A study into asymmetric Nicholas cyclisation reactions

Article abstract of DOI:10.1016/j.tet.2007.09.077

Three systematic approaches have been employed to investigate asymmetric Nicholas reactions. We found that the use of a chiral N-enoyl derivative provided acceptable levels of selectivity for an intermolecular Nicholas reaction, however, we were unable to identify an auxiliary that could be utilized in an asymmetric conjugate addition and a tandem inter/intramolecular series of Nicholas reactions. The use of chiral pool non-racemic propargyl alcohols, derived from citronellal, provided enhanced levels of selectivity. As a result of these studies we developed a series of Nicholas cyclisations derived from chiral non-racemic salicylaldehyde derivatives. These underwent an extremely rapid and highly efficient cyclisation, under Nicholas conditions, to afford a range of benzopyrans. The adjacent stereogenic centres appear to be formed with high levels of stereocontrol.

Full text of DOI:10.1016/j.tet.2007.09.077

Tetrahedron 63 (2007) 12769–12778
A study into asymmetric Nicholas cyclisation reactions
*
Elizabeth Tyrrell, Julien Millet, Kibur Hunie Tesfa, Neil Williams, Alastair Mann,
Caroline Tillett and Christophe Muller
School of Pharmacy and Chemistry, Kingston University, Penrhyn Road, Kingston, Surrey KT1 2EE, United Kingdom
Received 2 July 2007; revised 13 September 2007; accepted 27 September 2007
Available online 29 September 2007
Abstract—Three systematic approaches have been employed to investigate asymmetric Nicholas reactions. We found that the use of a chiral
N-enoyl derivative provided acceptable levels of selectivity for an intermolecular Nicholas reaction, however, we were unable to identify an
auxiliary that could be utilized in an asymmetric conjugate addition and a tandem inter/intramolecular series of Nicholas reactions. The use of
chiral pool non-racemic propargyl alcohols, derived from citronellal, provided enhanced levels of selectivity. As a result of these studies we
developed a series of Nicholas cyclisations derived from chiral non-racemic salicylaldehyde derivatives. These underwent an extremely rapid
and highly efficient cyclisation, under Nicholas conditions, to afford a range of benzopyrans. The adjacent stereogenic centres appear to be
formed with high levels of stereocontrol.
Ó 2007 Published by Elsevier Ltd.
1. Introduction
technology, substrates derived from the chiral pool and
thirdly the use of chiral propargyl alcohols.
Previously we reported an extremely efficient and highly
diastereoselective synthesis of tricyclic compounds 11 and
benzopyrans 2a and 2b2 (Scheme 1). The chemistry, which
was developed in our laboratory, involves a novel variant
of an intramolecular Nicholas cyclisation reaction3 followed
by an in situ oxidative decomplexation step.
2. Results and discussion
For our initial study we envisaged that exposure of the chiral
complex 3 with a Lewis acid would initiate an intramolecular
Nicholas cyclisation reaction. Oxidative decomplexation of
cobalt hexacarbonyl should, by analogy with the formation
of 1, facilitate a further ring closure to afford 4 (Scheme 2).
O
OEt
O
H
H
H
O
O
H
HBF4
1
Xc
Xc
OH
OEt
Co(CO)3
Co(CO)3
H
Co2(CO)6
3
F
O
O
O
O
2a
2b
O
Xc
Scheme 1.
Xc
H
CAN
(CO)3Co
Co
In common with others working in this area of organocobalt
chemistry4 we were keen to explore any stereoconvergent
capabilities5 of Nicholas cation in an effort to enhance the
stereoselective outcome of the reaction. Most recently we
have focused upon investigating an asymmetric variant of
Nicholas cyclisation reactions summarized above. Three ap-
proaches are discussed involving the use of chiral auxiliary
(CO)3
4
Scheme 2.
The synthesis of compound 4 should be readily achieved in
three steps comprising of an asymmetric conjugate addition
to an N-acyloxazolidinone such as 5 to provide 6. Exposure
of the boron enolate6 derivative of 6 to hexacarbonyl[propiol-
aldehyde diethyl acetal]dicobalt would provide the
* Corresponding author. Tel.: +44 208 547 8810; fax: +44 208 547 7562;
e-mail: e.tyrrell@kingston.ac.uk
0040–4020/$ - see front matter Ó 2007 Published by Elsevier Ltd.
doi:10.1016/j.tet.2007.09.077

12770
E. Tyrrell et al. / Tetrahedron 63 (2007) 12769–12778
cyclisation precursor 7 via an intermolecular Nicholas reac-
tion (Fig. 1). The choice of chiral auxiliary (Xc) was crucial
in order to provide optimum facial selectivity for the conju-
gate addition reaction as well as for both the intermolecular
and intramolecular Nicholas reactions.
The corresponding dicobalt hexacarbonyl complex was
formed in a quantitative yield by exposure of phenylpro-
pargyl aldehyde diethyl acetal to dicobalt octacarbonyl in di-
chloromethane. Analysis of the reaction mixture, by TLC,
30 min after the addition of the complex to the preformed
enolate showed the presence of a new compound. This was
isolated and purified to afford Nicholas adduct 12 in a very
low yield.15
O
O
R1
R1
R2
Conjugate
addition
R3
R3
Xc
Xc
Xc
R2
R
R4
R4
R
6
5
O
O
O
R1
R2
Intermolecular
Nicholas reaction
OEt
OEt
O
N
Ph
10
R
Co2(CO)6
Ph
OEt
Co2(CO)6
EtO
Ph
i. i(Pr2)NEt2,
-78 °C
ii. Bu2BOTf
7
15%
Co2(CO)6
12
Figure 1.
Bu
O
Bu
O
B
The use of organocopper reagents, in conjugate addition re-
actions, is of major importance as a synthetic methodology7
and recent development in this chemistry is in the use of ac-
tivating agents to promote the reaction.8 In addition, the use
of chiral 2-oxazolidinones9 that serve as an efficient chiral
auxiliaries have also made an impact in providing access
to asymmetric conjugate additions.10 Although we screened
a number of chiral auxiliaries for the conjugate addition re-
action11 we obtained optimum levels of diastereoselectivity
with the use of (S)-(ꢀ)-4-benzyl-2-oxazolidinone 8. The
method of choice12 involves addition of a mixture containing
copper(I) bromide–dimethyl sulfide complex and an appro-
priate Grignard derivative, maintained at ꢀ78 ꢁC, to a pre-
cooled THF solution of the chiral N-enoyl derivative 9
(Scheme 3).13
O
N
Ph
11
Scheme 4.
1
Analysis of complex 12 by H NMR spectroscopy enabled
the diastereomeric excess (de) of 50% to be determined.
Our attempts to improve the unexpectedly poor yield of
this rather routine transformation were thwarted. In particu-
lar we explored changes in the stoichiometry of the reagents,
the temperature and solvent effects as well as the in situ
generation of the boron enolate, which provided no enhance-
ment in yield. Molecular modelling of enolate 11 (Quantam
CAChe) suggested that steric hindrance between the phenyl
group, at C-4 of the isoxazolidinone ring, and the b-methyl
group offered an explanation. Thus although the N-enoyl de-
rivative 9 provided the highest levels of diastereoselectivity
for asymmetric conjugate addition reactions the correspond-
ing intermolecular Nicholas reaction was impeded as a result
of steric congestion about the alkylating centre.
O
O
O
i. MgBr
ii. CuBr-Me2S
i. nBuLi
ii. ROCl
HN
Ph
O
N
O
iii. -78 °C
85%, de 86%
8
9
Ph
O
O
N
O
In our efforts to identify a versatile auxiliary we considered
the use of 4-methyl-5-phenyl-2-oxazolidinone. This has
been shown to provide good levels of selectivity for intermo-
lecular Nicholas reactions5 involving simple N-acyl deriva-
tives such as 13a, however, our investigation required the
use of more elaborate N-acylated compounds such as 13b/
13c (Scheme 5).
10
Ph
Scheme 3.
The adduct 10 was obtained efficiently with a diastereomeric
excess of 86%.14 With the appropriately functionalised acyl-
ated auxiliary 10 in hand we turned our attention to investi-
gate its suitability in an intermolecular Nicholas reaction.
Previously it has been shown that Nicholas cation is prone
to enantiomerisation as a result of the fluxional nature of
the cobalt stabililised cation, which exposes both faces to
the attacking nucleophile. The same authors, however,
have also shown that with chiral propionimide metal eno-
lates, such as 11, a stereodifferentiation process results in
kinetic resolution of the racemising cation.5
O
OEt
O
O
O
i. Bu2OTf
OEt
OEt
ii. (iPr)2NEt
R
+
O
N
O
N
iii. 0 °C
60-85%
R
Co2(CO)6
Co2(CO)6
CH3
Ph
CH3
Ph
13
14 a-c
13a R = CH3
13b R = (CH2)4CH=CH2 (80%)
13c R = CH2CH(CH3)(CH2)2CH=C(CH3)2 (82%)
O
OEt
O
O
N
R
Co2(CO)6
Our attempt at Nicholas reaction with a chiral boron enolate
is shown (Scheme 4). The boron enolate 11 was generated by
exposure of 10 with Hunig’s base and dibutylboron triflate.
CH3
15 a-c
Ph
Scheme 5.

E. Tyrrell et al. / Tetrahedron 63 (2007) 12769–12778
12771
In contrast to our previous attempts Nicholas adducts were
obtained in good yields and consistently enhanced diastereo-
selectivities 14a/15a (60% and de of 84%),17 14b/15b (80%
and de of 72%) and 14c/15c (85% and de of 80%). Alkyl-
ation reactions with this particular auxiliary have been
shown to favour the major diastereoisomer bearing a syn
relationship.4c,5,16 In these examples the coupling constant,
J, for the propargylic proton for the major diastereoisomer
varied from 1.83 Hz (14b) to 4.4 Hz (14c). The rationale5
proposes a double stereodifferentiation via the two syn co-
balt cations shown as 16 and 17 (Fig. 2). Reaction of the
Z-boron enolate with cation 16 is predicted to take place rap-
idly to afford the syn product. Cation 16 can also undergo an-
tarafacial migration of the alkylidene moiety to afford the
second syn cation 17. The reaction of cation 17 with the bo-
ron enolate is predicted to be slower than 16 as a result of
a ‘steric mismatch’ between the OEt of cation 17 and the
bulky butyl group bound to the boron atom of the enolate.
This coupling is predicted to afford the anti-isomer. The
stereochemical outcome for this reaction may be explained
in terms of the rapid fluxional nature of the cation. This
occurs at a rate faster than the alkylation reaction itself, how-
ever, the alkylation reaction then occurs at different rates
with the chiral enolate affording a kinetic resolution.
in the subsequent tandem inter/intramolecular Nicholas reac-
tion/s could not be realized with these substrates.
In order to pursue our goal we investigated the use of sub-
strates derived from the chiral pool of natural products.
Initially we identified citronellal 20 as a suitable candidate
that could provide a chiral centre, b- to the propargyl alcohol
moiety in 21, and containing an appropriately positioned
trisubstituted alkenyl group to effect an intramolecular
Nicholas cyclisation. However, despite the fact that the
alkynylation reactions occurred in virtually quantitative
yields the levels of diastereoselectivity achieved were dis-
appointingly low (Scheme 7).
OH
MgBr
R
99%
de 10%
O
R
21
20 R = H, Ph
Scheme 7.
In an attempt to overcome this we focused our attention to
the synthesis of the corresponding chiral optically pure prop-
argyl alcohols. We found that the direct asymmetric alkyny-
lation of 20, as described by Carreira,19 to be a far more
efficient approach than the alternative route involving an
initial oxidation of propargyl alcohol 21, to a propargyl
ketone, followed by a diastereoselective reduction to a chiral
propargyl alcohol.20
Bu
B
Ph
O
O
Me
O
Bu
N
H
antarafacial
migration
R
H
H
Co(CO)3
EtO
H
The asymmetric alkynylation involved the addition of a zinc
acetylide to an aldehyde such as 20 in the presence of a stoi-
chiometric chiral ligand such as N-methylephedrine. For
these studies the two propargyl alcohols 22a/22b were
produced with good selectivity17,21 and each were then
subjected to our one-pot Nicholas cyclisation. This provided
optically active cyclised products 23a/23b in an average
80% yield for each of the three transformations consisting
of complexation, cyclisation and oxidative decomplexation
of the cobalt carbonyls (Scheme 8).
H
.
enantiomerisation
EtO
Co(CO)3
Co(CO)3
17
Co(CO)3
16
Figure 2.
Having established the utility of 4-methyl-5-phenyl-2-oxazo-
lidinone in a Nicholas reaction we next determined its suit-
ability in an asymmetric conjugate addition reaction. This
requirement was essential in order to extend the range of
cyclisation precursors (Scheme 6). Conjugate addition to
the N-enoyl 18 took place in a yield of 78% to afford 19
and, from our initial analysis, with excellent stereoselectiv-
ity. However, as a precaution we hydrolysed 19 to the acid
for conversion to the corresponding chiral ester derivative.
With the ester in hand 1H NMR studies were used to deter-
mine the selectivity of the conjugate addition reaction.18
Results from these chiral derivatisation studies showed that
the conjugate addition reaction had produced an equimolar
mixture of adducts with no apparent selectivity at all. Thus
our endeavours to investigate a stereoselectiveNicholas reac-
tion using a chiral auxiliary to providevariation in the alkenyl
derivatives, via conjugate additions, as well as stereocontrol
CH3 OH
CH3
i. (Co2(CO)8,
dichloromethane
R
ii. BF3OEt2
iii. CAN 0 °C
51-52%
R
22a R = Ph (de 85%)
22b R = Tolyl (de 86%)
23a (de 58%)
23b (de 60%)
CH3
Co2(CO)6
R
O
O
O
O
24
i. RMgBr, THF
ii. CuBr-Me2S
O
N
O
N
Scheme 8.
Ph
CH3
Ph
CH3
19
18
A noteworthy feature of these reactions was the predominant
formation of the disubstituted alkenyl derivative 23, derived
Scheme 6.

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E. Tyrrell et al. / Tetrahedron 63 (2007) 12769–12778
from cluster 24, in preference to a more stable tetrasubsti-
tuted exocyclic double bond. The diastereoselectivity of
the crude product mixtures of 23a and 23b was determined
by GC–MS. This method of analysis provided sufficiently
good separation of diastereoisomers to enable the diastereo-
selectivity to be ascertained. Attempts to separate the major
diastereoisomer from the minor, by chromatography, met
with limited success, however, we are fairly confident that
both 23a and 23b share the same relative cis/trans configura-
tion at the newly formed stereocentres. This deduction is
based upon the similar chemical shifts for C-1 and C-2 for
23a and 23b in the 13C NMR spectra. The use of 13C
NMR chemical shift data22 for comparing the relative
stereochemistry of a compound with 13C NMR data from li-
braries of analogous compounds is not without precedent.23
In Figure 3 the 13C NMR chemical shifts for C-1 and C-2 of
2-methylcyclohexanol are shown. For the cis compound C-1
resonates at d 71.1 ppm and C-2 at d 35.5 ppm whereas for
the corresponding trans isomer these chemical shifts are
deshielded at d 76.6 and 39.7 ppm, respectively. For com-
pound 23a C-1 occurred at d 34.8 ppm and C-2 at
d 51.2 ppm whereas for 23b C-1 resonated at d 34.2 ppm
and C-2 at d 51.2 ppm, respectively. We were left to
conclude from this study that the use of optically active
propargyl alcohols, based upon citronellal derivatives, pro-
vided optically active cyclised products, however, with an
optimised de of 58–60% stereochemical scrambling would
limit the usefulness of these substrates.
hence reduce the propensity for racemisation. The selection
of a suitable range of candidates for screening was based
upon results obtained from our previous study on the enan-
tioselectivity of the asymmetric alkynylation reaction.
During the course of these investigations, using salicylalde-
hyde derivatives,21,24 we established that both the yield and
the enantioselectivity of the zinc-mediated asymmetric alky-
nylation reactions with salicylaldehyde derivatives were
highly dependant upon the electronic nature of the aromatic
ring. We found that the highest levels of enantioselectivity
were observed in substrates in which the aromatic ring con-
tains strategically placed electron withdrawing groups. On
this basis our first candidate was identified (Scheme 9).
Ph
O
i. Zn(OTf)2,
(+)-N-methylephedrine
H
Cl
Cl
H
OH
TEA then
ii. Phenylacetylene
99%
O
O
Cl
Scheme 9.
Cl
25 ee 90%
In general the chiral non-racemic propargyl alcohols used
for these studies were obtained in excellent yields and
with a high level of enantioselectivity,24 for example,
(R)-(+)-25 was obtained in quantitative yield and with an
enantiomeric excess of 90%25 (Scheme 9). With the desired
propargyl alcohol 25 in hand we were able to investigate the
corresponding Nicholas cyclisation reaction. Exposure of 25
to a stirred dichloromethane solution of dicobalt octacar-
bonyl at an ambient temperature provided the corresponding
complex 26 in a quantitative yield. Exposure of the dicobalt
hexacarbonyl complex 26 to the Lewis acid, BF3$OEt2 at
0 ꢁC, led to an extremely rapid cyclisation reaction to afford
the complexed cycloadduct 27. The speed of the reaction
was a noteworthy feature as this was completed within the
time it took for us to carry out a TLC analysis (Scheme 10).
OH δ71.1 ppm
OH δ76.6 ppm
CH3 δ39.7 ppm
C-1
CH3 δ35.5 ppm
C-2
Figure 3.
In order to improve upon the observed selectivity we consid-
ered the use of a salicylaldehyde derivative. We reasoned
that with this substrate both the chiral non-racemic propargyl
alcohol as well as the alkenyl moiety would be constrained
by the presence of an aromatic ring. The presence of a bulky
substituent, R1, in the stabilized complex, has been shown to
strongly favour the formation of a cation as a single syn-
diastereoisomer.7 In the examples shown (Fig. 4) it may be
observed that for a substituent R1¼Me the ratio of syn/trans
diastereoisomers is 1.4:1, however, as the methyl substituent
is replaced by a bulkier group, i.e., R1¼tBu the syn-diaste-
reoisomer prevails >95:1.
Ph
Ph
Ph
Co2(CO)6
Co2(CO)6
H
OH
Cl
Cl
Cl
BF3.OEt2
CAN
F
F
98%
99%
O
O
O
Cl
28
Cl
27
Cl
26
Scheme 10.
We therefore concluded that this phenomenon may reduce
any tendency for scrambling at the propargylic centre and
As well as the speed of the reaction, with complete conver-
sion to products within 2-3 min by TLC analysis, we were
also surprised at the efficiency of the transformation, which
provided benzopyran 27 as a single optically active isolate in
a quantitative yield. Polarimetry, performed upon a dilute so-
lution of the highly coloured complex 27, gave an [a]1D8 +50
(c 0.02, CHCl3). Oxidative decomplexation was accom-
plished using ceric ammonium nitrate (CAN) to afford 28
as the sole product again in a virtually quantitative yield
and with an [a]1D8 ꢀ10 (c 0.1, CHCl3). Analysis of the crude
compound 28, using chiral HPLC25 and 1H NMR in the pres-
ence of a chiral shift reagent, indicated that it was synthes-
ised as a single isomer. We were very surprised at the high
H
R1
H
OR
OR
(CO)3Co
Co(CO)3
(CO)3Co
Co(CO)3
Co2(CO)6
R2
Ph
R2 = TMS, R1 = Me syn : trans 1.4:1 -80 °C
R2 = TMS, R1 = Et syn : trans 2.4:1 -70 °C
R2 = H, R1 = tBu syn : trans >95:1- 20 °C
Ph
Figure 4.

E. Tyrrell et al. / Tetrahedron 63 (2007) 12769–12778
12773
level of stereocontrol exhibited during Nicholas cyclisation
with minimal scrambling at either of the newly formed
asymmetric centres. We thus assume that as the cyclisation
proceeds via a dicobalt hexacarbonyl stabilized cation a tan-
dem convergence in stereochemistry occurs initially at the
propargyllic position as well as in the formation of the con-
tiguous stereogenic centre. The propargylic methine proton
in 28 appeared as a doublet at d 4.09 ppm with a coupling
constant J of 5.1 Hz suggesting a cis-relationship. In order
to probe the generality of the cyclisation reaction we carried
out further experiments with additional chiral non-racemic
propargyl alcohols 29a–d (Scheme 11).
reaction to afford optically active benzopyrans. A most note-
worthy feature in this series of cyclisations was that com-
plete control was exerted during the formation of the two
contiguous stereogenic centres.
4. Experimental
4.1. General26
Melting point determinations were recorded using a Stuart
Scientific SMP3 digital melting point apparatus tube appara-
tus and are uncorrected. IR spectra were recorded on a
Perkin–Elmer 1600 series FTIR spectrophotometer and
were calibrated using a standard polystyrene film. The spec-
tra were recorded either as thin films for liquids between
sodium chloride discs or for solids as a Nujol mull. All infra-
red data are quoted in wave numbers (cmꢀ1). Proton nuclear
magnetic resonance spectra (1H NMR) were recorded at
400 MHz using a JEOL Eclipse 400 MHz spectrometer.
Peak positions are quoted using the d scale relative to tetra-
methylsilane (d¼0) as an internal standard. Carbon-13 NMR
spectra (13C NMR) were recorded at 100 MHz on a JEOL
Eclipse 400 MHz spectrometer using deuterochloroform as
an internal standard. Low resolution mass spectra were
recorded on a VG TRIO-2 mass spectrometer under electron
impact conditions at an ionising potential of 70 eV and/or
with a Hewlett–Packard GC–MS HP5890 (GC) with capil-
lary column and HP 5971 (MS). Accurate mass analyses
were performed and reported on a VG-ZAB-E under EI con-
ditions by the EPSRC National Mass Spectrometry Service
Centre (Swansea) using the EI Peak Match on M+ method.
Reactions were carried out under an atmosphere of dry nitro-
gen unless otherwise stated.
Ph
Ph
H
OH
i. Co2(CO)8
ii. BF3.OEt2
R1
R1
F
iii. CAN
0 °C
O
O
R2
29 (84-96%)
29a R1& R2 = Br (ee 91%)
29b R1= Br, R2 = H (ee 84%)
R2
30 (a-d)
29c R1 = Cl, R2 = H (ee 75%)
29d R1=NO2, R2 = H (ee 78%)
Scheme 11.
It was very gratifying to us that the precursors 29a–d under-
went a swift and efficient intramolecular Nicholas cyclisa-
tion reaction to afford the optically active benzopyrans
30a–d. Having secured the synthesis of five cycloadducts
we were then able to use the available spectroscopic data,
obtained from the crude product, to ascertain that these ben-
zopyrans were all stereochemically related to each other.
Considering the coupling constant, J, for the benzylic proton
(entries 1–5) all show consistency in magnitude. A similar
trend emerges when comparing the chemical shift data for
C-3 and C-4 indicating that these benzopyrans share a com-
mon relative stereochemistry (Table 1).
4.1.1. (S)-4-Benzyl-N-3-(S)-(3,7-dimethyloct-6-enoyl)-
2-oxazolidinone (10). To a dry THF solution of 2-methyl-
6-bromopent-2-ene (0.9 mL, 6.7 mmol) was added
magnesium turnings (0.32 g, 12.6 mmol). The mixture was
stirred at an ambient temperature for 30 min and cooled to
ꢀ40 ꢁC whereupon a copper bromide dimethylsulfide com-
plex (0.67 g, 3.24 mmol) in dry THF (5 mL) and dimethyl-
sulfide (3 mL) were added. The reaction was left to stir for
about 15 min and then warmed to ꢀ15 ꢁC whereupon the
N-acyloxazolidinone 9 (0.50 g, 2.1 mmol) dissolved in dry
THF (5 mL) was added via a cannula. After 30 min the
cold bath was removed and the reaction mixture allowed
to reach an ambient temperature over a period of 2 h. The
reaction mixture was then quenched, by the addition of a sat-
urated solution of ammonium chloride (15 mL), and the sol-
vent removed in vacuo. Ethyl acetate was added (15 mL) and
the organic layer separated and washed sequentially with
a 10% aqueous solution of ammonia (2ꢂ20 mL), water
(1ꢂ20 mL) and a saturated solution of sodium chloride
(1ꢂ20 mL). The organic layer was dried over anhydrous
magnesium sulfate and the solvent removed in vacuo to af-
ford the title compound as a colourless oil. Purification by
chromatography on silica27 (7:3 hexane/ethyl acetate) gave
the Michael adduct 10 (0.60 g, 85%). vmax/cmꢀ1 (film)
2965, 1775, 1699, 1456, 1354, 1276, 1236, 1100; [a]D20
ꢀ25.8 (c 0.46, CHCl3); dH (300 MHz, CDCl3) 7.41–7.24
(5H, m, ArH), 5.42 (1H, dd, J 8.8, 3.7 Hz, O–CH2), 5.06–
5.01 (1H, m, CH](CCH3)2), 4.66 (1H, t, J 8.8 Hz, N–
Table 1
Entry
Compound
Ja Hz
db
dc
1
2
3
4
5
28
5.1
5.5
5.3
5.3
5.8
47.17
47.19
47.29
47.32
46.64
28.99
29.04
28.82
28.90
29.21
30a
30b
30c
30d
1H NMR d (ppm) for benzyl doublet.
13C NMR d (ppm) for C-4 benzyl carbon.
C-3.
a
b
c
3. Conclusions
During the course of these studies we have investigated three
methods to effect a stereoselective Nicholas reaction.
Although we were unable to find a suitable chiral auxiliary,
based upon an N-acylated oxazolidinone, for this purpose
citronellal derivatives underwent Nicholas cyclisations to
afford trisubstituted cyclohexanes with acceptable diastereo-
selectivities. In contrast chiral non-racemic propargyl alco-
hols derived from salicyladehydes underwent a smooth
and highly efficient intramolecular Nicholas cyclisation

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E. Tyrrell et al. / Tetrahedron 63 (2007) 12769–12778
CH), 4.25 (1H, dd, J 8.8, 3.7 Hz, O–CH2), 3.01 (1H, dd, J 16,
5.2 Hz, O]C–CH2), 2.74 (1H, dd, J 16.0, 8.5 Hz, O]C–
CH2), 2.09–1.90 (3H, m, CH2 and CH), 1.65 (3H, s, CH3),
1.55 (3H, s, CH3), 1.38–1.08 (2H, m, CH2), 0.84–0.82
(3H, d, J 6.6 Hz, CH3); dC (100 MHz, CDCl3) 172.3,
153.7, 139.2, 131.4, 129.1, 128.9, 125.9, 124.3, 69.8, 57.6,
42.4, 36.8, 29.3, 25.7, 25.4, 19.6, 17.6; m/z (EI+) Calcd for
C19H25NO3: 333.2173 [M+NH4]+, found: 333.2170.
evaporated in vacuo and dissolved in dichloromethane
(10 mL). In a separate flame-dried flask was added (4R,5S)-
4-methyl-5-phenyl-2-oxazolidinone (0.64 g, 3.61 mmol) in
THF (5 mL) and maintained at a temperature of ꢀ78 ꢁC
with stirring. After 10 min BuLi (1.5 mL, 3.61 mmol) was
added dropwise and left to stir for a further 10 min whereupon
the acid chloride derivative was added dropwise and left stir-
ring until the flask reached an ambient temperature. The sol-
ventwasremovedinvacuoandthecrudereactionmixturewas
purified by chromatography on silica to afford the title com-
pound as an oil (1.18 g, 82%). vmax/cmꢀ1 (film) 2933, 1781,
1699, 1455, 1347, 1221, 1197, 915, 733, 700; dH (300 MHz,
CDCl3) 7.43–7.27 (5H, m, ArH), 5.63 (1H, d, J 7.3 Hz, Ph–
CH), 5.11–5.07 (1H, m, ]CH), 4.80–4.73 (1H, m, N–CH),
2.85 (2H, d, J 6.9 Hz, COCH2), 2.11–1.92 (3H, m, CH2 and
CH), 1.67 (3H, s, ]CCH3), 1.59 (3H, s, ]CCH3), 1.46–
1.35 (1H, m, ]CH–CH2), 1.29–1.19 (1H, m, CH2), 0.97
(3H, d, J 6.6 Hz, N–CH–CH3), 0.87 (3H, d, J 7.2 Hz, CH3);
dC (75 MHz, CDCl3) 172.5, 153.2, 135.4, 133.3, 128.7,
125.6, 124.3, 78.8, 54.7, 42.5, 36.8, 29.2, 25.4, 19.5, 17.6,
14.5; m/z (EI+) Calcd for C20H27NO3: [M+H]+ 330.2064,
found: 330.2068.
4.1.2. (4R,5S)-(D)-4-Methyl-5-phenyl-N-(3-propionyl)-
2-oxazolidinone (13a). To a stirred dry THF solution
(20 mL) of (4R,5S)-(+)-4-methyl-5-phenyloxazolidinone
(1.5 g, 8.47 mmol) maintained at ꢀ78 ꢁC under an atmo-
sphere of nitrogen was added, dropwise, n-BuLi (3.4 mL
of a 2.5 mol solution, 8.5 mmol). When the addition was
complete freshly distilled propionyl chloride (0.82 mL,
9.32 mmol) was added dropwise to the orange reaction mix-
ture. The resulting solution was left to stir at ꢀ78 ꢁC for
30 min and then allowed to slowly reach an ambient temper-
ature. The reaction was quenched by the addition of a satu-
rated solution of ammonium chloride (40 mL). The solvent
was removed in vacuo and replaced with ethyl acetate
(30 mL). The organic layer was extracted and washed se-
quentially with saturated sodium bicarbonate solution
(1ꢂ20 mL) and brine (2ꢂ25 mL). The organic layer was
dried over anhydrous magnesium sulfate, filtered and the
solvent removed in vacuo. Purification of the crude product
was undertaken by chromatography on silica (hexane/ethyl
acetate 7:3) to afford the title compound as a white crystal-
line solid (1.88 g, 95%) mp 96–97 ꢁC. vmax/cmꢀ1 (film)
2981, 2939, 1780, 1694, 1644, 1371, 1243, 1070; [a]D20
+48.8 (c 0.25, CHCl3); dH (300 MHz, CDCl3) 7.42–7.27
(5H, m, ArH), 5.64 (1H, d, J 7.3 Hz, Ph–CH), 4.78–4.72
(1H, m, N–CH), 3.04–2.86 (2H, m, CH3–CH2), 1.15 (3H,
t, J 7.3 Hz, CH3), 0.87 (3H, d, J 6.6 Hz, CH–CH3); dC
(100 MHz, CDCl3) 173.8, 153.1, 133.3, 128.7, 128.6,
125.6, 78.9, 54.7, 29.2, 14.5, 8.2; m/z (EI+) Calcd for
C13H15NO3: [M+NH4]+ 251.1390, found: 251.1390.
4.1.5. Hexacarbonyl[(4R,5S)-(N)-[3-ethoxy-2-methyl-
pent-5-ynoyl]-4-methyl-5-phenyloxazolidin-2-one]dico-
balt (14a). (4R,5S)-(+)-4-Methyl-5-phenyl-N-(3-propionyl)-
2-oxazolidinone 13a (0.5 g, 2.14 mmol) was transferred to
a flame-dried round-bottomed flask under an atmosphere of
argon. Dry dichloromethane (10 mL) was added and the re-
sulting solution was cooled to ꢀ78 ꢁC. Diisopropylamine
(0.45 mL, 2.31 mmol) and dibutylboron triflate (4.75 mL of
a 1.0 M solution, 4.75 mmol) were added sequentially and
the mixture left to stir for 15 min. Propiolaldehyde diethyl
acetal–dicobalt hexacarbonyl complex (0.90 g, 2.35 mmol)
in DCM (5 mL) was added dropwise with continual stirring.
The cold temperature bath was removed and the mixture al-
lowed to warm to an ambient temperature (about 1 h) where-
upon the mixture was partitioned with water. The aqueous
phase was extracted with DCM (3ꢂ10 mL), and the com-
bined organic phases dried over anhydrous magnesium sul-
fate and filtered in vacuo to afford the title compound as
a dark red oil (0.76 g, 60%). The diastereoselectivity was
determined by analysis of the NMR of the crude reaction
mixture (de 84%). Major diastereoisomer: vmax/cmꢀ1 (film)
2965, 2930, 2355, 2093, 2056, 2030, 1783, 1694, 1339,
1192, 1118, 733; dH (300 MHz, CDCl3) 7.41–7.27 (5H, m,
ArH), 6.05 (1H, s, CH), 5.62 (1H, d, J 7.3 Hz, Ph–CH),
4.83–4.69 (1H, m, N–CH), 4.55 (1H, d, J 9.8 Hz, C–CH),
4.24–4.17 (1H, m, CH3–CH), 3.83–3.76 (1H, m, O–CH2),
3.57–3.50 (1H, m, OCH2), 1.24 (3H, d, J 6.9 Hz, CH3),
1.14 (3H, t, J 7 Hz, CH2CH3), 0.86 (3H, d, J 6.8 Hz, CH–
CH3); dC (100 MHz, CDCl3) 173.7, 153.1, 153.1, 152.5,
133.3, 128.7, 128.6, 125.6, 82.3, 78.9, 72.7, 66.7, 54.6,
44.7, 29.2, 14.8, 14.5, 8.2; m/z (EI+) Calcd for
C24H21NO10Co2: [MꢀCO]+ 528.9613, found: 528.9620.
4.1.3. (4R,5S)-(3)-(1-Oxo-3-methyloct-7-enoyl)-4-methyl-
5-phenyl-2-oxazolidinone (13b). This was prepared as pre-
viously described for 13a to afford the title compounds as
a colourless oil (0.93 g, 80%). vmax/cmꢀ1 (film) 2931,
1782, 1699, 1456, 1347, 1219, 1198; [a]2D0 +10.7 (c 0.48,
CHCl3); dH (300 MHz, CDCl3) 7.43–7.27 (5H, m, ArH),
5.85–5.75 (1H, m, CH]CH2), 5.66 (1H, d, J 7.3 Hz, CH–
Ph), 4.97 (1H, dd, J 17.2, 1.5 Hz, ]CH2), 4.91 (1H, dd,
J 10.2, 1.5 Hz, ]CH2), 4.79–4.73 (1H, m, N–CH), 2.96
(1H, dd, J 16.0, 8.4 Hz, CH2–CO), 2.91–2.80 (2H, m,
CH2), 2.67 (1H, dd, J 16.0, 8.4 Hz, CH2–CO), 2.14–1.96
(3H, m, CH2 and CH), 1.49 (2H, m, ]CH–CH2), 0.94
(3H, apparent dd, J 6.6, 5.9 Hz, N–CH–CH3), 0.87 (3H, d,
J 7.2 Hz, CH3); dC (100 MHz, CDCl3) 173.1, 153.2, 138.8,
135.3, 129.0, 128.7, 126.7, 114.4, 78.8, 54.7, 42.5, 36.3,
33.8, 29.2, 19.6, 14.5; m/z (EI+) Calcd for C19H25NO3:
[M+NH4]+ 333.2173, found: 333.2169.
4.1.6. Hexacarbonyl{(4R,5S)-N-[2-(1-ethoxy-2-pro-
pynyl)-hept-6-enoyl]-4-methyl-5-phenyloxazolidin-2-
one}dicobalt (14b). This was prepared, as previously
described for 14a, to afford the title compound as the major
diastereoisomer (de 72%) isolated as a red oil (0.93 g, 80%).
Major diastereoisomer: vmax/cmꢀ1 (film) 2977, 2933, 2341,
2095, 2054, 2029, 1785, 1695, 1456, 1397, 1339, 1192, 975,
4.1.4. (4R,5S)-(3)-(1-Oxo-3-methyloct-7,7-dienoyl)-4-
methyl-5-phenyl-2-oxazolidinone (13c). (S)-(ꢀ)-Citronel-
lic (1.0 mL, 5.42 mmol), oxalyl chloride (0.8 mL,
9.02 mmol) and 1 drop of DMF were stirred at an ambient
temperature under an atmosphere of nitrogen gas. Once
the acid was consumed, by TLC analysis, the mixture was

E. Tyrrell et al. / Tetrahedron 63 (2007) 12769–12778
12775
766, 699; dH (400 MHz, CDCl3) 7.43–7.30 (5H, m, ArH),
6.04 (1H, s, alkyne-CH), 5.83–5.71 (1H, m, CH]CH2),
5.61 (1H, d, J 7.3 Hz, CH–Ph), 5.03–4.95 (2H, m, ]CH2),
4.86–4.78 (1H, m, N–CH), 4.50 (1H, d, J 9.5 Hz, EtOCCH),
4.36–4.30 (1H, m, CHC]O), 3.81–3.74 (1H, m, O–CH2),
3.52–3.47 (1H, m, O–CH2), 2.08–2.03 (2H, m, ]CH–
CH2), 1.85–1.66 (2H, m, CH2), 1.49–1.30 (2H, m, CH2),
1.05 (3H, t, J 7.6 Hz, O–CH2–CH3), 0.93 (3H, d, J 6.6 Hz,
CH3); dC (100 MHz, CDCl3) 198.1, 176.5, 151.1, 136.7,
132.1, 129.0, 127.4, 124.3, 113.5, 78.8, 71.3, 65.2, 53.6,
48.5, 43.5, 38.2, 32.3, 27.8, 24.6, 13.4, 12.8; m/z obtained
from a sample of the decomplexed material (EI+) Calcd
for C22H27NO4: [M+H]+ 370.2013, found: 370.2014.
(400 MHz, CDCl3) 7.55–7.44 (2H, m, ArH), 7.34–7.21 (8H,
m, ArH), 5.73 (1H, dd, J 5.3, 8.7 Hz, CH]C(CH3)2), 5.02–
4.98 (1H, m, O–CH), 3.51 (3H, s, OCH3), 2.01–1.85 (3H, m,
CH2CH), 1.68–1.61 (2H, m, CH2), 1.59 (3H, s, C]CCH3),
1.51 (3H, s, C]CCH3), 1.36–1.26 (1H, m, CH2), 1.22–1.11
(1H, m, CH2), 0.90–0.89 (3H, d, J 6.2 Hz, CHCH3); dC
(100 MHz, CDCl3) 165.7, 132, 131.7, 131.6, 130, 129.5,
128.8, 128.3, 128.3, 127.4, 124.2, 122.1, 86.2, 85.2, 65.4,
55.5, 41.6, 36.8, 28.9, 25.5, 25.2, 19.0, 17.6; m/z (EI+) Calcd
for C28H31O3F3: [M+NH4]+ 490.2564, found: 490.2561.
4.1.8. (3S,5S)-5,9-Dimethyl-1-p-tolyldec-8-en-1-yn-3-ol
(22b). The typical procedure for the synthesis of 22a was
followed to afford the title compound as a clear oil
(0.85 g, 65%). The diastereoisomeric excess (de) was deter-
mined and corroborated by GC–MS, measurement of the in-
4.1.7. (3S,5S)-5,9-Dimethyl-1-phenyl-dec-8-en-1-yn-3-ol
(22a). A suspension of zinc triflate (2.2 g, 6.05 mmol) and
(ꢀ)-N-methylephedrine (1.19 g, 6.62 mmol) in 0.3 M tri-
ethylamine in dry toluene was stirred for 2 h at 25 ꢁC. After
2 h phenylacetylene (0.56 g, 0.61 mL, 5.52 mmol) was
delivered to the suspension via syringe followed by (S)-
(ꢀ)-citronellal (0.85 g, 5.52 mmol). The progress of the
reaction was monitored by thin layer chromatography.
Upon completion, ca. 30 h, the reaction mixture was
quenched by the addition of a saturated solution of ammoni-
um chloride (30 mL). The mixture was extracted with di-
ethyl ether (3ꢂ30 mL) and the combined organic layers
were dried over anhydrous magnesium sulfate, filtered and
concentrated in vacuo. Purification by column chromato-
graphy on silica using hexane/ethyl acetate (8:2) gave the
title compound as a colourless oil (0.99 g, 66%). The diaste-
reoisomeric excess (de) was determined and corroborated by
GC–MS, measurement of the integrations of the correspond-
ing 1H NMR spectrum of the crude reaction mixture and the
1H NMR spectrum of the corresponding Mosher ester17 and
found to be de 85%. [a]2D0 +8.3 (c 0.7, CHCl3); vmax/cmꢀ1
3422, 2929, 2202, 1664, 1489, 1444, 1379, 1285, 1069,
758; 1H NMR (CDCl3, 400 MHz) 7.42–7.39 (2H, m, ArH),
7.30–7.27 (3H, m, ArH), 5.11–5.07 (1H, m, CH]C(CH3)2,
4.67–4.62 (1H, m, HO–CH), 2.06–1.92 (2H, m,
CH2CH]), 1.82 (2H, dd, J 1.8, 5.6 Hz, CHCH2CH–),
1.80–1.72 (1H, m, CH3CH–), 1.65 (3H, s, C]CCH3), 1.58
(3H, s, C]CCH3), 1.4–1.33 (1H, m, CHCH2CH2–), 1.24–
1.15 (1H, m, CHCH2CH2–), 0.96–0.94 (3H, d, J 6.4 Hz,
CHCH3); 13C NMR (CDCl3, 100 MHz) 131.8, 131.5,
128.4, 128.3, 124.7, 122.8, 90.3, 85.0, 61.8, 45.2, 37.2,
29.5, 25.8, 19.8, 17.8; m/z (EI+) Calcd for C18H24O:
[M+NH4]+ 274.2165, found: 274.2165.
1
tegrations of the corresponding H NMR spectrum of the
crude reaction mixture and found to be de 86%; [a]D20
ꢀ10.4 (c 0.6, CHCl3); vmax/cmꢀ1 3406, 2959, 2926, 2199,
1718, 1664, 1606, 1508, 1378, 1289, 1062, 817, 755; HHhdH
(400 MHz, CDCl3) 7.30 (2H, d, J 8 Hz, ArH), 7.10 (2H, d, J
7.7 Hz, ArH), 5.13–5.08 (1H, m, CH]C(CH3)2), 4.63 (1H,
dd, J 5.9, 8.0 Hz, HO–CH), 2.34 (3H, s, ArCH3), 2.10–1.94
(2H, m, ]CHCH2), 1.86 (2H, dd, J 5.5, 8.0 Hz, CH2), 1.83–
1.73 (1H, m, CH3CH), 1.67 (3H, s, C]CCH3), 1.60 (3H, s,
C]CCH3), 1.40–1.21 (2H, m, CH2), 0.96 (3H, d, J 6.6 Hz,
CHCH3); dC (100 MHz, CDCl3) 138.5, 131.7, 129.4, 124.8,
119.7, 89.9, 84.9, 61.4, 45.2, 37.0, 29.1, 26.1, 25.0, 21.3,
19.2, 18.1; Calcd for C19H26O: [M+NH4]+ 288.2322, found:
288.2324.
4.2. Asymmetric Nicholas cyclisation reaction
4.2.1. 2-Phenylethynyl-1-isopropenyl-(S)-4-methylcyclo-
hexane (23a). To a 0 ꢁC stirred solution of (3S,5S)-
5,9-dimethyl-1-phenyl-dec-8-en-1-yn-3-ol (22a) (0.6 g,
2.34 mmol) in DCM (10 mL) maintained under an atmo-
sphere of nitrogen was added dicobalt octacarbonyl
(0.96 g, 2.8 mmol). After the evolution of carbon monoxide
had subsided BF3$OEt2 (0.35 mL, 2.8 mmol) was added and
the progress of the reaction was monitored by TLC analysis,
which revealed the presence of a new compound. A saturated
solution of CAN dissolved in methanol was added dropwise
until the evolution of CO was complete, observed as a change
of colour from reddish brown to orange. The solvent was re-
moved in vacuo and the base line impurities removed by
chromatography on silica to afford a colourless oil (0.85 g,
55%). The diastereoisomeric excess (de) was determined
by GC–MS and found to be 58%. [a]2D0 ꢀ0.45 (c 0.22,
CHCl3); vmax/cmꢀ1 3075, 2924, 2868, 2199, 1664, 1490,
1443, 1276, 1069, 888, 756; HHhdH (400 MHz, CDCl3)
7.37–7.33 (2H m, ArH), 7.28–7.22 (3H, m, ArH), 4.86–
4.81 (2H, m, ]CH2), 2.44 (1H, dt, J 3.5, 11.6 Hz, CH),
2.13–2.08 (2H, m, CH2), 2.00 (1H, dt, J 3.5, 11.5 Hz, CH),
1.76 (3H, s, ]CCH3), 1.75–1.68 (2H, m, CH2), 1.48–1.39
(1H, m, CH), 1.30 (1H, td, J 3.5, 12.4 Hz, CH3), 0.98 (1H,
td, J 3.5, 12.6 Hz, CH2), 0.92 (3H, d, J 6.4 Hz, CH–CH3);
dC (100 MHz, CDCl3) 148.3, 131.7, 128.1, 127.4, 124.2,
111.0, 93.3, 81.2, 51.2, 41.8, 34.8, 34.2, 32.2, 31.9, 22.3,
19.9; Calcd for C18H22: [M+H]+ 239.1794, found: 239.1792.
Mosher ester derivative. To a solution of (3S,5S)-5,9-
dimethyl-1-phenyl-dec-8-en-1-yn-3-ol (22a) (0.008 g,
0.031 mmol) were added (S)-(+)-a-methoxy-a-(trifluorome-
thyl)phenylacetylchloride (0.018 mL, 0.09 mmol), 4-(dime-
thylamino)pyridine (0.003 g, 0.002 mmol), dry pyridine
(0.006 mL, 0.07 mmol) and dry toluene (5 mL), and left to
stir at an ambient temperature for 1 h. The reaction was
quenched by the addition of water (2 mL) and the organics
partitioned with ethyl acetate (4ꢂ5 mL), and washed with
10% hydrochloric acid (0.5 mL) followed by a saturated so-
lution of sodium bicarbonate (0.5 mL). The organiclayer was
dried over anhydrous magnesium sulfate, filtered and con-
centrated in vacuo. Purification by chromatography on silica
gave the Mosher ester as an oil (0.012 g, 81%). vmax/cmꢀ1
3039, 2954, 2856, 1749, 1491, 1453, 1270, 1169, 1124; dH
4.2.2. 2-(4-Ethynyltoluene)-1-isopropenyl-(S)-4-methyl
cyclohexane (23b). This was synthesised according to

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E. Tyrrell et al. / Tetrahedron 63 (2007) 12769–12778
3
2
compound 23a using the following quantities: propargyl
alcohol 22b (0.89 g, 3.29 mmol), dicobalt octacarbonyl
(1.35 g, 3.95 mmol), Lewis acid (0.48 mL, 3.95 mmol) and
CAN (excess) to afford the title compound as a mixture of
diastereoisomers as a colourless oil (0.42 g, 51%). The dia-
stereoisomeric excess (de) was determined by GC–MS and
found to be 60%. [a]2D0 +3.8 (c 0.79, CHCl3); vmax/cmꢀ1
3027, 2923, 2868, 1666, 1455, 1376, 1277, 1177, 1106,
816; HHhdH (400 MHz, CDCl3) 7.29–7.23 (2H, m, ArH),
7.09–7.04 (2H, m, ArH), 4.86–4.80 (2H, m, ]CH2), 2.43
(1H, dt, J 3.5, 11.3 Hz, CH), 2.31 (3H, s, CH3), 2.06 (2H,
m, CH2), 1.99 (1H, dt, J 3.5, 11.3 Hz, CH), 1.76 (3H, s,
]CCH3), 1.75–1.67 (2H, m, CH2), 1.49–1.38 (1H, m,
CH), 1.30 (1H, dt, J 3.5, 12.4 Hz, CH3), 1.04 (1H, td,
J 3.5, 12.6 Hz, CH2), 0.92 (3H, d, J 6.4 Hz, CH–CH3); dC
(100 MHz, CDCl3) 148.4, 137.7, 131.5, 128.9, 121.1,
110.9, 92.5, 81.3, 51.2, 41.8, 34.8, 34.2, 32.2, 31.9, 22.3,
21.4, 19.9; Calcd for C19H24: [M]+ 252.1873, found:
252.1876.
2JC–F 23.0 Hz), 37.17 (d, JC–F 5.4 Hz), 26.27 (d, JC–F
24.6 Hz), 24.44 (d, JC–F 23.8 Hz); LRMS (EI) m/z
2
620 [MꢀCO]+ 592, 564, 536, 508, 480, 452, 362, 301,
292, 275.
4.2.3.3. (L)-6,8-Dichloro-3-(1-fluoro-1-methylethyl)-
4-(phenylethynyl)chromane (28). To a stirred solution of
complex (27) (0.484 g, 0.7 mmol) in acetone (100 mL)
maintained at an ambient temperature was added CAN
(2.03 g, 3.7 mmol). Stirring was maintained for about
30 min until the evolution of gas ceased. TLC analysis of
the reaction mixture indicated the presence of a new com-
pound (Rf 0.64, 6:1 hexane/diethyl ether). The reaction
was quenched, by the addition of a saturated solution of
sodium hydrogen carbonate (50 mL), and the mixture was
extracted with diethyl ether (3ꢂ50 mL). The organic layers
were recombined, dried over anhydrous magnesium sulfate,
filtered and the solvent removed in vacuo to afford the title
product as a viscous brown oil yield (0.27 g, 99%) and
99% de as determined by HPLC analysis (Chiralcel OD-H,
10% iPrOH in hexane, 254 nm), tR 5.40. The following spec-
troscopic analysis was conducted on the crude product from
this and all analogous cyclisation reactions. [a]2D1 ꢀ10 (c
0.1, CHCl3); vmax/cmꢀ1 2978, 2200, 1698, 1596, 1450,
1242, 1176; dH (400 MHz, CDCl3) 7.40–7.38 (2H, m,
ArH), 7.36 (1H, dd, J 0.9, 2.5 Hz, ArH), 7.32–7.28 (3H,
m, ArH), 7.25 (1H, dd, J 0.7, 2.6 Hz, ArH), 4.57 (1H, ddd,
J 2.2, 3.3, 11.7 Hz, CH2–H), 4.29 (1H, ddd, J 0.5, 5.7,
11.7 Hz, CH2–H), 4.09 (1H, d, J 5.1 Hz, PhC–H), 2.51–
2.44 (1H, m, H–C–F), 1.52 (3H, d, JH–F 22.2 Hz, CH3),
1.43 (3H, d, JH–F 22.7 Hz, CH3); dC (100 MHz, CDCl3)
148.65, 131.66, 128.69, 128.49, 128.41, 128.38, 125.68,
124.82, 122.73, 122.56, 96.07 (C, d, 1JC–F 168.8 Hz, C–F),
4.2.3. (L)-6,8-Dichloro-3-(1-fluoro-1-methylethyl)-4-
(phenylethynyl)chromane (28).
4.2.3.1. Hexacarbonyl[(1R)-(D)-1-{3,5,dichloro-2-[3-
methylbut-2-en-1-yl)oxy]phenyl}-3-phenylprop-2-yn-1-
ol]dicobalt (26). To a stirred solution of (1R)-(+)-1-{3,5-di-
chloro-2-[3-methylbut-2-en-1-yl]oxy}phenyl-3-phenylprop-
2-yn-1-ol (25) (0.169 g, 0.46 mmol) in dry dichloromethane
(10 mL) was added dicobalt octacarbonyl (0.171 g,
0.50 mmol). After 1 h TLC analysis showed the presence
of a new compound (Rf 0.46 (6:1 hexane/diethyl ether).
The solvent was removed in vacuo to afford the correspond-
ing cluster (26) (0.293 g, 99%). vmax/cmꢀ1 2926, 2092, 2054,
2026, 1670, 1566, 1442, 1380, 1160; HHhdH (400 MHz,
CDCl3) 7.66–7.03 (7H, m, ArH), 6.27 (1H, br s, Ph–C–H),
5.42 (1H, br s, C]C–H), 4.52 (2H, s, CH2), 2.54 (1H, br
d, OH), 1.61 (6H, br ds, CH3ꢂ2); dC (100 MHz, CDCl3)
151.42, 140.47, 137.62, 131.81, 130.33, 129.74, 129.01,
128.90, 128.45, 126.90, 122.16, 119.31, 87.94, 87.00,
70.98, 60.87, 25.95, 15.25; LRMS (EI) m/z 590
[Mꢀ2CO]+, 562, 534, 506, 478, 410, 301, 275, 235, 205.
3
90.38, 83.63, 65.39 (CH2, d, JC–F 9.9 Hz), 47.17 (CH, d,
2JC–F 23.0 Hz, C–C–F), 28.99 (CH, d, JC–F 5.4 Hz, CPh),
3
2
2
25.85 (CH3, d, JC–F 24.6 Hz), 25.48 (CH3, d, JC–F
24.6 Hz); LRMS (EI) m/z 362 [M]+ 327, 301, 274, 239,
176, 115, 105, 77, 61; Calcd for C20H1735Cl2FO [M]+
362.0635, found: 362.0636; UV (iPrOH) lmax1 296 nm,
lmax2 239 nm.
4.2.3.2. Hexacarbonyl[(D)-6,8-dichloro-3-(1-fluoro-1-
methylethyl)-4-(phenyl ethynyl)chromane]dicobalt (27).
To a stirred 0 ꢁC solution of (26) (0.641 g, 0.98 mmol) in
dry DCM (15 mL) was added boron trifluoride diethyl ether-
ate (0.14 g, 128 mL, 0.98 mmol). The reaction was left to stir
under a nitrogen atmosphere for 5 min. TLC analysis
showed the presence of a new faster moving compound (Rf
0.78 (6:1 hexane/diethyl ether). The reaction mixture was
quenched by the addition of a saturated solution of sodium
hydrogen carbonate (15 mL) and partitioned with DCM
(15 mL). The aqueous phase was extracted with DCM
(3ꢂ15 mL) and the combined organic phases were dried
over anhydrous magnesium sulfate, filtered in vacuo and
concentrated to afford a red oil (0.5 g, 80%); [a]1D8 +50
(c 0.2, CHCl3); vmax/cmꢀ1 2946, 2090, 2054, 2028, 1718,
1596, 1450, 1378, 1244; dH (400 MHz, CDCl3) 7.52–7.22
(7H, m, ArH), 6.95 (1H, br s, Ph–C–H), 4.48 (1H, br s, O–
CH2), 2.54 (1H, br dd, J 10.8 Hz, CF–CH), 1.48 (3H, d,
JH–F 22.7 Hz, CH3), 1.29 (6H, d, JH–F 22.2 Hz, CH3); dC
(100 MHz, CDCl3) 148.56, 138.10, 129.14, 128.98,
4.2.4. (D)-6,8-Dibromo-3-(1-fluoro-1-methylethyl)-4-
(phenylethynyl)chromane (30a). This compound was
synthesised according to the general procedure used for
the synthesis of compound (28) to afford the title compound
as a brown semi-solid (0.22 g, 75% over three steps). The
diastereomeric excess was determined by HPLC analysis
i
and found to be 99.5% (Chiralcel OD-H, 10% PrOH in
hexane, 254 nm), tR 5.42 min. [a]2D1 +10 (c 0.2, CHCl3);
vmax/cmꢀ1 2980, 2192, 1658, 1598, 1444, 1244; dH
(400 MHz, CDCl3) 7.64–7.48 (3H, m, ArH), 7.43–7.36
(2H, m, ArH), 7.31–7.26 (2H, m, Ar–H), 4.56 (1H, ddd,
J 2.5, 3.5, 11.9 Hz, CH–H), 4.29 (1H, dd, J 5.8, 11.9 Hz,
CH–H), 4.10 (1H, d, J 5.5 Hz, PhC–H), 2.50–2.44 (1H, m,
3
H–C–F), 1.51 (3H, d, JH–F 22.2 Hz, CH3), 1.43 (3H, d,
3JH–F 22.7 Hz, CH3); dC (100 MHz, CDCl3) 150.01,
134.19, 132.02, 131.68, 128.68, 128.51, 128.43, 125.25,
122.73, 113.07, 111.79, 96.04 (C, d, 1JC–F 168.4 Hz, C–F),
3
90.43, 83.69, 65.60 (CH2, d, JC–F 9.9 Hz), 47.19 (CH, d,
3
2JC–F 23.0 Hz, C–C–F), 29.04 (CH, d, JC–F 5.4 Hz, CPh),
2
2
25.87 (CH3, d, JC–F 24.6 Hz), 25.59 (CH3, d, JC–F
24.6 Hz); LRMS (EI) m/z 452 [M]+, 384, 364, 285, 202,
176, 115, 105, 77, 61; Calcd for C20H1779Br2FO [M]+
1
128.88, 128.01, 127.10, 125.48, 122.63, 96.07 (d, JC–F
169.8 Hz), 90.38, 83.63, 63.66 (d, JC–F 9.2 Hz), 49.22 (d,
3

E. Tyrrell et al. / Tetrahedron 63 (2007) 12769–12778
12777
449.9625, found: 449.9621; UV (iPrOH) lmax1 279 nm,
lmax2 239 nm.
1264; dH (400 MHz, CDCl3) 8.43 (1H, dd, J 0.9, 2.7 Hz,
ArH), 8.04 (1H, dd, J 2.7, 8.9 Hz, ArH), 7.43–7.37 (2H,
m, ArH), 7.33–7.27 (3H, m, ArH), 6.91 (1H, d, J 8.9 Hz,
ArH), 4.59 (1H, ddd, J 2.0, 3.3, 11.9 Hz, CH–H), 4.29
(1H, ddd, J 0.7, 6.0, 11.9 Hz, CH–H), 4.16 (1H, d,
J 5.8 Hz, PhC–H), 2.53–2.46 (1H, m, H–C–F), 1.53 (3H,
4.2.5. (D)-6-Bromo-3-(1-fluoro-1-methylethyl)-4-(phe-
nylethynyl)chromane (30b). This compound was synthes-
ised according to the general procedure used for the
synthesis of compound (28) to afford the title compound
as a yellow waxy solid (0.26 g, 93% over three steps). The
diastereomeric excess was determined by HPLC analysis
3
3
d, JH–F 7.5 Hz, CH3), 1.47 (3H, d, JH–F 8.2 Hz, CH3); dC
(100 MHz, CDCl3) 159.32, 141.83, 131.67, 128.61,
128.46, 126.53, 124.37, 122.68, 122.55, 117.64, 95.95 (C,
i
1
3
and found to be 88% (Chiralcel OD-H, 10% PrOH in hex-
d, JC–F 169.1 Hz, C–F), 89.90, 84.22, 65.37 (CH2, d, JC–
9.9 Hz), 46.64 (CH, d, JC–F 23.0 Hz, C–C–F), 29.21
(CH, d, JC–F 6.2 Hz, CPh), 26.28 (CH3, d, JC–F 24.6 Hz),
ane, 254 nm), tR 5.47 (major), 13.19 (minor). [a]2D1 +15 (c
0.2, CHCl3); vmax/cmꢀ1 2982, 2200, 1692, 1600, 1490,
1270, 1234; dH (400 MHz, CDCl3) 7.57 (1H, dd, J 0.7,
2.5 Hz, ArH), 7.41–7.38 (2H, m, ArH), 7.31–7.28 (3H, m,
ArH), 7.23 (1H, ddd, J 0.7, 2.4, 11.7 Hz, ArH), 6.62 (1H,
d, J 8.6 Hz, ArH), 4.46 (1H, ddd, J 2.2, 3.3, 11.7 Hz, CH–
H), 4.17 (1H, ddd, J 0.5, 5.7, 11.7 Hz, CH–H), 4.06 (1H,
d, J 5.3 Hz, PhC–H), 2.48–2.42 (1H, m, H–C–F), 1.50
2
F
3
2
25.21 (CH3, d, JC–F 24.6 Hz); LRMS (EI) m/z 339 [M]+,
2
296, 276, 261, 205, 176, 115, 61; Calcd for C20H18FNO3
[M]+ 339.1265, found: 339.1267; UV (iPrOH) lmax1
300 nm, lmax2 239 nm.
3
3
(3H, d, JH–F 19.7 Hz, CH3), 1.45 (3H, d, JH–F 22.7 Hz,
CH3); dC (100 MHz, CDCl3) 153.16, 133.69, 131.67,
131.29, 128.38, 128.33, 124.05, 122.98, 118.84, 113.24,
Acknowledgements
We wish to express our thanks to the EPSRC National Mass
Spectroscopy Service Centre, University of Swansea for the
provision of high resolution mass spectra. To Kingston
University BPSRG for a studentship to KHT.
1
96.29 (C, d, JC–F 169.1 Hz, C–F), 91.03, 83.19, 64.64
(CH2, d, JC–F 9.9 Hz), 47.29 (CH, d, JC–F 23.0 Hz, C–
C–F), 28.82 (CH, d, JC–F 5.4 Hz, CPh), 26.08 (CH3, d,
3
2
3
2JC–F 24.6 Hz), 25.32 (CH3, d, JC–F 24.6 Hz); LRMS (EI)
2
m/z 372 [M]+, 311, 285, 233, 205, 176, 151, 115, 61; Calcd
for C20H1879BrFO [M]+ 372.0520, found: 372.0521; UV
(iPrOH) lmax1 284 nm, lmax2 238 nm.
References and notes
1. Tyrrell, E.; Tillett, C. Tetrahedron Lett. 1998, 39, 9535–9538.
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1 1998, 1427–1438; Berge, J.; Claridge, S.; Mann, A.; Muller,
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Tetrahedron Lett. 1990, 44, 6277–6280; (b) Jacobi, P. A.;
Zheng, W. E. Tetrahedron Lett. 1993, 34, 2581–2584; (c)
Jacobi, P. A.; Zheng, W. E. Tetrahedron Lett. 1993, 34, 2585–
2588; (d) Muehldorf, A. V.; Guzman-Perez; Kluge, A. F.
Tetrahedron Lett. 1994, 35, 8755–8758; (e) Jacobi, P. A.;
Herradura, P. Tetrahedron Lett. 1996, 37, 8297–8300; (f)
Montana, A. M.; Cano, M. Tetrahedron Lett. 2001, 42, 7961–
7965; (g) Montana, A. M.; Cano, M. Tetrahedron 2002, 58,
933–951.
4.2.6. (D)-6-Chloro-3-(1-fluoro-1-methylethyl)-4-(phe-
nylethynyl)chromane (30c). This compound was synthes-
ised according to the general procedure used for the
synthesis of compound (28) to afford the title compound as
a viscous brown oil (0.41 g, 60% over three steps). The dia-
stereomeric excess was determined by HPLC analysis and
i
found to be 95% (Chiralcel OD-H, 10% PrOH in hexane,
254 nm), tR 5.37 (major), 11.17 (minor). [a]2D1 +12.5 (c 0.4,
CHCl3); vmax/cmꢀ1 2982, 2200, 1722, 1692, 1600, 1486,
1268, 1232; dH (400 MHz, CDCl3) 7.43 (1H, dd, J 0.7,
2.6 Hz, ArH), 7.41–7.37 (2H, m ArH), 7.31–7.28 (3H, m,
ArH), 7.10 (1H, ddd, J 0.5, 2.6, 8.6 Hz, ArH), 6.76 (1H, d,
J 8.6 Hz, ArH), 4.46 (1H, ddd, J 2.4, 3.3, 11.7 Hz, CH–H),
4.16 (1H, dd, J 5.9, 11.7 Hz, CH–H), 4.06 (1H, d, J 5.3 Hz,
3
PhC–H), 2.48–2.42 (1H, m, H–C–F), 1.50 (3H, d, JH–F
20.0 Hz, CH3), 1.45 (3H, d, JH–F 20.0 Hz, CH3); dC
3
(100 MHz, CDCl3) 152.64, 131.66, 129.74, 128.42, 128.37,
128.33, 125.96, 123.50, 122.99, 118.37, 96.30 (C, d, JC–F
5. Schreiber, S. L.; Klimas, M. T.; Sammakia, T. J. Am. Chem.
Soc. 1987, 109, 5749–5759.
6. Evans, D. A.; Ennir, M. D.; Mathre, D. J. J. Am. Chem. Soc.
1982, 109, 1737–1739.
7. Perlmutter, P. Conjugate Addition Reactions in Organic
Synthesis; Pergamon: Oxford, 1992.
8. The use of TMSI see: Dambacher, J.; Anness, R.; Pollock, P.;
Bergdahl, M. Tetrahedron 2004, 60, 2097–2110; Eriksson,
M.; Iliefski, T.; Nilsson, M.; Olsson, T. J. Org. Chem. 1997,
62, 182–187; Eriksson, M.; Hjelmencrantz, A.; Nilsson, M.;
Olsson, T. Tetrahedron 1995, 51, 12631–12644 and the refer-
ences cited therein; The use of BF3 see: Yamamoto, Y.
Angew. Chem., Int. Ed. Engl. 1986, 25, 947–959.
9. Reviewed by: Arya, P.; Qin, H. Tetrahedron 2000, 56, 917–
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10. (a) Lou, B.-S.; Li, G.; Lung, F.-D.; Hruby, V. J. J. Org. Chem.
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1
169.1 Hz, C–F), 91.01, 83.13, 64.69 (CH2, d, 3JC–F 9.9 Hz),
47.32 (CH, d, JC–F 23.0 Hz, C–C–F), 28.90 (CH, d, JC–F
2
3
2
5.4 Hz, CPh), 26.09 (CH3, d, JC–F 24.6 Hz), 25.31 (CH3,
d, 2JC–F 24.6 Hz); LRMS (EI) m/z 328 [M]+, 293, 265, 233,
205, 176, 151, 61; Calcd for C20H1835ClFO [M]+ 328.1025,
found: 328.1027; UV (iPrOH) lmax1 284 nm, lmax2 235 nm.
4.2.7. (D)-6-Nitro-3-(1-fluoro-1-methylethyl)-4-(phenyl-
ethynyl)chromane (30d). This compound was synthesised
according to the general procedure used for the synthesis
of compound (28) to afford the title compound as a yellow
viscous oil (0.074 g, 84% over three steps). The diastereo-
meric excess was determined by HPLC analysis and found
to be 84% (Chiralcel OD-H, 10% iPrOH in hexane,
254 nm), tR 8.72 (major), 26.70 (minor). [a]2D1 +5 (c 0.2,
CHCl3); vmax/cmꢀ1 2982, 2366, 1586, 1518, 1490, 1336,

12778
E. Tyrrell et al. / Tetrahedron 63 (2007) 12769–12778
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(b) Mosher, H. S.; Dale, J. A.; Dull, D. L. J. Org. Chem. 1969,
34, 2543–2549.
18. Formed under standard non-racemising conditions: DMAP,
methyl mandelate, DCCD.
19. (a) Frantz, D. E.; Fassler, R.; Carreira, E. M. J. Am. Chem. Soc.
2000, 122, 1806–1807; (b) Anand, N. K.; Carreira, E. M. J. Am.
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525–528.
11. These include (S)-(ꢀ)-4-benzyl-2-oxazolidinone and (S)-
4-benzyl-5,5-dimethyl-2-oxazolidinone (Quat).
12. Nicolas, E.; Russell, K. C.; Hruby, V. J. J. Org. Chem. 1993, 58,
766–770. See Ref. 10a.
13. For further examples of the use of this auxiliary in asymmetric
conjugate addition reactions see: Williams, D. R.; Kissel,
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Tetrahedron: Asymmetry 1997, 8, 3213–3221.
14. The de was obtained by 1H NMR spectroscopy from the mea-
surement of the integrals attributed to the b-methyl groups for
each of the diastereoisomers. The configuration of 10 was con-
firmed by its synthesis using an alternative route. This involved
reacting the lithium anion of isoxazolidinone 9 with the acyl
chloride derivative of (R)-citronellic acid. GC–MS analysis
of this derivative showed a retention time 16.26 min and the
corresponding diastereoisomer derived from(S)-citronellic
acid had a retention time of 16.12 min. GC–MS analysis of
compound 10, mixture of diastereisomers, showed a major
peak with a retention time of 16.11 min and a minor peak
with retention time of 16.25 min. With these data we were
able to confirm the configuration of the major diastereoisomer
of 10 as C3-(S).
21. Tyrrell, E.; Tesfa, K. H.; Millet, J.; Muller, C. Synthesis 2006,
18, 3099–3105.
22. Kalinowski, H.-O.; Berger, S. Carbon-13 NMR Spectroscopy;
John Wiley and Sons: New York, NY, 1988; p 129.
23. Fringuelli, F.; Pizzo, F.; Taticchi, A.; Halls, T. D. G.; Wenkert,
E. J. Org. Chem. 1982, 47, 5056–5065; Snider, B. A.; Kirk,
T. C. J. Am. Chem. Soc. 1983, 105, 2364–2368; Schinzer, D.;
Ringe, K. Synlett 1994, 463–467.
24. The absolute configuration was determined by single crystal
X-ray diffraction studies. Tyrrell, E.; Tesfa, K. H.; Mann, A.;
Singh, K. Synthesis 2007, 10, 1491–1498.
25. Determined by chiral HPLC (Chiral OD-H) eluted with 10%
iPrOH–hexane.
26. All compounds provided satisfactory spectral data that were
consistent with the assigned structures. Optical rotation data
and HPLC/GC–MS retention times are included for all relevant
examples.
15. Considerable amounts of degradation products resulted.
16. Davies, S. G.; Dixon, D. J.; Doisneau, G. J.-M.; Prodger,
J. C.; Sanganee, H. J. Tetrahedron: Asymmetry 2002, 13,
647–658.
27. To remove faster moving and base line residues only.