-enoyl)-
oxazolidinone, 6g. General procedure B performed on a 0.5 mmol
scale. The crude product (>95:5 syn/anti as determined by 1H NMR
analysis) was purified by column chromatography (20% diethyl
ether in hexanes) to afford amide 6g (25 mg, 54%) as a colourless oil.
Rf 0.51 (50% diethyl ether in hexanes); 1H NMR (400 MHz, chloro-
J¼10.4, 1.2 Hz, CH]CHtrans
H
cis), 4.08 (app q, 1H, J¼8.0 Hz, PhCH),
3.99 (d, 1H, J¼8.4 Hz, OCHH0), 3.91 (d, 1H, J¼8.4 Hz, OCHH0), 1.59 (s,
3H, NCMeMe0), 1.46 (s, 3H, NCMeMe0); 13C NMR (100 MHz, chlo-
roform-d1)
d
173.7, 153.9, 140.7, 139.5, 136.8, 128.5, 128.2, 127.8,
form-d1) d 7.43e7.41 (m, 2H, PhH), 7.33e7.25 (m, 3H, PhH), 5.67
126.4, 124.2, 123.5, 116.0, 74.9, 60.8, 54.1, 49.8, 24.9, 24.5; nmax
(film)/cmꢁ1 2929, 1771, 1702, 1305, 1176, 1091; HRMS (ESþ) mass
calcd for C20H21NO3S [(MþH)þ]: 356.1320; found: 356.1323.
(ddd, 1H, J¼17.3, 9.4, 8.8 Hz, CH2]CH), 5.11 (dd, 1H, J¼17.4, 1.8 Hz,
CH]CHtransHcis), 5.09 (dd, 1H, J¼9.5, 1.8 Hz, CH]CHtrans
H
cis), 5.02
(d, 1H, J¼10.6 Hz, PhCH), 3.92 (d, 1H, J¼8.3 Hz, OCHH0), 3.85 (d, 1H,
J¼8.3 Hz, OCHH0), 2.77 (ddt, 1H, J¼10.5, 9.5, 3.3 Hz, CH2¼CHCH),
1.53 (s, 3H, NCMeMe0), 1.37 (s, 3H, NCMeMe0), 1.20e1.14 (m, 1H,
CHH0CH3), 1.06e0.98 (m, 1H, CHH0CH3), 0.74 (t, 3H, J¼7.51 Hz,
3.5.4. rac-(2SR,3RS)-3-(2-Cyclohexyl-3-phenyl-pent-4-enoyl)-4,4-di-
methyloxazolidin-2-one, 6d. General procedure B performed on
a 0.26 mmol scale. The crude product (>95:5 syn:anti as de-
termined by 1H NMR analysis) was purified by column chroma-
tography (30% diethyl ether in hexanes) to afford amide 6d (70 mg,
66%) as a colourless oil. Rf 0.33 (50% diethyl ether in hexanes); 1H
CH2CH3); 13C NMR (100 MHz, chloroform-d1)
d 174.4, 153.9, 139.9,
137.2, 129.4, 128.4, 127.3, 117.1, 76.7, 74.8, 60.8, 53.5, 49.2, 24.9, 24.5,
11.2; nmax (film)/cmꢁ1 2968, 1786, 1700, 1403, 1302, 1173; HRMS
(ESþ) mass calcd for C18H23NO3 [(MþH)þ]: 302.1751; found:
302.1749.
NMR (400 MHz, chloroform-d1) d 7.30e7.24 (m, 3H, PhH), 7.20e7.17
(m, 2H, PhH), 6.14 (ddd, 1H, J¼17.1, 10.1, 1.4 Hz, CH2]CH), 5.07 (dd,
1H, J¼17.1,1.7 Hz, CH]CHtransHcis), 5.03 (dd, 1H, J¼10.1,1.7 Hz, CH]
3.5.8. rac-(2RS,3RS)-(E)-4,4-Dimethyl-3-(3-methyl-2-phenylhex-4-
enoyl)-oxazolidin-2-one, (ꢃ)-6h. General procedure B performed
on a 0.5 mmol scale. The crude product (>95:5 syn/anti as de-
termined by 1H NMR analysis) was purified by column chroma-
tography (30% diethyl ether in hexanes) to afford amide (ꢃ)-6h
(100 mg, 63%) as a white solid. Rf 0.61 (50% diethyl ether in
hexanes); mp 63e65 ꢀC; 1H NMR (400 MHz, chloroform-d1)
CHtrans
H
cis), 4.53 (dd, 1H, J¼9.4, 6.3 Hz, C(O)CH), 3.88 (d, 1H,
J¼8.4 Hz, OCHH0), 3.80e3.74 (m, 2H, OCHH0þPhCH), 1.79e1.60 (m,
3H, c-HexH), 1.56 (s, 3H, NCMeMe0), 1.40 (s, 3H, NCMeMe0),
1.25e0.83 (m, 8H, c-HexH); 13C NMR (100 MHz, chloroform-d1)
d
175.8, 142.0, 139.1, 128.5, 128.0, 126.4, 116.2, 74.5, 60.9, 51.6, 50.4,
38.9, 31.0, 28.9, 26.5, 26.4, 24.9, 24.5; nmax (film)/cmꢁ1 2928, 2853,
1767, 1694, 1305, 1172, 1089; HRMS (ESþ) mass calcd for C22H29NO3
[(MþH)þ]: 356.2226; found: 356.2228.
d
7.43e7.40 (m, 2H, PhH), 7.31e7.21 (m, 3H, PhH), 5.54 (ddq, 1H,
J¼17.2, 8.0, 6.3 Hz, MeHC]CH), 5.40 (dq, 1H, J¼17.1, 1.4 Hz,
MeHC]CH), 4.84 (d, 1H, J¼10.8 Hz, PhCH), 3.92 (d, 1H, J¼8.4 Hz,
OCHH0), 3.85 (d, 1H, J¼8.3 Hz, OCHH0), 2.93 (ddq, 1H, J¼10.8, 8.0,
6.2 Hz, MeHC]CHCH), 1.64 (dd, 3H, J¼6.3, 1.4 Hz, MeHC]C), 1.52
(s, 3H, NCMeMe0), 1.40 (s, 3H, NCMeMe0), 0.74 (d, 3H, J¼6.2 Hz,
3.5.5. (2R,3R)-4,4-Dimethyl-3-[2-phenyl-3-(4-trifluoromethyl-phe-
nyl)-pent-4-enoyl]-oxazolidin-2-one, 6e. General procedure B per-
formed on a 0.12 mmol scale. The crude product (>95:5 syn/anti as
determined by 1H NMR analysis) was purified by column chroma-
tography (20% diethyl ether in hexanes) to afford the amide 6e
(39 mg, 76%) as a white solid. Rf 0.42 (50% diethyl ether in hexanes);
MeCH); 13C NMR (100 MHz, chloroform-d1)
d 174.6, 153.9, 137.5,
135.5, 129.3, 128.4, 127.2, 125.6, 74.8, 60.6, 55.4, 41.2, 24.6, 18.5,
17.9; nmax (film)/cmꢁ1 2967, 2926, 1772, 1701, 1200, 1174, 1087;
HRMS (ESþ) mass calcd for C18H23NO3 [(MþH)þ]: 302.1751;
found: 302.1753.
1H NMR (400 MHz, chloroform-d1)
d
7.35 (d, 2H, J¼8.1 Hz, ArH),
7.21e7.16 (m, 2H, ArH), 7.16e7.07 (m, 5H, ArH), 6.09 (ddd, 1H,
J¼17.5, 11.0, 7.7 Hz, CH2]CH), 5.57 (d, 1H, J¼11.0 Hz, C(O)CH), 5.23
(dd, 1H, J¼17.2, 1.5 Hz, CH]CHtransHcis), 5.15 (dd, 1H, J¼11.0, 1.5 Hz,
3.5.9. (2S,3S)-(E)-4,4-Dimethyl-3-[2-phenyl-3-(4-trifluoromethyl-
phenyl)-hex-4-enoyl]-oxazolidin-2-one, (þ)-6i. General procedure B
performed on a 0.16 mmol scale. The crude product (>95:5 syn/anti
as determined by 1H NMR analysis) was purified by column chro-
matography (30% diethyl ether in hexanes) to afford the amide (þ)-6i
(41 mg, 60%) as a colourless oil. Rf 0.54 (50% diethyl ether in hex-
CH]CHtrans
H
cis), 4.25 (dd, 1H, J¼11.1, 7.7 Hz, CH2]CHCH), 3.99 (d,
1H, J¼8.4 Hz, OCHH0), 3.89 (d, 1H, J¼8.4 Hz, OCHH0), 1.57 (s, 3H,
NCMeMe0), 1.41 (s, 3H, NCMeMe0); 13C NMR (100 MHz, chloroform-
d1)
d
173.9, 154.2, 146.3, 136.4, 133.1, 130.8, 129.6 (q, J¼32.5 Hz),
129.2, 128.2, 127.4, 125.3 (q, J¼3.9 Hz), 123.4 (q, J¼275.0 Hz), 121.7,
61.2, 54.3, 54.2, 25.3, 24.8; nmax (film)/cmꢁ1 2871, 1782, 1698, 1302,
1173; HRMS (ESþ) mass calcd for C23H22F3NO3 [(MþH)þ]: 418.1630;
found: 418.1632.
anes); 1H NMR (400 MHz, chloroform-d1)
d
7.34 (d, 2H, J¼8.4 Hz,
ArH), 7.22e7.18 (m, 2H, ArH), 7.14e7.08 (m, 5H, ArH), 5.68 (dd, 1H,
J¼17.1, 7.3 Hz, MeHC]CH), 5.64 (dq, 1H, J¼17.1, 5.9 Hz, MeHC]CH),
5.55 (d, 1H, J¼11.1 Hz, PhCH), 4.14 (dd, 1H, J¼11.1, 7.3 Hz, MeHC]
CHCH), 3.97 (d, 1H, J¼8.4 Hz, OCHH0), 3.89 (d, 1H, J¼8.4 Hz, OCHH0),
1.66 (d, 3H, J¼5.9 Hz, MeCH]CH), 1.57 (s, 3H, NCMeMe0), 1.43 (s, 3H,
3.5.6. rac-(2RS,3SR)-(E)-4,4-Dimethyl-3-(2-phenyl-3-vinylhex-4-
enoyl)-oxazolidin-2-one, 6f. General procedure B performed on
a 0.16 mmol scale. The crude product (>95:5 syn:anti as de-
termined by 1H NMR analysis) was purified by column chroma-
tography (20% diethyl ether in hexanes) to afford the amide 6f
(28 mg, 59%) as a colourless oil. Rf 0.65 (50% diethyl ether in hex-
NCMeMe0); 13C NMR (100 MHz, chloroform-d1)
d 173.7, 153.9, 145.9,
136.1, 131.6, 129.2, 128.6, 128.4 (q, J¼32.3 Hz), 128.2, 127.2, 125.0 (q,
J¼3.8 Hz), 123.7 (q, J¼272.0 Hz), 122.8, 74.9, 60.8, 53.1, 52.1, 24.9,
24.5, 18.0; nmax (film)/cmꢁ1 2964, 2923, 1782, 1303, 1201, 1174, 1087;
anes); 1H NMR (400 MHz, chloroform-d1)
d
7.37e7.34 (m, 1H, PhH),
[
a
]
25 þ37.6 (c 0.019, CHCl3); HRMS (ESþ) mass calcd for C24H24F3NO3
D
7.30e7.28 (m, 2H, PhH), 7.24e7.22 (m, 2H, PhH), 5.85 (ddd, 1H,
J¼17.8, 10.3, 7.9 Hz, CH2]CH), 5.26e5.19 (m, 1H, MeHC]CH),
5.14e5.04 (m, 4H, CH2]CH þMeHC]CHþC(O)CH), 3.93 (d, 1H,
J¼8.4 Hz, OCHH0), 3.86 (d, 1H, J¼8.4H, OCHH0), 3.53 (br q, 1H,
J¼8.8 Hz, PhCHCH), 1.55 (s, 3H, NCMeMe0), 1.44 (dm, 3H, J¼7.6 Hz,
MeHC]C), 1.39 (s, 3H, NCMeMe0); 13C NMR (100 MHz, chloroform-
[(MþH)þ]: 432.1787; found: 432.1807.
Chiral separation: column: Chiralpak AD-H; flow rate: 0.5 mL/
min; solvent: 99% hexane/IPA; retention times: enantiomer 1:
25.74 min, enantiomer 2: 34.28 min.
3.5.10. (S)-4-tert-Butyl-3-((2S,3S)-2,3-diphenylpent-4-enoyl)-
d1)
d
174.0, 153.8, 139.2, 137.0, 130.1, 129.5, 128.3, 127.4, 127.2, 115.8,
oxazolidin-2-one, (þ)-6j. General procedure
B performed on
a 0.12 mmol scale. The crude product (90:10 syn/anti as determined
74.9, 60.8, 53.5, 50.4, 24.9, 24.5, 18.0; nmax (film)/cmꢁ1 2924, 1776,

6436
N.P. Grimster et al. / Tetrahedron 66 (2010) 6429e6436
by 1H NMR analysis) was purified by column chromatography (50%
diethyl ether in hexanes) to afford amide (þ)-6j (39 mg, 79%) as
a white solid. Rf 0.52 (50% diethyl ether in hexanes); mp 176e178 ꢀC;
data associated with this article can be found in the online version,
at doi:10.1016/j.tet.2010.05.045.
1H NMR(400 MHz,chloroform-d1)
d7.22e7.19(m, 2H, ArH), 7.11e7.02
References and notes
(m, 8H, ArH), 6.19 (ddd, 1H, J¼17.4, 9.7, 7.7 Hz, CH2]CH), 5.71 (d, 1H,
J¼11.4 Hz, C(O)CH), 5.32 (d, 1H, J¼17.2 Hz, CH]CHtransHcis), 5.16 (d,
1. (a) Modern Aldol Reactions; Mahrwald, R., Ed.; Wiley-VCH: Weinheim, Germany,
2004; (b) Mukaiyama, T. Org. React. 1982, 28, 203; (c) Cowden, C. J.; Paterson, I.
Org. React. 1997, 51, 1; (d) Kim, B. M.; Williams, S. F.; Masamune, S. In Com-
prehensive Organic Synthesis; Trost, B. M., Ed.; Pergamon: London, 1991; (e)
Evans, D. A.; Nelson, J. V.; Taber, T. R. Top. Stereochem. 1982, 13, 1.
2. For reviews see: (a) Shibasaki, M. Multimetallic Catalysis in Organic Synthesis;
Wiley-VCH: Weinhem, 2004; (b) Shibasaki, M.; Yoshikawa, N. Chem. Rev. 2002,
102, 2187; (c) Johnson, J. S.; Evans, D. A. Acc. Chem. Res. 2000, 33, 325; (d) For
recent examples, please see Shibasaki, M.; Sasai, H.; Arai, T. Angew. Chem., Int.
Ed. 1997, 36, 1236; (e) Trost, B. M.; Müller, C. J. Am. Chem. Soc. 2008, 130, 2438
and references therein; (f) Northrup, A. B.; MacMillan, D. W. C. J. Am. Chem. Soc.
2002, 124, 6798.
1H, J¼10.3 Hz, CH]CHtrans
H
cis), 4.36 (dd, 1H, J¼7.6, 1.3 Hz, CH2]
CHCH),4.22e4.19(m, 2H, OCH2),4.02(dd,1H, J¼9.2,7.6 Hz, NCH),0.98
(s, 9H, t-Bu); 13C NMR (100 MHz, chloroform-d1)
d 173.0,154.5,140.5,
139.8, 136.4, 129.4, 128.5, 128.2, 128.1, 127.1, 126.3, 116.0, 64.9, 61.9,
53.9, 52.4, 35.8, 25.9; nmax (film)/cmꢁ1 2961, 1759, 1703, 1370, 1212,
25
1184, 1106; [
a
]
þ13.5 (c 0.1, CHCl3); HRMS (ESþ) mass calcd for
D
C24H27NO3 [(MþNH4)þ]: 395.2329; found: 395.2324.
3.5.11. (S)-4-(tert-butyl)-3-((R)-2-((S)-1-phenylallyl)octanoyl)-
3. For examples of multi-catalytic systems, see: (a) Cernak, T. A.; Lambert, T. H. J.
Am. Chem. Soc. 2009, 131, 3124; (b) Kelly, B. D.; Allen, J. M.; Tundel, R. E.;
Lambert, T. H. Org. Lett. 2009, 11, 1381; (c) Evans, P. A.; Cui, J.; Gharpure, S. J.;
Hinkle, R. J. J. Am. Chem. Soc. 2003, 125, 11456.
4. (a) Suzuki, T.; Tokunaga, M.; Wakatsuki, Y. Org. Lett. 2001, 3, 735; (b) Acker-
mann, L.; Kaspar, L. T. J. Org. Chem. 2007, 72, 6149; (c) Clay, J. M.; Vedejs, E. J. Am.
Chem. Soc. 2005, 127, 5766; (d) Kabalka, G. W.; Shoup, T. M.; Goudgaon, N. M. J.
Org. Chem. 1989, 54, 5930; (e) Chen, Y.; Ho, D. M.; Lee, C. J. Am. Chem. Soc. 2005,
127, 12184; (f) Marion, N.; Ramon, R.; Nolan, S. P. J. Am. Chem. Soc. 2009, 131,
448.
5. Witham, C. A.; Mauleon, P.; Shapiro, N. D.; Sherry, B. D.; Toste, F. D. J. Am. Chem.
Soc. 2007, 129, 5838.
6. For examples, see: (a) Saito, N.; Katayama, T.; Sato, Y. Org. Lett. 2008, 10, 3829;
(b) Gourdet, B.; Lam, H. W. J. Am. Chem. Soc. 2009, 131, 3802; (c) Das, J. P.;
Chechlik, H.; Marek, I. Nat. Chem. 2009, 1, 128.
oxazolidin-2-one, (þ)-6k. General procedure
B performed on
a 0.13 mmol scale. The crude product (91:9 syn/anti as determined
by 1H NMR analysis) was purified by column chromatography (20%
diethyl ether in hexanes) to afford amide (þ)-6k (39 mg, 79%) as
a colourless oil. Rf 0.69 (50% diethyl ether in hexanes); 1H NMR
(400 MHz, chloroform-d1)
d 7.33e7.26 (m, 4H, PhH), 7.23e7.20 (m,
1H, PhH), 6.16 (ddd, 1H, J¼17.1, 9.9, 7.3 Hz, CH2]CH), 5.15 (dd, 1H,
J¼16.4, 0.9 Hz, CH]CHtransHcis), 5.00 (dd, 1H, J¼10.2, 1.5 Hz, CH]
CHtrans
H
cis), 4.50 (td, 1H, J¼10.6, 7.1 Hz, C(O)CH), 4.44 (dd, 1H, J¼7.5,
0.9 Hz, NCH), 4.30 (dd, 1H, J¼9.2, 0.9 Hz, OCHH0), 4.17 (dd, 1H, J¼9.1,
7.6 Hz, OCHH0), 3.53 (t, 1H, J¼9.8 Hz, PhCH), 1.18e1.06 (m, 10H,
7. For a review of ynamide chemistry: Zificsak, C. A.; Mulder, J. A.; Hsung, R. P.;
Rameshkumar, C.; Wei, L. L. Tetrahedron 2001, 57, 7575.
8. Yamamoto, H.; Futatsugi, K. Angew. Chem., Int. Ed. 2005, 44, 1924.
9. Sun, J.; Kozmin, S. A. Angew. Chem., Int. Ed. 2006, 45, 4991.
(CH2)5CH3), 0.95 (s, 9H, t-Bu), 0.80 (t, 3H, J¼6.9 Hz, (CH2)5CH3); 13
C
NMR (100 MHz, chloroform-d1)
d 175.9, 154.9, 142.1, 139.9, 128.7,
128.0, 126.6, 116.0, 65.8, 65.3, 62.1, 54.4, 46.5, 35.9, 31.6, 29.1, 27.0,
10. See Supplementary data for details.
25.9, 22.5, 15.2, 14.0; nmax (film)/cmꢁ1 2923, 1778, 1700, 1370, 1319,
11. (a) Evans, D. A.; Tedrow, J. S.; Shaw, J. T.; Downey, C. W. J. Am. Chem. Soc. 2002,
124, 392; (b) Evans, D. A.; Downey, C. W.; Shaw, J. T.; Tredow, J. S. Org. Lett. 2002,
4, 1127; (c) Saito, S.; Kobayashi, S. J. Am. Chem. Soc. 2006, 128, 8704.
12. (a) Ficini, J.; Lumbroso-Bader, N.; Pouliquen, J. Tetrahedron Lett. 1968, 39, 4139;
(b) Ficini, J.; Barbara, C. Tetrahedron Lett. 1966, 52, 6425; (c) Martin Castro, A. M.
Chem. Rev. 2004, 104, 2939.
25
1182, 1100; [
a
]
þ28.6 (c 1.0, CHCl3); HRMS (ESþ) mass calcd for
D
C24H35NO3 [(MþH)þ]: 386.2685; found: 386.2687.
Acknowledgements
13. Mulder, J. A.; Hsung, R. P.; Frederick, M. O.; Tracey, M. R.; Zificsak, C. A. Org. Lett.
2002, 4, 1383.
14. As the metal triflate catalyst controls the release of TfOH (see Experimental for
details) it is possible that the reaction is catalyzed solely by the Brønsted acid.
However, the use of solely catalytic amounts of TfOH only provides the re-
arranged product in <10% yield (cf. 88% with the catalytic metal triflate).
15. For recent examples of catalytic [3,3]-Claisen-type rearrangements, see: (a)
Nelson, S. G.; Wang, K. J. Am. Chem. Soc. 2006, 128, 4232; (b) Bourgeois, D.;
Craig, D.; King, N. P.; Mountford, D. M. Angew. Chem., Int. Ed. 2004, 44, 618; (c)
Akiyama, K.; Mikami, K. Tetrahedron Lett. 2004, 45, 7217; (d) Sherry, B. D.; Toste,
F. D. J. Am. Chem. Soc. 2004, 126, 15978; (e) Nelson, S. G.; Bungard, C. J.; Wang, K.
J. Am. Chem. Soc. 2003, 125, 13000; (f) Hiersemann, M.; Abraham, L. Eur. J. Org.
Chem. 2002, 1461; (g) Uyeda, C.; Jacobsen, E. J. Am. Chem. Soc. 2008, 130, 9228;
(h) Linton, E. C.; Kozlowski, M. C. J. Am. Chem. Soc. 2008, 130, 16162; (i) Yoon, T.
P.; Dong, V. M.; MacMillan, D. W. C. J. Am. Chem. Soc. 1999, 121, 9726.
16. Frederick, M. O.; Mulder, J. A.; Tracey, M. R.; Hsung, R. P.; Huang, J.; Kurtz, K. C.
M.; Shen, L.; Douglas, C. J. J. Am. Chem. Soc. 2003, 125, 2368.
We gratefully acknowledge Syngenta, AstraZeneca, Pfizer and
EPSRC for studentships (to N.P.G., D.A.A.W. and L.K.M.C.), the Royal
Society for University Research Fellowship (to M.J.G.), Phillip &
Patricia Brown for a Next Generation Fellowship (to M.J.G.) and the
EPSRC Mass Spectrometry service (University of Swansea). We are
also grateful to Professor Steven Ley for valuable support.
Supplementary data
Spectral data and compound characterization are available as
Supplementary data free of charge via the Internet. Supplementary