Asymmetric conjugate additions to 1,1′-diactivated cyclic enones-a comparative study

Article abstract of DOI:10.1016/j.tetasy.2009.07.006

A study of copper-phosphoramidite-catalysed ZnR₂ and AlR₃ additions to 1,1′-dicarbonyl-activated cyclic Michael acceptors has revealed high enantioselectivities for AlR₃ (R = Me, Et) 1,4-addition to a range of 3-acylcoumarins (85-98% ee, trans:cis ～90:10) using commercial or readily available ligands. Large substituents at the 6-position, and to some extent at the 5-position, of the coumarin are less well tolerated, nor is truncation of the coumarin motif to a comparable 2-acylcyclohexenone (ee values up to 78%).

Full text of DOI:10.1016/j.tetasy.2009.07.006

Tetrahedron: Asymmetry 20 (2009) 1881–1891
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Asymmetric conjugate additions to 1,10-diactivated cyclic enones—
a comparative study
*
Xiaoping Tang, Alexander J. Blake, William Lewis, Simon Woodward
School of Chemistry, The University of Nottingham, University Park, Nottingham NG7 2RD, United Kingdom
a r t i c l e i n f o
a b s t r a c t
A study of copper-phosphoramidite-catalysed ZnR2 and AlR3 additions to 1,10-dicarbonyl-activated cyclic
Michael acceptors has revealed high enantioselectivities for AlR3 (R = Me, Et) 1,4-addition to a range of
3-acylcoumarins (85–98% ee, trans:cis ꢀ90:10) using commercial or readily available ligands. Large sub-
stituents at the 6-position, and to some extent at the 5-position, of the coumarin are less well tolerated,
nor is truncation of the coumarin motif to a comparable 2-acylcyclohexenone (ee values up to 78%).
Ó 2009 Elsevier Ltd. All rights reserved.
Article history:
Received 17 June 2009
Accepted 2 July 2009
Available online 31 August 2009
1. Introduction
tions to 3; 70–98% ee) using 10 mol % of a peptidic amine catalyst)
and that of Feringa4 (who studied nitro derivative 4; 16–92% ee)
Asymmetric conjugate addition (ACA) reactions of organozinc
and organoalane reagents using unsaturated malonic ester as sub-
strate have been described,1a however, the use of cyclic enone sub-
strates bearing two 1,10-related activating carbonyl groups has
scarcely been reported.1 Such substrate architectures are exempli-
fied by the 2-acylcyclohex-2-enones 1 and coumarin derivatives 2
(Scheme 1).
using a his phosphoramidite ligand. No 1,4-alane additions to 1–
2, or any related substrates, appear to have been disclosed. To more
fully define the catalyst system requirements for ACA reactions to
1,10-dicarbonyl-activated substrates we have carried out a study
focussing on enones
1 and in particular, coumarin 2 (with
R = Ph). In general, there is a shortage of highly selective ap-
proaches to enantioenriched 3,4-dihydrocoumarin cores. Aside
from the catalytic studies mentioned above, only two auxiliary-
based approaches have been described.5,6 As a result most medic-
inal chemistry studies on these molecules have used mixtures of
stereoisomers; clearly this situation is undesirable and the attain-
ment of general selective ACA catalysts for substituted coumarins
is desirable.
O
O
O
O
R
HO
iPr2N
R
O
Ph
1
2
tolterodine
O
O
2. Results and discussion
O
O
OMe
2.1. Synthesis of Michael acceptors
O
N
n
O
4
3 n = 0,1
Samples of 2-benzoyl-cyclohex-2-enone 1a were attained from
cyclohex-2-enone via oxidation of the known alcohol 57 (Scheme
2). Dess–Martin periodinane is the preferred oxidant giving a com-
pletely clean conversion to 1a. The use of other oxidants led to an
impure product and associated decomposition. The 3-acylcouma-
rins 2 are attractive starting materials as they are attained easily
from mixtures of salicylaldehydes and 1,3-dicarbonyls as crystal-
line, easily purified, solids. Good literature procedures are avail-
able, but most of them rely on piperidine catalysis,8 whose use is
now associated with regulatory restrictions. In our experience,
the use of pyrrolidine results in broadly equivalent yields while
the use of either amine leads to the small collection 2a–j encom-
passing a range of steric and electronic factors at all available cou-
marin substation positions (Scheme 2).
Scheme 1. Exemplary 1,10-dicarbonyl-activated cyclic substrates and the related
structures of 3-nitrocoumarin and tolerodine.
In particular, the 3,4-dihydrocoumarin ACA products constitute
potentially valuable fragments for the construction of enantiopure
bioactive compounds. For example, recent routes to tolterodine (a
muscarinic receptor drug marketed by Pfizer) are reported to use
Rh-catalysed 1,4-addition of arylboronic acids to coumarin precur-
sors.2 The only enantioselective 1,4-addition of ZnR2 to substrates
closely related to 1–2 that we are aware is that of Hoveyda3 (addi-
* Corresponding author. Fax: +44 115 9513564.
E-mail address: simon.woodward@nottingham.ac.uk (S. Woodward).
0957-4166/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2009.07.006

1882
X. Tang et al. / Tetrahedron: Asymmetry 20 (2009) 1881–1891
O
OH
Ph
ee sample] using ent-LA.9 This 3-BrPh analogue was itself secured
on the basis of an X-ray structure of its precursor ACA-aldol cas-
cade product isolated in 32% yield from cyclohex-2-enone, ZnEt2
and 3-BrPhCHO. A pure sample of 6 (Run 3) also showed negative
rotations indicating that the (2R,3S) configuration corresponded to
the second eluting stereoisomer on a Chiralpak OJ-H column in our
studies. This is exactly the same facial selectivity [when using
(R,S,S)-LA] as delineated explicitly by X-ray studies in coumarin
analogies (see later). The reversal of the sign of the specific rotation
between the ethyl 6 and methyl 7 ACA products is also identical to
the behaviour in the analogous crystallographically defined dihy-
drocoumarin products (see next Section). Although in our route
from 1a, a lower stereoselectivity is attained for 6, the isolated
yields of the equivalent products are much higher. The most
intriguing result from Table 1 is the very low enantioselectivity
associated with the use of dichloromethane (Run 10). The use of
this solvent resulted in a very significant rate acceleration of the
background reaction for reasons that are not at present clear to us.
In light of the results of Table 1, we speculated that the poorer
performance of the 2-benzoyl-cyclohex-2-enone 1a might be due
to the similar size of the phenyl and cyclohex-2-enone substituents
in the substrate. We proposed to combat this in two ways. Firstly,
by increasing the steric profile of the cyclohex-2-enone group
through buttressing to a phenylene group (i.e., use of the coumarin
2); and secondly, by diversifying the ligand structure of the phos-
phoramidite used to promote the asymmetric reaction.
O
O
O
DMP
PhCHO
Ref. 7
Ph
84%
91%
5
1a
1
O
R1
8
R1
2
3
O
OH
cat.
O
O
7
+
O
R2
OMe
6
CHO
NH
1,2
5
4
R2
Ref. 8
R2
R1
2
4
5
3
2
O
O
O
O
68%
87%
61%
74%
68%
6
2a
2b
Ph
Ph
H
8-Br
O
Ph
O
7
2c 8-OMe Ph
1
Ph
10
8
2d
2e
7-OMe Ph
6-OMe Ph
9
2g 53%
2h 10%
69%
87%
75%
2f 6-Me Ph
CO2Et
Bn
H
H
2i
2j
Scheme 2. Preparation of the Michael acceptors used in this study.
2.2. Studies using 2-benzoyl-cyclohex-2-enone 1a
As simple cyclohex-2-enone is known to give exceptionally high
levels of enantioselectivity for the ACA reaction of ZnEt2 using
2.3. Studies using 3-acylcoumarins 2
9
(R,S,S)-phosphoramidite LA this seemed an appropriate point to
begin our studies. However, screening of a range of solvents and
copper(I) precursor salts (17 variations) revealed a system that
optimised to only moderate stereoselectivities (eemax. 77%) for
additions to 1a. Some representative results are given in Table 1;
the best being attained in toluene (ZnMe2), THF (ZnEt2) or Et2O
(AlMe3) using Cu(TC) (TC = 2-thiophenecarboxylate). In all cases,
complete (>99% by GC) conversion was attained and, in general,
AlMe3 gave the most selective ACA reactions.
Compound 2a was selected as a parent substrate for system opti-
misation. Since AlMe3 had provided the highest level of stereoselec-
tivity in the studies with 1a, the use of organoalanes over organozinc
reagents was also selected in the initial trials. However, in case of
unexpected advantages for organozincs over organoalanes, we also
tested ZnEt2 on substrate 2a, but no reaction occurred. Therefore,
in the ACA study of coumarin derivatives we selected organoalanes
as the nucleophile. In addition to commercial LA, 11 other phospho-
ramidites LB–LI (Scheme 3) were selected as these represent modu-
lations of the ‘ligand space’ around the ligated phosphorus atom.
The absolute stereochemistry of products 6–7 has been as-
signed on the basis of Feringa0s synthesis of a 3-bromophenyl ana-
logue of 6 [with a (2R,3S)-configuration and ½aꢁD ¼ ꢂ26:4 for a 93%
Table 1
ACA studies of ZnR2 (R = Et, Me) and AlMe3 to 2-benzoyl-cyclohex-2-enone 1aa
Ph
N
Ph
N
Ph
N
O
O
O
P
P
P
O
O
O
Ph
Ph
O
O
R
Ph
N
Ph
O
O
MR (1.5 equiv.)
Cu(TC) 2 mol%
O
Ph
Ph
P
O
(R,R)
(S,S)
(R,S,S)
LA
LD
LG
LA 4 mol%
Ph
1a
(-)-(2R,3S)-6 R = Et
(+)-(2R,3S)-7 R = Me
or enantiomers
Ph
Ph
N
2-MeOPh
(R,S,S)
LA
O
O
Et
Et
O
P
N
P
P N
O
O
O
Run
MR
Solvent
Temp. (°C)
Time (h)
trans:cis
eeb (%)
Ph
Ph
2-MeOPh
1
2
3
4
5
6
7
8
9
ZnEt2
ZnEt2
ZnEt2
ZnEt2
ZnMe2
ZnMe2
ZnMe2
ZnMe2
AlMe3
AlMe3
AlMe3
DMF
THF
Et2O
Toluene
THF
ꢂ30
ꢂ50
ꢂ30
ꢂ30
ꢂ30
ꢂ30
ꢂ30
ꢂ30
ꢂ50
ꢂ50
ꢂ50
2
4
2
2
3
2
2
2
2
2
2
40:60
58:42
78:22
64:36
36 (2S,3R)
57 (2S,3R)
18 (2R,3S)
24 (2S,3R)
—
62 (2R,3S)
73 (2R,3S)
73 (2R,3S)
77 (2R,3S)
12 (2R,3S)
62 (2R,3S)
(S,S,S)
LB
(R,R)
(S,S)
LH
LE
c
—
2-Nap
2-Nap
2-Nap
Et2O
86:14
82/18
78/22
81:19
91:9
O
O
O
Toluene
CH2Cl2
Et2O
CH2Cl2
Toluene
P
N
P
N
P
N
O
O
O
2-Nap
2-Nap
2-Nap
10
11
54:46
(R,R)
(R,S,S)
LC
(S,S)
a
LF
LI
Ratio of MR/1a/Cu(TC)/LA = 0.75/0.5/0.01/0.02 mmol; 2 ml solvent.
Diastereoselectivity 1a determined by 1H NMR on freshly quenched sample; ee
b
by HPLC (Daicel Chiralpak OJ-H column).
Scheme 3. Phosphamidites LA–LI used in comparison of ligand effects for AlMe3
additions to 2a.
c
No conversion.

X. Tang et al. / Tetrahedron: Asymmetry 20 (2009) 1881–1891
1883
Initial tests confirmed that Et2O was the optimal solvent with
respect to the enantioselectivity but revealed that Cu(TC) could
be replaced with air-stable, low cost Cu(OAc)2 monohydrate in line
with the findings of Alexakis.10a Additionally, Alexakis demon-
strated that sometimes in ACA processes, there is a radical side-
reaction which can lower the enantioselectivity of the reaction,
and that by adding styrene such by-reaction can be suspended.10b
In the optimisation, we trialled the use of 10 equiv of styrene in the
reaction, however, no obvious change was noted. The modularity
of phosphoramidite ligands allows excellent opportunities for ra-
tional optimisation of ‘ligand space’ effects for these additives
(Table 2). Comparison of commercial LA with its diastereomer LB
confirmed that the (R,S,S)-configuration is the stereochemically
matched case (Runs 1–2). The induced atropisomeric ligands LD–
LF confirmed that increasing the bulk of the ‘diol portion’ of the li-
gand was of small benefit (Run 1 vs Run 4), while increasing the
size of the amine had at best a neutral effect (Run 1 vs Run 3
and Runs 4–6). These trends were confirmed by the use of the
unsubstituted biphenyls LG and LI (Runs 7 and 9) while the inclu-
sion of a potentially coordinating OMe had a catastrophic effect
on the reaction’s selectivity (LH, Run 8). In conclusion, commercial
LA and easily prepared11 LD were identified as optimal phospho-
ramidites. Conveniently this pair of ligands allows access to both
enantiomeric series of 8. The ‘selective modification of ligand
space’ approach proved much the most efficient optimisation pro-
cedure in this study. Speculative screening of other ligand classes
(e.g., Duphos, Ferrophites,12 Josiphos and chiral carbenes) revealed
only very poorly performing systems.
that additions to other members of the substrate family 2 proceed
with equivalent facial selectivity using (R,R)-LD. The trans diaxially
3
related 3,4-CH groups in 10 provide a J3,4 coupling of only 5.6 Hz
in its 1H NMR spectrum. Support for the retention of solid state con-
formations of these dihydrocoumarins in solution comes from the
crystal structureof closely related 13. Here it is the ethyl and benzoyl
groups that are placed axially (Fig. 1b, the absolute and relative
3
stereochemistries are equivalent to 10). In 13 the equivalent J3,4
coupling is only 2.2 Hz indicating that an equatorially placed CHCH
pair is retained in solution. Compound 18 (not shown) is present in
the same conformer as 10 in the solid state and similarly shows a
3J3,4 coupling of 5.6 Hz in its solution 1H NMR spectrum.
The specific rotations of the methyl (ꢂ) and ethyl (+) series ACA
products are reversed compared to one another but their HPLC elu-
tion order remains identical. Reversal of the enantiofacial selectivity
between methyl and ethyl nucleophiles when using the same phos-
phoramidite ligand is not reported in the entirety of the ACA alane
literature.1 We believe that observed reversal of the sign of the opti-
cal specific rotation between the methyl and ethyl cases is associ-
ated with the conformation effects seen in Figure 1. A less extreme
case of [a] reversal between methyl and ethyl adducts is known
D
in acyclic ACA products.13 A similar situation exists in products 6
and 7, but here we could not attain supporting X-ray structures.
Allowing for the differences in ligand topicity (LD provides the
opposite enantiomeric series to LA), the facial selectivity observed
in the 3-acylcoumarins 2 is identical to the 2-acylcyclohex-2-enone
1 supporting our idea that the phosphoramidite ligand LA struggles
to differentiate between the steric profiles presented by the cyclo-
hexenyl and the aryl rings in Michael acceptor 1. In general, the
enantioselectivity attained in ACA reactions of the 3-acylcoumarins
2 using LD is dominated by steric rather than electronic or coordina-
tion effects. Substitution at the 7- and 8-position is well tolerated
(Runs 3–6). However, the catalyst copes more poorly with substitu-
tion at the 5- and 6-position, especially in the cases where a methyl
nucleophile is used (Runs 7–13). Steric discrimination, rather than
electronic effects, seems best to account for these outcomes as the
closely electronically related 6- and 8-methoxy compounds (Runs
3 and 7) give radically different ee values. In accord with this picture,
reducing the steric crowding at the 6-position to a methyl group
leads to a recovery in the enantioselectivity (Runs 9–10). In the case
of the methyl addition product 18 synthetically useful levels of
enantioselectivity can be attained through simple recrystallisation.
Values of 88% ee with 99:1 trans:cis ratio are attained after crystalli-
sation from dichloromethane–pentane. In these demanding 6-
substituted coumarins reducing the steric profile of the ligand from
LD to LA can sometimes be helpful. Such an approach is successful in
ethylation of the 5,6-phenylene derivative 2g where use of LA results
in synthetically useful enantioselectivities (Run 11). However, in the
case of the methyl addition, the use of both LA and LD led to catalysts
of low activity. Similar improvement could be achieved with the use
of LA for AlMe3 additions to the 3-ester derivative 2i (Run 13 vs <10%
ee with LD). Overall, optimal enantioselectivities are attained for the
addition of AlEt3 compared to both small and larger nucleophiles
(Runs 3–5). It is worthy to note however that in the case of AliBu3
no competing b-elimination-derived reduction products are formed.
The use of b,b-disubstituted 2h with both LA and LD was not toler-
ated; presumably due to adverse steric congestion. Finally, the ben-
zyl derivative 2j underwent facile conjugate addition but analyses of
the product enantioselectivities were highly complicated by the
presence of an enol tautomer and studies in this area were not
continued.
Table 2
Ligand effects in 1,4-addition of AlMe3 to coumarin 2aa
AlMe3 (1.5 equiv.)
-40 oC, Et2O, 20 h
O
O
O
O
O
O
Cu(OAc)2 H2O 2 mol%
Ph
L
A 4 mol%
Ph
2a
(or other ligand
(+)-(3S,4R)-8
or enantiomer
library member)
Run
L
Yield (%)
trans:cis
eeb (%)
1
2
3
4
5
6
7
8
9
LA
LB
LC
LD
LE
LF
LG
LH
LI
64
49
56
89
89
64
62
80
30
88:12
91:9
88:12
91:9
86:14
85:15
86:14
85:15
90:10
86 (3S,4R)
23 (3S,4R)
71 (3S,4R)
88 (3R,4S)
88 (3R,4S)
77 (3R,4S)
66 (3S,4R)
33 (3S,4R)
12 (3S,4R)
a
Ratio of AlMe3/2a/Cu(OAc)2ꢃH2O/ligand = 1.5/1/0.02/0.04 mmol; 2 ml solvent.
b
Diastereoselectivity determined by 1H NMR on purified sample after flash
chromatography; ee by HPLC (Daicel Chiralpak OD-H column); absolute configu-
ration based on X-ray determination of a derivative from a run using (R,R)-LD (see
later).
The generality of the alane ACA reaction was now tested against
the 3-acyl coumarin family 2 of Scheme 2 (Table 3).
Initially, the absolute stereochemical selectivity induced by li-
gand (R,R)-LD was confirmed by a crystallographic study on the 8-
bromo methyl addition product 10 attained from this ligand
(Fig. 1a). Flack analysis confirmed the ACA reaction results in a 4S
stereocentre in the derived (ꢂ)-methyl product and that a trans rela-
tionship was present between the 3,4-related substituents. An
advantage of the crystallinity of 10 (and many of the other coumarin
products) is that it enables essentially enantiomerically and
diastereomerically pure materials to be attained easily. We assume
In addition, we tested the readily available vinylalane, prepared
by hydroalumination,14 on the coumarin substrate 2 (Scheme 4).
The products were obtained in good to excellent yields (Scheme
4), however, no enantioselectivity was observed. We then checked
the background reaction, and the results showed that the

1884
X. Tang et al. / Tetrahedron: Asymmetry 20 (2009) 1881–1891
Table 3
Substituent effects in 1,4-addition of AlR3 (R = Me, Et, iBu) to coumarins 2
Al(R3)3 (1.5 equiv.)
-40 oC, Et2O, 20 h
1
R1
8
5
R1
2
O
O
O
O
7
3
*
O
6
*
O
Cu(OAc)2 H2O 2 mol%
4
R2
R3
R2
L
A or LD 4 mol%
2a-i
Addition products...
R2 R3
R1
R1
R2 R3
8
9
10
11
H
H
8-Br
8-Br
Ph Me
Ph Et
Ph Me
Ph Et
16 6-OMe Ph Me
17 6-OMe Ph Et
18 6-Me Ph Me
19 6-Me Ph Et
12 8-OMe Ph Me
13 8-OMe Ph Et
-(CH)4-
20
21
22
Ph Et
CO2Et Me
CO2Et Et
14 8-OMe Ph iBu
15 7-OMe Ph Et
H
H
Run
Coumarin
R1 aryl substituent
L
Alane
Yield (%) (product)
trans:cis
eea (%)
1
2
3
4
3
4
5
6
7
2a
2a
2b
2b
2c
2c
2c
2d
2e
2e
2f
H
H
8-Br
8-Br
LD
LD
LD
LD
LD
LD
LD
LD
LD
LD
LD
LD
LA
LD
LA
LD
AlMe3
AlEt3
AlMe3
AlEt3
AlMe3
AlEt3
AliBu3
AlEt3
AlMe3
AlEt3
AlMe3
AlEt3
AlEt3
AlEt3
AlMe3
AlEt3
89 (8)
86 (9)
91:9
93:7
85:15
82:8
90:10
95:5
75:25
>99:1
88:12
90:10
90:10
97:3
88 (3R,4S)
96 (3R,4S)
88 (3R,4S)
96 (3R,4S)
87 (3R,4S)
96 (3R,4S)
75 (3R,4S)
98 (3R,4S)
37 (3R,4S)
48 (3R,4S)
67 (3R,4S)
85 (3R,4S)
90 (1R,2S)b
—
62 (10)
72 (11)
64 (12)
78 (13)
71 (14)
74 (15)
40 (16)
55 (17)
78 (18)
94 (19)
79 (20)
—
8-OMe
8-OMe
8-OMe
7-OMe
6-OMe
6-OMe
6-Me
6-Me
5,6-Phenylene
H
8
9
10
11
12
13
14
2f
2g
2h
2i
97:3
—
89:11
93:7
H
H
67 (21)
68 (22)
53 (3S,4R)
90 (3R,4S)
2i
a
Diastereoselectivity determined by 1H NMR on purified sample after flash chromatography; ee by HPLC (Daicel Chiralpak OD-H column).
The nomenclature of the 2-benzoyl-1-ethyl-1,2-dihydro-benzo[f]chromen-3-one product is unique; the 2 and 1 positions correspond to the equivalent 3 and 4 positions
b
in the other coumarin products.
vinylalane could be added to the substrate in the absence of cop-
per-catalyst, supporting the earlier findings. Because of the reactiv-
ity these sp2 carbon nucleophiles towards these combinations
were not further investigated.
This is of considerable interest in small heterocyclic
species, potentially derived from coumarins, as potential medici-
nal chemical leads. For example, 3-hydroxypyrazoles demonstrate
a wide range of biological activity including antihyperglycaemic,
angiotensin II antagonist and phytotoxicity.15 Recently, closely
related edaravone (Scheme 4) has recently been introduced as a
therapeutic agent for post-stroke trauma.16 Simple reflux of 3-
substituted 4,5-dihydrocoumarin 12 with ethanolic H2NNHMe
Figure 1. Conformational biasing in the solid-state structures of (a) (ꢂ)-(3R,4S)-10 (methyl adduct) and (b), (+)-(3R,4S)-13 (ethyl adduct).

X. Tang et al. / Tetrahedron: Asymmetry 20 (2009) 1881–1891
1885
O
O
O
O
O
O
O
O
O
Ph
O
Ph
O
Ph
O
Ph
Ph
Br
Br
Br
MeO
C8H17
23
24
84% yield
25
86% yield
26
69% yield
81% yield
Scheme 4. Vinylalane addition to coumarin 2.
Me
bonyl species (1 equiv, 10 mmol), was added a few drops of piper-
idine or pyrrolidine. The neat mixture was kept stirring at room
temperature, until a solid was formed. The solid was then dissolved
in CH2Cl2 and neutralised with HCl (1 M). After extracting with
CH2Cl2, the organic phase was dried over MgSO4 and concentrated.
The crude product was then recrystallised from CH2Cl2–pentane to
give a pure product.
N
N
Ph
Ph
HO
N
N
Me
HO
Et
OH
edaravone
OMe
96% ee
27
4.2. General procedure B—ACA reactions with AlMe3 or AlEt3
Scheme 5. 3-Hydroxyprazoles.
In a dry argon-flashed Schlenk tube, Cu(OAc)2ꢃH2O (2 mol %,
0.01 mmol) and ligand (4 mol %, 0.02 mmol; ligand (R,R)-LD is pre-
ferred unless stated otherwise) were dissolved in Et2O (2 ml). After
stirring at room temperature for 30 min, the mixture was cooled to
–40 °C; AlMe3 (or AlEt3) (1.5 equiv, 0.75 mmol) was then added
dropwise, after 5 min, starting material (1 equiv, 0.5 mmol) was
added, and the mixture was stirred at –40 °C for 20 h. The reaction
was then quenched with HCl (1 M) and the reaction mixture was
extracted with Et2O. The organic phase was dried over MgSO4
and concentrated under reduced pressure. The crude product was
then purified by flash column chromatography (light petroleum/
Et2O) over silica gel to give pure product. The pure product was
then recrystallised from CH2Cl2/pentane to effect stereoenrich-
ment if desired. Reactions with ZnR2 (R = Me, Et) were conducted
in an equivalent manner.
resulted in the formation of 3-hydroxypyrazoles in high enantio-
purity (Scheme 5).
3. Conclusion
The use of the readily available phosphoramidites LA (commer-
cial) and LD (one-pot preparation) allows highly selective ACA reac-
tions of AlR3 to 3-acylcoumarins affording products with up to 98%
ee. Steric encumbrance at the 5- or 6-position can lead to a reduc-
tion in selectivity but in many cases the products can be enriched
to enantiopurity through simple recrystallisation. Overall, a gener-
alised procedure providing these useful chiral building blocks has
been realised. Attempted extension of the process to ACA reactions
of 2-acylcyclohex-2-enone is not possible due to the reduced steric
profile of such substrates present to the present ligand set.
4.3. General procedure—preparation of iBu2Al(CH@CH2R)
4. Experimental
In a dry argon-flashed Schlenk tube, terminal alkynes (1 equiv,
0.75 mmol) were dissolved in hexane (1.5 ml). The mixture was
cooled with a water bath, and DIBAL-H (0.14 ml, 0.75 mmol) was
added dropwise. The mixture was then heated to 60 °C for 6 h,
and used immediately.
The general instrumentation used has been described previ-
ously.12 All reactions involving air sensitive materials were carried
out under argon using standard Schlenk techniques. THF and
diethyl ether were distilled under argon from Na-benzophenone.
Light petroleum refers to the fraction bp 40–60 °C. Solutions of
AlR3 and ZnR2 were commercial products (Aldrich). Infrared spec-
tra were recorded using Perkin–Elmer 983 G infrared and Perkin–
Elmer 882 infrared spectrophotometers. 1H and 13C NMR spectra
were recorded on either Jeol (JNM-GX270) or Bruker (AM400,
AV400 or DRX500) spectrometers using CHCl3 (7.27 ppm) or tetra-
methylsilane (0.00 ppm) as standard; J values are given in hertz;
the term ‘app.’ indicates signals with significant 2nd order NMR
distortions, typically associated with the phenyl groups. All spectra
were recorded at ambient temperature. Mass spectra were ob-
tained on Finnigan-MAT 1020 or Autospec VG (electron impact
ionisation, EI), Finnigan-QMS (electrospray ionisation, ESI), VG-
ZAB, or Autospec VG (fast atom bombardment, FAB). Elemental
Analyses were performed using a Fisons Instruments EA 1108
CHN elemental analyser. Optical rotations were measured on a
APD440 polarimeter in units of 10ꢂ1°cm2 gꢂ1 (c in g/100 cm3).
HPLC analyses were carried out on an Agilent Technologies system.
4.4. General procedure C—1,4-addition with iBu2Al(CH@CH2R)
In a dry argon-flashed Schlenk tube, Cu(OAc)2ꢃH2O (2 mol %,
0.01 mmol) and ligand (4 mol %, 0.02 mmol) were dissolved in
Et2O (2 ml). After stirring at room temperature for 30 min, the mix-
ture was cooled to ꢂ40 °C, freshly prepared iBu2Al(CH@CH2R)
(1.5 equiv, 0.75 mmol) was added dropwise. After 5 min, starting
material (1 equiv, 0.5 mmol) was added, and the mixture was stir-
red at ꢂ40 °C for 20 h. The reaction was then quenched with HCl
(1 M) and the reaction mixture was extracted with Et2O. The or-
ganic phase was dried over MgSO4 and concentrated under re-
duced pressure, the crude product was then purified by flash
column chromatography (light petroleum/Et2O) over silica gel to
give pure product.
4.5. Preparation of the ACA Michael acceptors
4.1. General procedure A—preparation of 3-acylcoumarins 2
The substrates for this study were prepared by the procedures
outlined in Scheme 2 and in general procedure A (for coumarins
2). Substrate 1a was prepared from cyclohex-2-enone via 5–6.
Spectroscopic data for these compounds are given below.
To a mixture of
a-hydroxyl benzylaldehyde (1 equiv typically
10 mmol) and ethyl benzoylacetate or an equivalent 1,3-dicar-

1886
X. Tang et al. / Tetrahedron: Asymmetry 20 (2009) 1881–1891
4.5.1. 2-Benzoylcyclohex-2-enone 1a
1735sh, 1731 (2 ꢄ C@O), 1666, 1611, 1577, 1476, 1439, 1366,
Compound
5
(1.67 g, 8.3 mmol) was dissolved in CH2Cl2
1318, 1275, 1240, 1178, 1105, 925, 863 cmꢂ1. HRMS: [M+Na+]
C17H12NaO3, found 303.0613, theoretical mass 303.0628. This com-
pound has appeared in the literature but no spectroscopic data
have been reported.19
(30 ml), Dess–Martin Periodinane (4.2 g, 9.9 mmol) was added,
and the mixture was stirred at room temperature overnight. The
solvent was removed under reduced pressure and the crude prod-
uct was purified by flash column chromatography (light petro-
leum/Et2O: 4/6) over silica gel to give pure product 1a (1.5 g,
4.5.5. 3-Benzoyl-7-methoxy-2H-chromen-2-one 2d
91%) as
a
low melting point solid (mp ꢀ44 °C). 1H NMR
2-Hydroxy-4-methoxybenzaldehyde (1.52 g, 10 mmol) and
ethyl benzoylacetate (1.73 ml, 10 mmol) were treated according
to the general procedure A; the pure product 2d was obtained as
yellow microcrystals (2.08 g, 74% yield). Mp: 147–148 °C (CH2Cl2–
light petroleum) [Lit. 152–153 °C (EtOH)20]. 1H NMR (400 MHz,
CDCl3, 25 °C, TMS) d = 8.12 (s, 1H, H-4), 7.89 (app. dd, J = 8.3 and
1.2 Hz, 2H, Ph-o), 7.63 (app. t, J = 7.4 Hz, 1H, Ph-p), 7.53–7.48 (m,
3H, Ph-m and H-5), 6.94 (dd, J = 8.6 and 2.4 Hz, 1H, H-6), 6.90 (d,
J = 2.4 Hz, 1H, H-8), 3.95 (s, 3H, OMe). 13C NMR (100 MHz, CDCl3,
25 °C, TMS) d = 192.0 (C@O), 164.7 (C@O), 158.8, 157.1, 146.4,
136.8, 133.4, 130.5, 129.5, 128.5, 122.9, 113.6, 111.8, 100.7, 56.0.
(400 MHz, CDCl3, 25 °C, TMS) d = 7.81 (app. d, J = 8.8 Hz, 2H, Ph-
o), 7.57 (app. t, J = 7.8 Hz, 1H, Ph-p), 7.46 (app. t, J = 7.8 Hz, 2H,
Ph-m), 7.29 (t, J = 4.1 Hz, 1H, @CH), 2.64–2.59 (m, 4H, 2 ꢄ ring-
CH2), 2.22–2.19 (m, 2H, ring-CH2). 13C NMR (100 MHz, CDCl3,
25 °C, TMS) d = 196.5 (C@O), 194.9 (C@O), 152.1 (@CH), 141.1,
136.7, 133.5, 129.5, 128.5, 38.4, 25.9, 22.5. IR (CHCl3 solution)
m
= 3011, 2956, 2872, 1684 (C@O), 1667 (C@O), 1598, 1449, 1424,
1359, 1273, 1164, 939, 913, 835 cmꢂ1. HRMS: [MꢂH+] C13H11O2,
theoretical mass 199.0762, found 199.0765. Compound 1a has ap-
peared briefly in the literature but no spectroscopic data were
presented.17
IR (CHCl3 solution)
m
= 3011, 1724 (2 ꢄ C@O), 1660, 1609, 1559,
1507, 1372, 1293, 1147, 1026, 841 cmꢂ1. HRMS: [MꢂH+] C17H11
-
4.5.2. 3-Benzoyl-2H-chromen-2-one 2a
O4, found 279.0652, theoretical mass 279.0663. The spectroscopic
Salicylaldehyde (1.05 ml, 10 mmol) and ethyl benzoylacetate
(1.73 ml, 10 mmol) were treated according to the general proce-
dure A; the pure product 2a was obtained as colourless microcrys-
tals (1.70 g, 68% yield). Mp: 130–132 °C (CH2Cl2/light petroleum)
[Lit. 134–136 °C (EtOH)18]. 1H NMR (400 MHz, CDCl3, 25 °C, TMS)
d = 8.11 (s, 1H, H-4), 7.92 (app. dd, J = 8.4 Hz and 1.3 Hz, 2H, Ph-
o), 7.68–7.62 (m, 3H, Ph-p and H-5,7), 7.52 (app. t, J = 7.7 Hz, 2H,
Ph-m), 7.45 (d, J = 8.4 Hz + unresolved 4J coupling, 1H, H-8), 7.39
(dd, J = 6.6 and 7.7 Hz, 1H, H-6). 13C NMR (100 MHz, CDCl3, 25 °C,
TMS) d = 191.7 (C@O), 158.4 (C@O), 154.8, 145.4, 136.2, 133.8,
133.7, 129.6, 129.2, 128.6, 127.0, 124.9, 118.2, 116.9. IR (CHCl3
data were consistent with the published values.20
4.5.6. 3-Benzoyl-6-methoxy-2H-chromen-2-one 2e
2-Hydroxy-5-methoxybenzaldehyde (1.52 g, 10 mmol) and
ethyl benzoylacetate (1.73 ml, 10 mmol) were treated according
to the general procedure A; the pure product 2e was obtained as
yellow microcrystals (1.90 g, 68% yield). Mp: 158–160 °C
(CH2Cl2–light petroleum) [Lit. 160–162 °C (CH2Cl2–hexane)18]. 1H
NMR (400 MHz, CDCl3, 25 °C, TMS) d = 8.05 (s, 1H, H-4), 7.91
(app. dd, J = 8.4 and 1.3 Hz, 2H, Ph-o), 7.64 (tt, J = 7.7 and 1.4 Hz,
1H, Ph-p), 7.51 (app. t, J = 7.7 Hz, 2H, Ph-m), 7.36 (d, J = 9.1 Hz,
1H, H-8), 7.25 (dd, J = 9.1 and 2.9 Hz, 1H, H-7), 7.03 (d, J = 2.9 Hz,
1H, H-5), 3.89 (s, 3H, OMe). 13C NMR (100 MHz, CDCl3, 25 °C,
TMS) d = 191.8 (C@O), 158.6 (C@O), 156.4, 149.3, 145.2, 136.3,
133.8, 129.6, 128.6, 127.3, 121.7, 118.5, 118.0, 110.6, 55.9. IR
solution)
m = 3011, 1747 (C@O), 1718 (C@O), 1665, 1610, 1567,
1455, 1367, 1318, 1165, 1145, 1121, 942, 889 cmꢂ1. HRMS: [M]+
C16H10O3, theoretical mass 250.0630, found 250.0631. These data
were consistent with the published values.18
(CHCl3 solution)
m
= 3011, 1729 (2 ꢄ C@O), 1665, 1573, 1492,
4.5.3. 3-Benzoyl-8-bromo-2H-chromen-2-one 2b
1465, 1368, 1253, 1178, 1156, 1034, 929, 868, 844, 826 cmꢂ1
.
3-Bromo-2-hydroxybenzaldehyde (1.00 g, 5 mmol) and ethyl
benzoylacetate (0.86 ml, 5 mmol) were treated according to the
general procedure A; the pure product 2b was obtained as yellow
microcrystals (1.40 g, 87% yield). Mp: 173–174 °C (CH2Cl2–light
petroleum). 1H NMR (400 MHz, CDCl3, 25 °C, TMS) d = 8.07 (s, 1H,
H-4), 7.93–7.89 (m, 3H, Ph-o and H-7), 7.66 (tt, J = 7.4 and 1.4 Hz,
1H, Ph-p), 7.59 (dd, J = 7.7 and 1.4 Hz, 1H, H-5), 7.52 (app. t,
J = 7.7 Hz, 2H, Ph-m), 7.27 (t, J = 7.7 Hz, 1H, H-6). 13C NMR
(100 MHz, CDCl3, 25 °C, TMS) d = 191.1 (C@O), 157.4 (C@O), 151.5,
144.9, 136.9, 135.9, 134.1, 129.7, 128.7, 128.4, 127.8, 125.7, 119.5,
HRMS: [M+H+] C17H13O4, theoretical mass 281.0808, found
281.0810. The data were consistent with the published values.20
4.5.7. 3-Benzoyl-6-methyl-2H-chromen-2-one 2f
2-Hydroxy-5-methylbenzaldehyde (1.36 g, 10 mmol) and ethyl
benzoylacetate (1.73 ml, 10 mmol) were treated according to the
general procedure A; the pure product 2f was obtained as colour-
less microcrystals (1.82 g, 69% yield). Mp: 172–174 °C (CH2Cl2–
light petroleum) [Lit. 174 °C (CH2Cl2–hexane)18]. 1H NMR
(400 MHz, CDCl3, 25 °C, TMS) d = 8.06 (s, 1H, H-4), 7.91 (app. dd,
J = 8.4 and 1.3 Hz, 2H, Ph-o), 7.64 (tt, J = 7.4 and 1.4 Hz, 1H, Ph-p),
7.53–7.47 (m, 3H, Ph-m overlapped by H-7), 7.41 (br s, 1H, H-5),
7.33 (d, J = 8.4 Hz, 1H, H-8), 2.47 (s, 3H, Me). 13C NMR (100 MHz,
CDCl3, 25 °C, TMS) d = 191.8 (C@O), 158.7 (C@O), 152.9, 145.6,
136.3, 134.8, 134.8, 133.8, 129.6, 128.9, 128.6, 126.8, 117.9, 116.7,
110.5. IR (CHCl3 solution)
1613, 1557, 1445, 1364, 1318, 1290, 1244, 1161, 958, 924,
839 cmꢂ1 HRMS: [M+Na+] C16H9BrNaO3, theoretical mass
m = 3011, 1736 (C@O), 1667 (C@O),
.
350.9609, found 350.9627.
4.5.4. 3-Benzoyl-8-methoxy-2H-chromen-2-one 2c
20.8. IR (CHCl3 solution) m = 3011, 1736 (C@O), 1731 (C@O), 1665,
2-Hydroxy-3-methoxybenzaldehyde (1.52 g, 10 mmol) and
ethyl benzoylacetate (1.73 ml, 10 mmol) were treated according
to the general procedure A; the pure product 2c was obtained as
yellow microcrystals (1.71 g, 61% yield). Mp: 140–142 °C
(CH2Cl2–light petroleum) [Lit. 145–146 °C (EtOAc/petroleum)19].
1H NMR (400 MHz, CDCl3, 25 °C, TMS) d = 8.09 (s, 1H, H-4), 7.91
(app. d, J = 7.8 Hz, 2H, Ph-o), 7.64 (app. t, J = 7.4 Hz, 1H, Ph-p),
7.51 (app. t, J = 7.5 Hz, 2H, Ph-m), 7.31 (app. t, J = 7.8 Hz, 1H, H5,
6, or 7), 7.21 (app. t, J = 7.8 Hz, 2H, H5, 6, or 7), 4.03 (s, 3H, OMe).
13C NMR (100 MHz, CDCl3, 25 °C, TMS) d = 191.7 (C@O), 157.9
(C@O), 147.2, 145.6, 144.5, 136.2, 133.8, 129.6, 128.5, 127.4,
1623, 1574, 1490, 1449, 1363, 1292, 1250, 1155, 929, 860,
820 cmꢂ1. HRMS: [M] C17H12O3, theoretical mass 264.0786, found
264.0773. The data were consistent with the published values.18
4.5.8. 2-Benzoyl-3H-benzo[f]chromen-3-one 2g
2-Hydroxy-1-naphthaldehyde (1.72 g, 10 mmol) and ethyl ben-
zoylacetate (1.73 ml, 10 mmol) were treated according to the gen-
eral procedure A; the pure product 2g was obtained as yellow
microcrystals (1.59 g, 53% yield). Mp: 220–222 °C (CH2Cl2–light
petroleum). [Lit. >200 °C (EtOH)18]. 1H NMR (400 MHz, CDCl3,
25 °C, TMS) d = 8.96 (s, 1H, H-4), 8.31 (d, J = 8.4 Hz, 1H, H-5 or 8),
8.15 (d, J = 9.0 Hz, 1H, H-5 or 8), 8.00–7.95 (m, 3H, Ph-o overlapped
124.8, 120.4, 118.8, 115.3, 56.4. IR (CHCl3 solution)
m = 3011,

X. Tang et al. / Tetrahedron: Asymmetry 20 (2009) 1881–1891
1887
by phenylene-H), 7.77 (tt, J = 7.0 Hz and 1.2 Hz, 1H, Ph-p), 7.70–
7.64 (m, 2H, Ph-m), 7.59–7.52 (m, 3H, phenylene-H). 13C NMR
(100 MHz, CDCl3, 25 °C, TMS) d = 192.1 (C@O), 158.6 (C@O),
155.4, 141.9, 136.5, 135.4, 133.7, 130.3, 129.6, 129.4, 129.3,
129.0, 128.6, 126.6, 125.4, 121.5, 116.8, 112.7. IR (CHCl3 solution)
C13H13O2, theoretical mass 201.0921, found 201.0910. The com-
pound had the expected spectroscopic properties.23
4.6. Preparation of the ACA products
m
= 3011, 1734 (2 ꢄ C@O), 1662, 1600, 1565, 1518, 1464, 1449,
The 1,4-addition products were all attained by general proce-
dure B or minor variations thereof.
1394, 1344, 1262, 1179, 1097, 993, 946, 922, 820 cmꢂ1. HRMS:
[M+Na+] C20H12NaO3, found 323.0677, theoretical mass 323.0679.
The data were consistent with the published values.18
4.6.1. (ꢂ)-(2R,3S)-2-Benzoyl-3-ethylcyclohexanone 6
To a dry argon-flashed Schlenk tube, CuTC (1.9 mg, 0.01 mmol)
and (R,S,S)-LA (11.0 mg, 0.02 mmol) were dissolved in Et2O (2 ml).
After stirring at room temperature for 30 min, the mixture was
cooled to –30 °C, Et2Zn (0.36 ml, 2.0 M solution in hexanes,
0.75 mmol) was then added dropwise, after 5 min, compound 1a
(100 mg, 0.5 mmol) was added, and the mixture was stirred at –
30 °C for 2 h. The reaction was then quenched with HCl (1 M)
and the reaction mixture was extracted with Et2O, the organic
phase was dried over MgSO4 and concentrated under reduced pres-
sure, and the crude product was then purified by flash column
chromatography (light petroleum/Et2O) over silica gel to give the
pure product as a colourless solid 6 (179 mg, 78%). Mp: 68–70 °C.
4.5.9. 3-Benzoyl-4-methyl-2H-chromen-2-one 2h
20-Hydroxyacetophenone (1.2 ml, 10 mmol), ethyl benzoylace-
tate (1.73 ml, 10 mmol) and NaOH (200 mg, 5 ml) were mixed neat
and heated to 90 °C for two days. The mixture was diluted by CH2Cl2
and washed with HCl (1 M), H2O and brine. The organic phase was
dried over MgSO4 and concentrated under reduced pressure, the
crude product was then purified by flash column chromatography
(light petroleum/Et2O) over silica gel to give pure product 2h as pale
tan solid (270 mg, 10% yield). Mp: 136–138 °C (CH2Cl2–light petro-
leum) [Lit. 138–139 °C (petroleum)21]. 1H NMR (400 MHz, CDCl3,
25 °C, TMS) d = 7.97 (app. d, J = 7.1 Hz, 2H, Ph-o), 7.75 (dd, J = 7.9
and 1.4 Hz, 1H, Ar), 7.65 (t, J = 7.6 Hz, 2H, Ar), 7.52 (app. t,
J = 7.7 Hz, 2H, Ph-m), 7.45–7.39 (m, 2H, Ar), 2.39 (s, 3H, Me). 13C
NMR (100 MHz, CDCl3, 25 °C, TMS) d = 193.2 (C@O), 158.7 (C@O),
153.2, 149.9, 136.1, 134.3, 132.6, 129.4, 128.9, 126.0, 125.2, 124.8,
½
a 2D4
ꢁ
¼ ꢂ1:6 (c 2.4, CHCl3, 18% ee, trans:cis 78:22). 1H NMR
(400 MHz, CDCl3, 25 °C, TMS) d = 7.92–7.89 (m, 2H, Ph-o), 7.59–
7.55 (m, 1H, Ph-p), 7.49–7.45 (m, 2H, Ph-m), 4.20 (d, J = 8.0 Hz,
1H, H-2), 2.62–2.56 (m, 1H, CH2 CO), 2.48–2.40 (m, 2H, CH2bCO
a
and H-3), 2.16–2.05 (m, 2H, CH2Me), 1.86–1.80 (m, 1H, ring-
119.6, 117.3, 15.9. IR (CHCl3 solution)
m = 3413, 3011, 1714
(2 ꢄ C@O), 1243, 1081, 909 cmꢂ1. HRMS: [M+H+] C17H13O3, found
265.0857, theoretical mass 265.0859. Compound 2h has appeared
in the literature but only limited data were presented.21
CH2 ), 1.57–1.42 (m, 2H, ring-CH2), 1.33–1.26 (m, 1H, ring-CH2b),
a
0.94–0.90 (t, J = 7.2 Hz, 3H, Me). 13C NMR (100 MHz, CDCl3, 25 °C,
TMS) d = 208.4 (C@O), 197.8 (C@O), 137.2, 132.8, 128.3, 127.9,
63.6, 42.0, 41.5, 27.6, 27.0, 23.9, 10.8. IR (CHCl3 solution)
m
= 2936, 2876, 1710 (C@O), 1677 (C@O), 1597, 1448, 1342, 1126,
4.5.10. Coumarin 2i
1001 cmꢂ1 HRMS: [M+Na+] C15H18O2Na, theoretical mass
.
Coumarin 2i is commercially available from Aldrich.
253.1202, found 253.1199. HPLC: Daicel Chiralpak OJ-H, hexane/
iPrOH = 97/3, flow rate: 1.0 ml minꢂ1. T2S,3R = 25.5 min, T2R,3S
=
4.5.11. 3-(2-Phenylacetyl)-2H-chromen-2-one 2j
35.5 min.
2-Hydroxybenzaldehyde (0.29 ml, 2.73 mmol) and ethyl 3-oxo-
4-phenylbutanoate (500 mg, 2.73 mmol) were treated according
to the general procedure A; the pure product 2j was obtained as yel-
low microcrystals (540 mg, 75% yield). Mp: 154–155 °C (CH2Cl2–
light petroleum). 1H NMR (400 MHz, CDCl3, 25 °C, TMS) d = 8.50 (s,
1H, H-4), 7.69–7.64 (m, 2H, Ph-o), 7.40–7.27 (m, 7H, Ar), 4.51 (s,
2H, CH2). 13C NMR (100 MHz, CDCl3, 25 °C, TMS) d = 195.6 (C@O),
159.1 (C@O), 155.3, 148.2, 134.4, 133.9, 130.2, 129.9, 128.5, 127.0,
The isolated compound had properties equivalent to those of
known (2R,3S)-6 prepared by a different route.24
4.6.2. (+)-(2S,3R)-2-Benzoyl-3-methylcyclohexanone 7
To a dry argon-flashed Schlenk tube, CuTC (1.9 mg, 0.01 mmol)
and (R,S,S)-LA (11 mg, 0.02 mmol) were dissolved in Et2O (2 ml).
After stirring at room temperature for 30 min, the mixture was
cooled to –30 °C, after which Me2Zn (0.75 ml, 1.0 M solution in tol-
uene, 0.75 mmol) was added dropwise. After 5 min, compound 1a
(100 mg, 0.5 mmol) was added, and the mixture was stirred at –
30 °C for 2 h. The reaction was then quenched with HCl (1 M)
and the reaction mixture was extracted with Et2O, the organic
phase was dried over MgSO4 and concentrated under reduced pres-
sure, and the crude product was then purified by flash column
chromatography (light petroleum/Et2O) over silica gel to give pure
product 7 as a pale yellow solid (174 mg, 81%). Mp: 60–62 °C.
125.0, 124.4, 118.3, 116.7, 48.6. IR (CHCl3 solution)
m = 2960, 1728
(2 ꢄ C@O), 1609, 1561, 1454, 1172, 977 cmꢂ1. HRMS: [M+H+]
C17H13O3, found 265.0864, theoretical mass 265.0859. Compound
2j has appeared in the literature but only limited spectroscopic data
were presented.22
4.5.12. 2-(Hydroxy(phenyl)methyl)cyclohex-2-enone 5
Cyclohexenone (2.0 ml, 20 mmol), benzylaldehyde (1.0 ml,
10 mmol) and N,N,N0,N0-tetramethyl-1,3-propanediamine (1.7 ml,
10 mmol) were dissolved in THF/H2O (8 ml, 1:1). The mixture was
then stirred at room temperaturefor three days. A saturated solution
of NH4Cl(aq) was added, and the mixture was extracted with Et2O.
The organic phase was dried over MgSO4, concentrated under re-
duced pressure and the crude product was then purified by flash col-
umn chromatography (light petroleum/Et2O: 4:6) over silica gel to
give pure product 5 (1.7 g, 84%) as a yellow oil. 1H NMR (400 MHz,
CDCl3, 25 °C, TMS) d = 7.36–7.26 (m, 5H, Ph), 6.79–6.77 (t,
J = 4.0 Hz, 1H, @CH), 5.55 (d, J = 4.4 Hz, 1H, CHOH), 3.70 (br s, 1H,
OH), 2.44–2.36 (m, 4H, 2 ꢄ ring CH2), 2.00–1.96 (m, 2H, ring-CH2).
13C NMR (100 MHz, CDCl3, 25 °C, TMS) d = 200.3 (C@O), 147.4,
141.9, 141.1, 128.3, 127.4, 126.5, 72.1 (CH), 38.5, 25.8, 22.5. IR (CHCl3
½
a 2D4
ꢁ
¼ þ10:5 (c 1.2, CHCl3, 62% ee, trans:cis 86:14). 1H NMR
(400 MHz, CDCl3, 25 °C, TMS) d = 7.90 (app. d, J = 7.4 Hz, 2H, Ph-
o), 7.59 (app. t, J = 7.4 Hz, 1H, Ph-p), 7.49 (app. t, J = 7.4 Hz, 2H,
Ph-m), 4.10 (d, J = 9.9 Hz, 1H, H-2), 2.65–2.54 (m, 2H, CH2 CO
a
and H-3), 2.43 (dd, J = 13.9 and 5.6 Hz, 1H, CH2bCO), 2.14–2.04
(m, 2H, ring-CH2), 1.88–1.83 (m, 1H, ring-CH2 ), 1.63–1.53 (m,
a
1H, ring-CH2b). 13C NMR (100 MHz, CDCl3, 25 °C, TMS) d = 208.5
(C@O), 198.1 (C@O), 137.7, 133.2, 128.7, 128.3, 65.6, 41.7, 36.5,
32.2, 24.8, 20.9. IR (CHCl3 solution)
m = 3011, 2960, 1712 (C@O),
1681 (C@O), 1448, 1348, 1240, 1179, 1125, 1075 cmꢂ1. HRMS:
[M+Na+] C14H16O2Na, theoretical mass 239.1042, found 239.1043.
HPLC: Daicel Chiralpak OJ-H, hexane/iPrOH = 97/3, flow rate:
1.0 ml minꢂ1. T2S,3R = 26.0 min, T2R,3S = 36.0 min. The isolated com-
pound had properties equivalent to those of known ent-7 prepared
by a different route.24
solution) m = 3603 (OH), 3011, 2954, 2890, 1664 (C@O), 1493, 1454,
1407, 1383, 1239, 1171, 1019, 975, 916, 895 cmꢂ1. HRMS: [MꢂH+]

1888
X. Tang et al. / Tetrahedron: Asymmetry 20 (2009) 1881–1891
4.6.3. (ꢂ)-(3R,4S)-3-Benzoyl-4-methylchroman-2-one 8
Compound 2a (125 mg, 0.5 mmol) was treated according to the
general procedure B; the pure product 8 was obtained as colourless
1624, 1597, 1449, 1304, 1239, 1140 cmꢂ1. HRMS: [MꢂH+] C18H14
-
BrO3, found 357.0119, theoretical mass 357.0132. Elemental Anal.
Calcd for C18H15BrO3: C, 60.18; H, 4.21. Found: C, 60.21; H, 4.24.
HPLC: Daicel Chiralpak OD-H, hexane/iPrOH = 95/5, flow rate:
0.5 ml minꢂ1. T3S,4R = 35.4 min, T3R,4S = 38.8 min.
low melting solid (118 mg, 89% yield). ½a D25
¼ ꢂ35:7 (c 1.00, CHCl3,
ꢁ
88% ee, trans:cis 91:9). 1H NMR (400 MHz, CDCl3, 25 °C, TMS)
d = 7.95 (app. dd, J = 8.4 and 1.2 Hz, 2H, Ph-o), 7.65 (app. t,
J = 7.4 Hz, 1H, Ph-o), 7.53 (app. t, J = 7.7 Hz, 2H, Ph-m), 7.32 (dt,
J = 1.6 and 7.6 Hz, 1H, H-6), 7.19–7.14 (m, 3H, H-5,7,8), 4.60 (d,
J = 5.9 Hz, 1H, H-3), 3.63 (dq, J = 5.9 and 7.0 Hz, 1H, H-4), 1.46 (d,
J = 7.0 Hz, 3H, Me). 13C NMR (100 MHz, CDCl3, 25 °C, TMS)
d = 193.9 (C@O), 165.7 (C@O), 150.6, 135.4, 134.1, 128.9, 128.8,
128.7, 127.0, 125.4, 125.0, 116.9, 55.1, 33.7, 20.1. IR (CHCl3 solu-
4.6.7. (ꢂ)-(3R,4R)-3-Benzoyl-8-methoxy-4-methylchroman-2-
one 12
Compound 2c (140 mg, 0.5 mmol) was treated according to the
general procedure B; pure product 12 was obtained as waxy white
solid (95 mg, 64% yield). Mp: <50 °C. ½a D25
¼ ꢂ27:0 (c 1.00, CHCl3,
ꢁ
87% ee, trans:cis 90:10) 1H NMR (400 MHz, CDCl3, 25 °C, TMS)
d = 7.95 (app. d, J = 7.5 Hz, 2H, Ph-o), 7.63 (app. t, J = 7.4 Hz, 1H,
Ph-p), 7.50 (app. t, J = 7.5 Hz, 2H, Ph-m), 7.09 (t, J = 7.8 Hz, 1H, H-
6), 6.91 (dd, J = 7.8 and 1.1 Hz, 1H, H-5 or 7), 6.77 (d, J =
7.8 Hz + unresolved 4J coupling, 1H, H-5 or 7), 4.57 (d, J = 5.9 Hz,
1H, H-3), 3.92 (s, 3H, OMe), 3.62 (dq, J = 5.9 and 7.0 Hz, 1H, H-4),
1.43 (d, J = 7.0 Hz, 3H, CHMe). 13C NMR (100 MHz, CDCl3, 25 °C,
TMS) d = 193.7 (C@O), 165.0 (C@O), 147.6, 139.8, 135.4, 133.9,
128.9, 128.8, 126.7, 124.9, 118.3, 111.5, 56.2, 54.9, 33.8, 19.9. IR
tion)
m = 2975, 1760 (C@O), 1687 (C@O), 1489, 1448, 1240, 1174,
1085, 1001, 906 cmꢂ1. HRMS: [MꢂH+] C17H13O3, found 265.0862,
theoretical mass 265.0870. HPLC: Daicel Chiralpak OD-H, hexane/
iPrOH = 95/5, flow rate: 1.0 ml minꢂ1. T3S,4R = 18.6 min, T3R,4S
=
28.4 min.
4.6.4. (+)-(3R,4S)-3-Benzoyl-4-ethylchroman-2-one 9
Compound 2a (125 mg, 0.5 mmol) was treated according to the
general procedure B; pure product 9 was obtained as colourless oil
(CHCl3 solution)
m = 2968, 1765 (C@O), 1687 (C@O), 1486, 1277,
(120 mg, 86% yield). ½a D25
ꢁ
¼ þ83:8 (c 1.00, CHCl3, 96% ee, trans:cis
1181, 1115, 1068, 1002, 910 cmꢂ1. HRMS: [MꢂH+] C18H15O4, found
295.0959, theoretical mass 295.0976. HPLC: Daicel Chiralpak OD-
H, hexane/iPrOH = 90/10, flow rate: 1.0 ml minꢂ1. T3S,4R = 22.4 min,
T3R,4S = 46.1 min.
93:7). 1H NMR (400 MHz, CDCl3, 25 °C, TMS) d = 7.90 (app. d,
J = 7.3 Hz, 2H, Ph-o), 7.64 (app. t, J = 7.3 Hz, 1H, Ph-p), 7.51 (app.
t, J = 7.3 Hz, 2H, Ph-m), 7.33–7.28 (m, 1H, H-6), 7.14–7.03 (m, 3H,
H-5,7,8), 4.83 (d, J = 2.1 Hz, 1H, H-3), 3.26 (dt, J = 2.1 and 6.8 Hz,
1H), 1.90–1.73 (m, 2H, CH2Me), 1.07 (t, J = 7.3 Hz, 3H, Me). 13C
NMR (100 MHz, CDCl3, 25 °C, TMS) d = 193.6 (C@O), 165.7 (C@O),
150.9, 134.3, 134.0, 129.0, 128.8, 128.7, 128.5, 124.6, 123.1,
4.6.8. (+)-(3R,4S)-3-Benzoyl-4-ethyl-8-methoxychroman-2-one
13
Compound 2c (140 mg, 0.5 mmol) was treated according to the
general procedure B; pure product 13 was obtained as white solid
(121 mg, 78% yield). Mp: 139–140 °C (CH2Cl2–light petroleum).
117.1, 54.6, 41.7, 28.7, 11.2. IR (CHCl3 solution)
m = 2965, 1763
(C@O), 1683 (C@O), 1626, 1603, 1458, 1308, 1239, 835 cmꢂ1
.
HRMS: [MꢂH+] C18H15O3, found 279.1021, theoretical mass
279.1027. HPLC: Daicel Chiralpak OD-H, hexane/iPrOH = 95/5, flow
rate: 1.0 ml/min. T3S,4R = 14.8 min, T3R,4S = 20.9 min.
½
a 2D5
ꢁ
¼ þ32:2 (c 1.00, CHCl3, 96% ee, trans:cis 95:5). 1H NMR
(400 MHz, CDCl3, 25 °C, TMS) d = 7.92 (app. dd, J = 8.4 and 1.2 Hz,
2H, Ph-o), 7.64 (tt, J = 7.4 and 1.1 Hz, 1H, Ph-p), 7.52 (app. t,
J = 7.7 Hz, 2H, Ph-m), 7.04 (t, J = 8.3 Hz, 1H, H-6), 6.90 (dd, J = 8.3
and 1.3 Hz, 1H, H-5 or 7), 6.64 (dd, J = 8.3 and 1.3 Hz, 1H, H-5 or
7), 4.80 (d, J = 2.2 Hz 1H, H-3), 3.94 (s, 3H, OMe), 3.26 (dt, J = 2.2
and 7.3 Hz, 1H, H-4), 1.87–1.76 (m, 2H, CH2Me), 1.07 (t,
J = 7.3 Hz, 3H, CH2Me). 13C NMR (100 MHz, CDCl3, 25 °C, TMS)
d = 193.3 (C@O), 164.9 (C@O), 147.6, 140.1, 134.4, 133.9, 128.9,
128.7, 124.5, 124.4, 119.9, 111.6, 56.1, 54.3, 41.7, 28.4, 11.2. IR
4.6.5. (ꢂ)-(3R,4S)-3-Benzoyl-8-bromo-4-methylchroman-2-one
10
Compound 2b (164 mg, 0.5 mmol) was treated according to the
general procedure B; pure product 10 was obtained as low melting
yellow solid (107 mg, 62% yield). Mp: <50 °C. ½a D25
¼ ꢂ9:3 (c 1.00,
ꢁ
CHCl3, 88% ee, trans:cis 85:15). 1H NMR (400 MHz, CDCl3, 25 °C,
TMS) d = 7.97 (app. dd, J = 8.4 and 1.2 Hz, 2H, Ph-o), 7.66 (app. t,
J = 7.4 Hz, 1H, Ph-p), 7.56–7.52 (m, 3H, Ph-m and H-7), 7.15 (d,
J = 7.7 Hz, 1H, H-5), 7.04 (t, J = 7.7 Hz, 1H, H-6), 4.62 (d, J = 5.6 Hz,
1H, H-3), 3.68–3.61 (dq, J = 5.6 and 7.1 Hz, 1H, H-4), 1.46 (d,
J = 7.1 Hz, 3H, Me). 13C NMR (100 MHz, CDCl3, 25 °C, TMS)
d = 193.2 (C@O), 164.4 (C@O), 147.5, 135.2, 134.2, 132.6, 129.0,
128.8, 127.5, 126.1, 125.7, 110.8, 54.8, 34.2, 20.0. IR (CHCl3 solu-
(CHCl3 solution)
m = 2968, 1767 (C@O), 1685 (C@O), 1486, 1278,
1240, 1176, 1115, 1075, 1003 cmꢂ1. HRMS: [MꢂH+] C19H17O4,
found 309.1121, theoretical mass 309.1132. Elemental Anal. Calcd
for C19H18O4: C, 73.53; H, 5.85. Found: C, 73.56; H, 5.89. HPLC: Dai-
cel Chiralpak OD-H, hexane/iPrOH = 90/10, flow rate: 1.0 ml minꢂ1
T3S,4R = 17.7 min, T3R,4S = 39.0 min.
.
tion)
m
= 2969, 1772 (C@O), 1686 (C@O), 1624, 1598, 1446, 1239,
4.6.9. (+)-(3R,4S)-3-Benzoyl-4-isobutyl-8-methoxychroman-2-
one 14
1139 cmꢂ1. HRMS: [MꢂH+] C17H12BrO3, found 342.9958, theoreti-
cal mass 342.9975. HPLC: Daicel Chiralpak OD-H, hexane/
Compound 2c (140 mg, 0.5 mmol) was treated according to the
general procedure B; pure product 14 was obtained as colourless
powder (120 mg, 71% yield). Mp: 128–129 °C (CH2Cl2–light petro-
iPrOH = 95/05, flow rate: 1.0 ml minꢂ1. T3S,4R = 25.0 min, T3R,4S
=
27.8 min.
leum). ½a 2D5
ꢁ
¼ þ7:3 (c 1.00, CHCl3, 75% ee, trans:cis 75:25). 1H NMR
4.6.6. (+)-(3R,4S)-3-Benzoyl-8-bromo-4-ethylchroman-2-one 11
Compound 2b (164 mg, 0.5 mmol) was treated according to the
general procedure B; pure product 11 was obtained as colourless
(400 MHz, CDCl3, 25 °C, TMS) d = 7.90 (app. d, J = 7.2 Hz, 2H, Ph-o),
7.63 (app. t, J = 7.4 Hz, 1H, Ph-p), 7.51 (app. t, J = 7.7 Hz, 2H, Ph-m),
7.02 (dd, 1H, J = 8.3 and 7.7 Hz, 1H, H-6), 6.89 (dd, J = 8.3 and
1.4 Hz, 1H, H-5 or 7), 6.62 (dd, J = 7.6 and 1.3 Hz, 1H, H-5 or 7),
4.74 (d, J = 1.7 Hz, 1H, H-3), 3.93 (s, 3H, OMe), 3.38 (dt, J = 1.7
and 7.6 Hz, 1H, H-4), 1.75–1.70 (m, 1H, CHMe2), 1.60 (t,
oil (128 mg, 72% yield). ½a D25
¼ þ90:7 (c 0.50, CHCl3, 96% ee, trans:-
ꢁ
cis 82:8). 1H NMR (400 MHz, CDCl3, 25 °C, TMS) d = 7.92 (app. dd,
J = 8.4 and 1.2 Hz, 2H, Ph-o), 7.66 (app. t, J = 7.4 Hz, 1H, Ph-p),
7.55–7.53 (m, 3H, Ar), 7.01–6.98 (m, 2H, Ar), 4.84 (d, J = 2.1 Hz,
1H, H-3), 3.26 (dt, J = 2.1 and 6.3 Hz, 1H, H-4), 1.89–1.73 (m, 2H,
CH2Me), 1.07 (t, J = 7.4 Hz, 3H, Me). 13C NMR (100 MHz, CDCl3,
25 °C, TMS) d = 192.9 (C@O), 164.4 (C@O), 147.8, 134.2, 132.6,
129.1, 128.8, 128.7, 128.1, 127.6, 125.3, 110.8, 54.3, 42.1, 28.4,
J = 7.6 Hz, 2H, CH2iPr), 1.03 (d, J = 6.5 Hz, 3H, CH2Me ), 0.95 (d,
a
J = 6.5 Hz, 3H, CH2Meb). 13C NMR (100 MHz, CDCl3, 25 °C, TMS)
d = 193.2 (C@O), 164.9 (C@O), 147.7, 139.9, 133.9, 128.9, 128.7,
128.6, 128.3, 124.6, 119.7, 111.6, 56.2, 55.2, 44.8, 38.2, 24.9, 22.7,
22.3. IR (CHCl3 solution)
m = 2961, 1766 (C@O), 1686 (C@O),
11.2. IR (CHCl3 solution)
m
= 2969, 1773 (C@O), 1685 (C@O),
1486, 1280, 1240, 1175, 1089, 1004 cmꢂ1. HRMS: [MꢂH+] C21H21
-

X. Tang et al. / Tetrahedron: Asymmetry 20 (2009) 1881–1891
1889
O4, found 337.1443, theoretical mass 337.1445. HPLC: Daicel Chir-
ꢂ43:9 (c 1.00, CHCl3, 67% ee, trans:cis 90:10). 1H NMR (400 MHz,
CDCl3, 25 °C, TMS) d = 7.96 (app. dd, J = 8.4 and 1.2 Hz, 2H, Ph-o),
7.65 (app. t, J = 7.4 Hz, 1H, Ph-p), 7.53 (app. t, J = 7.7 Hz, 2H, Ph-
m), 7.11 (dd, J = 8.3 and 1.8 Hz, 1H, H-7), 7.03 (d, J = 8.2 Hz, 1H,
H-8), 6.98 (d, J = 1.8 Hz, 1H, H-5), 4.58 (d, J = 5.6 Hz, 1H, H-3),
3.61–3.54 (m, 1H, H-4), 2.34 (s, 3H, Me-6), 1.44 (d, J = 7.0 Hz, 3H,
CHMe). 13C NMR (100 MHz, CDCl3, 25 °C, TMS) d = 193.9 (C@O),
165.9 (C@O), 148.5, 135.4, 134.6, 134.0, 129.2, 128.9, 128.8,
127.4, 125.0, 116.7, 55.2, 33.8, 20.9, 20.2. IR (CHCl3 solution)
alpak OD-H, hexane/iPrOH = 90/10, flow rate: 1.0 ml minꢂ1. T3S,4R
12.0 min, T3R,4S = 26.6 min.
=
4.6.10. (+)-(3R,4S)-3-Benzoyl-4-ethyl-7-methoxychroman-2-
one 15
Compound 2d (140 mg, 0.5 mmol) was treated according to the
general procedure B; pure product 15 was obtained as colourless
oil (115 mg, 74% yield). ½a D25
¼ þ56:8 (c 1.00, CHCl3, 97% ee, trans:
ꢁ
cis >99:1). 1H NMR (400 MHz, CDCl3, 25 °C, TMS) d = 7.89 (app. dd,
J = 8.3 and 1.2 Hz, 2H, Ph-o), 7.65 (app. t, J = 7.4 Hz, 1H, Ph-p), 7.52
(app. t, J = 7.7 Hz, 2H, Ph-m), 6.92 (d, J = 8.4 Hz, 1H, H-5), 6.71 (d,
J = 2.5 Hz, 1H, H-8), 6.64 (dd, J = 8.4 and 2.5 Hz, 1H, H-6), 4.79 (d,
J = 2.1 Hz, 1H, H-3), 3.82 (s, 3H, OMe), 3.19 (dt, J = 2.1 and 7.2 Hz,
1H, H-4), 1.87–1.69 (m, 2H, CH2Me), 1.05 (t, J = 7.4 Hz, 3H, CH2Me).
13C NMR (100 MHz, CDCl3, 25 °C, TMS) d = 193.8 (C@O), 165.8
(C@O), 160.0, 151.7, 134.3, 134.0, 129.0, 128.7, 128.1, 114.8,
110.8, 102.5, 55.5, 54.8, 41.2, 28.9, 11.2. IR (CHCl3 solution)
m .
= 2961, 1731 (C@O), 1600 (C@O), 1498, 1374, 1250, 1045 cmꢂ1
HRMS: [MꢂH+] C18H15O3, found 279.1021, theoretical mass
279.1027. HPLC: Daicel Chiralpak OD-H, hexane/iPrOH = 95/05,
flow rate: 1.0 ml minꢂ1. T3S,4R = 16.5 min, T3R,4S = 29.6 min.
4.6.14. (+)-(3R,4S)-3-Benzoyl-4-ethyl-6-methylchroman-2-one
19
Compound 2f (132 mg, 0.5 mmol) was treated according to the
general procedure B; pure product 19 was obtained as colourless
m
= 2967, 1764 (C@O), 1683 (C@O), 1627, 1508, 1155 cmꢂ1. HRMS:
oil (140 mg, 94% yield). ½a D25
¼ þ46 (c 1.00, CHCl3, 85% ee, trans:cis
ꢁ
[MꢂH+] C19H17O4, found 309.1117, theoretical mass 309.1132.
HPLC: Daicel Chiralpak OD-H, hexane/iPrOH = 90/10, flow rate:
1.0 ml minꢂ1. T3S,4R = 13.8 min, T3R,4S = 26.8 min.
97:3). 1H NMR (400 MHz, CDCl3, 25 °C, TMS) d = 7.92 (app. dd,
J = 8.4 and 1.2 Hz, 2H, Ph-o), 7.65 (app. t, J = 7.4 Hz, 1H, Ph-p), 7.52
(app. t, J = 7.7 Hz, 2H, Ph-m), 7.09 (dd, J = 8.3 and 1.5 Hz, 1H, H-7)
7.03 (d, J = 8.3 Hz, 1H, H-8), 6.84 (d, J = 1.5 Hz, 1H, H-5), 4.80 (d,
J = 2.1 Hz, 1H, H-3), 3.20 (dt, J = 2.0 and 7.3 Hz, 1H, H-4), 2.30 (s,
3H, Me-6), 1.90–1.71 (m, 2H, CH2Me), 1.08 (t, J = 7.4 Hz, 3H, CH2Me).
13C NMR (100 MHz, CDCl3, 25 °C, TMS) d = 193.6 (C@O), 165.9 (C@O),
148.7, 134.4, 134.1, 134.0, 129.3, 129.0, 128.9, 128.8, 122.8, 116.7,
4.6.11. (ꢂ)-(3R,4R)-3-Benzoyl-6-methoxy-4-methylchroman-2-
one 16
Compound 2e (140 mg, 0.5 mmol) was treated according to the
general procedure B; pure product 16 was obtained as colourless
oil (60 mg, 40% yield). ½a D25
ꢁ
¼ ꢂ13:1 (c 1.00, CHCl3, 37% ee, trans:cis
54.6, 41.7, 28.8, 20.8, 11.2. IR (CHCl3 solution) m = 2967, 1763
88:12). 1H NMR (400 MHz, CDCl3, 25 °C, TMS) d = 7.95 (app. dd,
J = 8.4 and 1.2 Hz, 2H, Ph-o), 7.65 (tt, J = 7.4 Hz, 1H, Ph-p), 7.52
(app. t, J = 7.7 Hz, 2H, Ph-m), 7.07 (d, J = 8.9 Hz, 1H, H-8), 6.83
(dd, J = 8.9 and 2.9 Hz, 1H, H-7), 6.71 (d, J = 2.7 Hz, 1H, H-5), 4.57
(d, J = 5.8 Hz, 1H, H-3), 3.80 (s, 3H, OMe), 3.63–3.54 (m, 1H, H-4),
1.44 (d, J = 7.0 Hz, 3H, CHMe). 13C NMR (100 MHz, CDCl3, 25 °C,
TMS) d = 193.9 (C@O), 165.8 (C@O), 156.6, 144.4, 135.4, 134.0,
128.9, 128.7, 126.5, 117.7, 113.3, 112.5, 55.7, 55.0, 33.9, 19.9. IR
(C@O), 1685 (C@O), 1602, 1498, 1458, 1304, 1257, 1194 cmꢂ1
.
HRMS: [MꢂH+] C19H17O3, found 293.1176, theoretical mass
293.1183. HPLC: Daicel Chiralpak OD-H, hexane/iPrOH = 95/5, flow
rate: 1.0 ml minꢂ1. T3S,4R = 12.8 min, T3R,4S = 20.7 min.
4.6.15. (ꢂ)-(1R,2S)-2-Benzoyl-1-ethyl-1,2-dihydro-
benzo[f]chromen-3-one 20
Compound 2g (150 mg, 0.5 mmol) was treated according to the
general procedure B, but by using ligand (R,S,S)-LA, pure product
(CHCl3 solution)
m = 2967, 1759 (C@O), 1686 (C@O), 1598, 1497,
1267, 1179, 1038 cmꢂ1
.
HRMS: [MꢂH+] C18H15O4, found
20 was obtained as a colourless oil (130 mg, 79% yield). ½a D25
¼
ꢁ
295.0966, theoretical mass 295.0976. HPLC: Daicel Chiralpak OD-
H, hexane/iPrOH = 80/20, flow rate: 1.0 ml minꢂ1. T3S,4R = 11.3 min,
T3R,4S = 20.8 min.
ꢂ38:1 (c 1.00, CHCl3, 90% ee, trans:cis 97:3). 1H NMR (400 MHz,
CDCl3, 25 °C, TMS) d = 7.91 (app. dd, J = 8.4 and 1.2 Hz, 2H, Ph-o),
7.87–7.81 (m, 2H, Ar), 7.73 (d, J = 8.3 Hz, 1H, Ar), 7.63 (app. t,
J = 7.4 Hz, 1H, Ph-p), 7.52–7.45 (m, 4H, Ar), 7.34 (d, J = 8.9 Hz, 1H,
H-6), 5.02 (d, J = 1.4 Hz, 1H, H-2), 4.01 (dt, J = 1.4 and 7.3 Hz, 1H,
4.6.12. (+)-(3R,4S)-3-Benzoyl-4-ethyl-6-methoxychroman-2-
one 17
H-1), 2.06–1.84 (m, 2H, CH2Me), 1.20 (t, J = 7.4 Hz, 1H, CH2Me). 13
C
Compound 2e (140 mg, 0.5 mmol) was treated according to the
general procedure B; pure product 17 was obtained as colourless
NMR (100 MHz, CDCl3, 25 °C, TMS) d = 193.4 (C@O), 165.6 (C@O),
148.6, 134.0, 131.3, 130.8, 129.6, 129.0, 128.7, 128.3, 127.2, 125.0,
122.3, 117.4, 116.8, 53.6, 37.6, 28.1, 11.4. IR (CHCl3 solution)
oil (85 mg, 55% yield). ½a D25
¼ þ1:0 (c 1.00, CHCl3, 48% ee, trans:cis
ꢁ
90:10). 1H NMR (400 MHz, CDCl3, 25 °C, TMS) d = 7.90 (app. dd,
J = 8.4 and 1.2 Hz, 2H, Ph-o), 7.63 (app. t, J = 7.4 Hz, 1H, Ph-p),
7.51 (app. t, J = 7.7 Hz, 2H, Ph-m), 7.07 (d, J = 8.9 Hz, 1H, H-8),
6.81 (dd, J = 8.9 and 2.9 Hz, 1H, H-7), 6.56 (d, J = 2.9 Hz, 1H, H-5),
4.78 (d, J = 2.1 Hz, 1H, H-3), 3.76 (s, 3H, OMe), 3.20 (dt, J = 2.0
and 7.2 Hz, 1H, H-4), 1.88–1.72 (m, 2H, CH2Me), 1.07 (t,
J = 7.4 Hz, 3H, CH2Me). 13C NMR (100 MHz, CDCl3, 25 °C, TMS)
d = 193.6 (C@O), 165.8 (C@O), 156.2, 144.7, 134.3, 134.0, 129.0,
128.7, 124.1, 117.7, 113.8, 113.5, 55.5, 54.4, 41.9, 28.6, 11.2. IR
m = 2969, 1765 (C@O), 1685 (C@O), 1239, 1174, 1070, 1002,
909 cmꢂ1. HRMS: [MꢂH+] C22H17O3, found 329.1178, theoretical
mass 329.1183. HPLC: Daicel Chiralpak OD-H, hexane/iPrOH = 95/
5, flow rate: 1.0 ml minꢂ1. T1S,2R = 19.7 min, T1R,2S = 22.1 min.
4.6.16. (+)-(3S,4R)-Ethyl-4-methyl-2-oxochroman-
3-carboxylate 21
Compound 2i (109 mg, 0.5 mmol) was treated according to the
general procedure B, but by using ligand (R,S,S)-LA, pure product 21
(CHCl3 solution)
m
= 2967, 1761 (C@O), 1684 (C@O), 1597, 1497,
was obtained as a colourless oil (78 mg, 67% yield). ½a D25
¼ þ13:8 (c
ꢁ
1178, 1037 cmꢂ1. HRMS: [MꢂH+] C19H17O4, found 309.1121, theo-
0.50, CHCl3, 54% ee, trans:cis 89:11). 1H NMR (400 MHz, CDCl3,
25 °C, TMS) d = 7.33–7.24 (m, 2H, H-5,7), 7.17 (ddd, J = 8.1, 7.5
and 1.1 Hz, 1H, H-6), 7.10 (dd, J = 8.1 and 1.1 Hz, 1H, H-8), 4.23–
4.13 (m, 2H, OCH2), 3.62–3.55 (m, 2H, H-3,4), 1.39 (d, J = 6.9 Hz,
3H, CH2Me), 1.17 (t, J = 7.1 Hz, 3H). 13C NMR (100 MHz, CDCl3,
25 °C, TMS) d = 167.3 (C@O), 164.7 (C@O), 150.6, 128.7, 127.1,
125.6, 125.0, 116.9, 62.1, 53.6, 33.6, 19.3, 13.9. IR (CHCl3 solution)
retical mass 309.1132. HPLC: Daicel Chiralpak OD-H, hexane/
iPrOH = 80/20, flow rate: 1.0 ml minꢂ1
. T3S,4R = 9.0 min, T3R,4S =
13.0 min.
4.6.13. (ꢂ)-(3R,4R)-3-Benzoyl-4,6-dimethylchroman-2-one 18
Compound 2f (132 mg, 0.5 mmol) was treated according to the
general procedure B; pure product 18 was obtained as white solid
m
= 2939, 1772 (C@O), 1736 (C@O), 1488, 1462, 1345, 1265, 1239,
(110 mg, 78% yield). Mp: 103–104 °C (CH2Cl2–pentane). ½a D25
ꢁ
¼
1170, 1115, 1083, 1028 cmꢂ1. HRMS: [MꢂH+] C13H13O4, found

1890
X. Tang et al. / Tetrahedron: Asymmetry 20 (2009) 1881–1891
233.0815, theoretical mass 233.0819. HPLC: Daicel Chiralpak
OD-H, hexane/iPrOH = 95/5, flow rate: 0.5 ml minꢂ1
T3S,4R
6.13 (dd, J = 15.7 and 8.0 Hz, 1H, H C@CH), 4.83 (d, J = 6.9 Hz, 1H, H-
3), 4.42 (t, J = 7.4 Hz, 1H, H-4). 13C NMR (100 MHz, CDCl3, 25 °C,
TMS) d = 192.6 (C@O), 163.9 (C@O), 147.7, 135.7, 135.4, 134.7,
134.2, 133.0, 129.0, 128.8, 128.6, 128.3, 127.9, 127.3, 126.6,
.
=
34.2 min, T3R,4S = 46.5 min. The racemic compound has been briefly
reported.25
125.7, 125.0, 110.9, 52.9, 42.6. IR (CHCl3 solution)
m = 3011, 1772
4.6.17. (+)-(3R,4S)-Ethyl-4-ethyl-2-oxochroman-3-carboxylate
22
(C@O), 1687 (C@O), 1448, 1239, 1156, 1135. HRMS: [MꢂH+]
C24H16BrO3, found 431.0268, theoretical mass 431.0288.
Compound 2i (109 mg, 0.5 mmol) was treated according to the
general procedure B; pure product 22 was obtained as colourless
4.6.21. (E)-3-Benzoyl-8-bromo-4-(3-methylbuta-
1,3-dienyl)chroman-2-one 26
oil (85 mg, 68% yield). ½a D25
ꢁ
¼ þ19:4 (c 1.00, CHCl3, 90% ee, trans:cis
93:7). 1H NMR (400 MHz, CDCl3, 25 °C, TMS) d = 7.29 (ddd, J = 8.1,
7.5 and 1.8 Hz, 1H, H-7), 7.18 (dd, J = 7.5 and 1.8 Hz, 1H, H-5), 7.13
(dd, J = 7.5 and 1.2 Hz, 1H, H-6), 7.09 (dd, J = 8.1 and 1.2 Hz, 1H, H-
8), 4.13–4.01 (m, 2H, OCH2), 3.80 (d, J = 2.6 Hz, 1H, H-3), 3.30 (dt,
J = 2.6 and 7.5 Hz, 1H, H-4), 1.72–1.60 (m, 2H, CH2Me), 1.04 (t,
J = 7.1 Hz, 3H, CH2Me), 0.99 (t, J = 7.4 Hz, 3H, CH2Me). 13C NMR
(100 MHz, CDCl3, 25 °C, TMS) d = 167.2 (C@O), 164.6 (C@O), 150.8,
128.7, 124.6, 124.0, 117.0, 62.1, 51.8, 41.4, 27.4, 13.8, 11.1. IR (CHCl3
Compound 2b (123 mg, 0.375 mmol) was treated according to
the general procedure C; the pure product 26 was obtained as a
yellow oil (120 mg, 81% yield). 1H NMR: (400 MHz, CDCl3, 25 °C,
TMS) d = 7.96 (app. d, J = 7.2 Hz, 2H, Ph-o), 7.66 (app. t, J = 7.4 Hz,
1H, Ph-p), 7.58 (d, J = 7.9 Hz, 1H, H-7), 7.53 (app. t, J = 7.5 Hz, 2H,
Ph-m), 7.13 (d, J = 7.6 Hz, 1H, H-5), 7.04 (t, J = 7.8 Hz, 1H, H-6),
6.27 (d, J = 15.5 Hz, 1H, H C@CH), 5.59 (dd, J = 15.5 and 7.8 Hz,
1H, H C@CH), 5.03 (d, J = 12.1 Hz, 2H, CH2=), 4.78 (d, J = 6.3 Hz,
1H, H-3), 4.35–4.23 (t, J = 7.0 Hz, 1H, H-4), 1.80 (s, 1H, CH3). 13C
NMR (100 MHz, CDCl3, 25 °C, TMS) d = 192.7 (C@O), 163.9 (C@O),
147.7, 140.5, 137.3, 135.3, 134.2, 132.9, 129.0, 128.8, 127.3,
125.8, 125.7, 125.0, 118.5, 110.8, 53.3, 42.5, 18.5. IR (CHCl3 solu-
solution)
m = 2936, 1771 (C@O), 1736 (C@O), 1487, 1460, 1259,
1168, 1098, 1030, 913 cmꢂ1. HRMS: [MꢂH+] C14H15O4, found
247.0971, theoretical mass 247.0976. HPLC: Daicel Chiralpak OD-
H, hexane/iPrOH = 95/05, flow rate: 1.0 ml minꢂ1. T3S,4R = 8.3 min,
T3R,4S = 9.7 min. The racemic compound has been briefly reported.25
tion)
m = 2975, 1772 (C@O), 1687 (C@O), 1448, 1240, 1156, 1136.
HRMS: [MꢂH+] C21H16BrO3, found 395.0275, theoretical mass
4.6.18. (E)-3-Benzoyl-4-(dec-1-enyl)-7-methoxychroman-2-one
23
396.0288.
Compound 2d (140 mg, 0.5 mmol) was treated according to the
general procedure C; pure product 23 was obtained as yellow oil
(145 mg, 69% yield). 1H NMR (400 MHz, CDCl3, 25 °C, TMS)
d = 7.92 (app. d, J = 7.2 Hz, 2H, Ph-o), 7.63 (app. t, J = 7.4 Hz, 1H,
Ph-p), 7.51 (app. t, J = 7.7 Hz, 2H, Ph-m), 7.04 (d, J = 9.4 Hz, 1H,
Ar), 6.71–6.69 (m, 2H, Ar), 5.61–5.53 (m, 1H, HC@CH), 5.44–5.38
(m, 1H, HC@CH), 4.66 (d, J = 6.8 Hz, 1H, H-3), 4.09 (t, J = 7.0 Hz,
1H, H-4), 3.83 (s, 3H, OMe), 2.04–1.94 (m, 2H), 1.35–1.16 (m,
12H), 0.90 (t, J = 7.0 Hz, 3H). 13C NMR (100 MHz, CDCl3, 25 °C,
TMS) d = 193.8 (C@O), 165.5 (C@O), 160.1, 151.5, 135.8, 135.6,
133.9, 128.9, 128.7, 127.3, 115.1, 111.1, 102.4, 55.5, 53.7, 41.6,
32.3, 31.9, 29.4, 29.2, 29.0, 28.9, 22.7, 14.1. IR (CHCl3 solution)
4.6.22. (S)-4-(1-(2-Hydroxy-3-methoxyphenyl)propyl)-
1-methyl-3-phenyl-1H-pyrazol-5-ol 27
Compound (+)-13 (240 mg, 0.77 mmol) and methylhydrazine
(0.41 ml, 7.7 mmol) were dissolved in EtOH (15 ml). The mixture
was then heated at reflux for 4 h. After cooling to room tempera-
ture, the mixture was diluted with CH2Cl2, washed with HCl
(1 M), NaHCO3 (satd) and H2O. The organic layer was dried over
MgSO4 and concentrated under reduced pressure, and the crude
product was then purified by flash column chromatography
(Et2O) over silica gel to give pure product as a colourless powder
(105 mg, 40% yield). Mp: 172–173 °C (CH2Cl2–light petroleum).
½
a 2D3
ꢁ
¼ ꢂ3:5 (c 1.00, CHCl3, 96% ee). 1H NMR (400 MHz, CDCl3,
m
= 2928, 1764 (C@O), 1686 (C@O), 1625, 1508, 1448, 1156. HRMS:
25 °C, TMS) d = 7.47–7.45 (m, 3H, Ar), 7.27–7.24 (m, 2H, Ar), 7.00
(dd, J = 7.8 and 1.5 Hz, 1H, Ar), 6.80 (t, J = 7.9 Hz, 1H, Ar), 6.74–
6.72 (m, 1H, Ar), 3.90 (s, 3H, OMe), 3.90–3.87 (m, 1H, CHEt), 3.55
[MꢂH+] C27H31O4, found 419.2221, theoretical mass 419.2228.
4.6.19. (E)-3-Benzoyl-8-bromo-4-(2-cyclohexenylvinyl)chroman-
2-one 24
(s, 3H, NMe), 2.17–2.09 (m, 1H, CH2 ), 2.00–1.93 (m, 1H, CH2b),
a
0.87 (t, J = 7.3 Hz, 3H, CH2Me). 13C NMR (100 MHz, CDCl3, 25 °C,
TMS) d = 159.3, 146.5, 142.9, 142.6, 131.6, 130.4, 130.2, 128.7,
128.3, 121.5, 119.5, 108.4, 105.4, 56.0, 36.7, 36.1, 26.0, 13.0. IR
Compound 2b (123 mg, 0.375 mmol) was treated according to
the general procedure C, the pure product 24 was obtained as yel-
low oil (137 mg, 84% yield). 1H NMR: (400 MHz, CDCl3, 25 °C, TMS)
d = 7.95 (app. d, J = 7.3 Hz, 2H, Ph-o), 7.65 (app. t, J = 7.3 Hz, 1H, Ph-
p), 7.55–7.51 (m, 3H, Ph-m, H-7), 7.14–7.11 (m, 1H, H-5), 7.02 (t,
J = 7.8 Hz, 1H, H-6), 6.15 (d, J = 15.4 Hz, 1H, H C@CH), 5.81–5.76
(m, 1H, H C@CH), 5.46 (dd, J = 15.4 and 7.9 Hz, 1H, H C@CH), 4.76
(d, J = 6.1 Hz, 1H, H-3), 4.23 (t, J = 6.9 Hz, 1H, H-4), 2.17–1.99 (m,
4H), 1.69–1.60 (m, 4H). 13C NMR (100 MHz, CDCl3, 25 °C, TMS)
d = 192.8 (C@O), 164.1 (C@O), 147.7, 137.9, 135.3, 134.5, 134.1,
132.8, 131.7, 128.9, 128.8, 127.4, 125.6, 125.4, 121.6, 110.7, 53.6,
(CHCl3 solution)
m .
= 2966, 1712, 1520, 1477, 1276, 1074 cmꢂ1
HRMS: [M+H] C20H23N2O3, found 339.1706, theoretical mass
339.1703.
4.7. X-ray crystallography
Diffraction data for (ꢂ)-(3R,4S)-10 and (+)-(3R,4S)-13 were re-
corded at 150(2) K on Bruker SMART CCD area detector diffractom-
eters. The Flack parameter for (ꢂ)-(3R,4S)-10 refined to 0.022(12),
confirming the absolute structure shown. Crystal data for (ꢂ)-
(3R,4S)-10 and (+)-(3R,4S)-13 have been deposited with the Cam-
bridge Crystallographic Data Centre (CCDC reference numbers
722200 and 722201, respectively).26
42.8, 25.9, 24.4, 22.3, 22.2. IR (CHCl3 solution)
m = 2930, 1772
(C@O), 1686 (C@O), 1448, 1239, 1157. HRMS: [MꢂH+] C24H20BrO3,
found 435.0588, theoretical mass 435.0601.
4.6.20. (E)-3-Benzoyl-8-bromo-4-styrylchroman-2-one 25
Compound 2b (123 mg, 0.375 mmol) was treated according to
the general procedure C; pure product 25 was obtained as a yellow
oil (138 mg, 86% yield). 1H NMR: (400 MHz, CDCl3, 25 °C, TMS)
d = 7.97 (app. d, J = 7.2 Hz, 2H, Ph-o), 7.65 (app. t, J = 7.4 Hz, 1H,
Ph-p), 7.59 (app. d, J = 7.4 Hz, 2H, Ph-m), 7.54–7.50 (m, 3H, Ph),
7.33–7.32 (m, 2H, Ph), 7.27–7.25 (m, 1H, Ar), 7.20 (d, J = 7.1 Hz,
1H, Ar), 7.06 (d, J = 7.1 Hz, 1H, Ar), 6.56 (d, J = 15.7 Hz, 1H, H C@CH),
Acknowledgments
One of us (XT) is grateful to the FP6 Programme for providing a
Marie Curie Early Stage Fellowship under Contract MEST-CT-2005–
019780 (INDAC-CHEM). SW acknowledges the helpful input from
the COST D40 Programme on ‘Innovative Catalysis’ and from the
UK government (EPSRC grant EP/F033478/1). We thank Prof.

X. Tang et al. / Tetrahedron: Asymmetry 20 (2009) 1881–1891
1891
13. Garcia-Ruiz, V.; Woodward, S. Tetrahedron: Asymmetry 2002, 13, 2177–2180.
14. Vuagnoux-d’Augustin, M.; Alexakis, A. Chem. Eur. J. 2007, 13,
9647–9662.
Alexakis for his kind support of testing ligands. We thank Mr Dan-
iel Bailey for assistance in acquiring the X-ray data.
15. Selected recent examples: (a) Kees, K. L.; Fitzgerald, J. J.; Steiner, K. E.; Mattes, J.
F.; Mihan, B.; Tosi, T.; Mondoro, D.; McCaleb, M. L. J. Med. Chem. 1996, 39,
3920–3928; (b) Nicolai, E.; Cure, G.; Goyard, J.; Kirchner, M.; Teulon, J.-M.;
Versigny, A.; Cazes, M.; Vironeoddos, A.; Caussade, F.; Cloarec, A. Chem. Pharm.
Bull. 1994, 42, 1617–1630; (c) Zhang, J.; Didierlaurent, S.; Fortin, M.; Lefrancois,
D.; Uridat, E.; Vevert, J. P. Bioorg. Med. Chem. Lett. 2000, 10, 1351–1355; (d)
Siddall, T. L.; Ouse, D. G.; Benko, Z. L.; Garvin, G. M.; Jackson, J. L.; McQuiston, J.
M.; Ricks, M. J.; Thibault, T. D.; Turner, J. A.; Van Heertum, J. C.; Weimer, M. R.
Pest Manag. Sci. 2002, 58, 1175–1186.
16. Watanabe, T. Cardiovasc. Ther. 2008, 26, 101–114.
17. Tamura, Y.; Inoue, M.; Wada, A.; Fujita, M.; Kita, Y. Chem. Pharm. Bull. 1981, 29,
3226–3231.
18. Roa, H. S. P.; Sivakumar, S. J. Org. Chem. 2006, 71, 8715–8723.
19. Horning, E. C.; Horning, M. G. J. Am. Chem. Soc. 1947, 69, 968–969.
20. Specht, D. P.; Martic, P. A.; Farid, S. Tetrahedron 1982, 38, 1203–1211.
21. (a) Holmberg, G. A.; Malmström, F.; Wensström, U.; Holmberg, G. A. Acta Chem.
Scand. 1973, 27, 2023–2026; (b) Gustafsson, B.; Wennström, U.; Holmberg, G.
A. Acta Chem. Scand. 1975, B29, 273–274.
22. Chodankar, N. K.; Joshi, S. D.; Sequeria, S.; Seshardri, S. Ind. J. Chem. B 1987, 26B,
427–430.
23. Kataoka, T.; Iwama, T.; Tsujiyama, S.-I.; Iwamura, T.; Watanabe, S.-I.
Tetrahedron 1998, 54, 11813–11824.
24. (a) Feringa, B. L.; Pineschi, M.; Arnold, L. A.; Imbos, R.; DeVries, A. H. M. Angew.
Chem., Int. Ed. 1997, 36, 2620–2623; (b) Agapiou, K.; Cauble, D. F.; Krische, M. J.
J. Am. Chem. Soc. 2004, 126, 4528–4529.
25. Patra, A.; Misra, S. K. Ind. J. Chem. B 1988, 27B, 272–273.
26. These data can be obtained free of charge from The Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
References
1. (a) Schuppan, J.; Minnaard, A. J.; Feringa, B. L. Chem. Commun. 2004, 792–793;
For reviews: (b) Alexakis, A.; Benhaim, C. Eur. J. Org. Chem. 2002, 3221–3236;
(c) Alexakis, A.; Backvall, J. E.; Krause, N.; Pamies, O.; Dieguez, M. Chem. Rev.
2008, 108, 2796–2823.
2. Castaldi, G.; Colombo, L.; Rossi, R.; Allegrini, P. Can. Pat. Appl. 2005, A1
20050930 [Chem. Abst. 143, 367211]. For the primary literature in this area see:
Chen, G.; Tokunaga, N.; Hayashi, T. Org. Lett. 2005, 7, 2285–2288.
3. Hird, A. W.; Hoveyda, A. H. J. Am. Chem. Soc. 2005, 127, 14988–14989.
4. Versleijen, J. P. G.; Van Leusen, A. M.; Feringa, B. L. Tetrahedron Lett. 1999, 40,
5803–5806.
5. Tanaka, K.; Nuruzzaman, M.; Yoshida, M.; Asakawa, N.; Yang, X.-S.; Tsubaki, K.;
Fuji, K. Chem. Pharm. Bull. 1999, 47, 1053–1055.
6. Stephan, E.; Rocher, R.; Aubouet, J.; Pourcelot, G.; Cresson, P. Tetrahedron:
Asymmetry 1994, 5, 41–44.
7. (a) Pei, W.; Wei, H.-X.; Li, G. Chem. Commun. 2002, 2412–2413; (b) Lee, K. Y.;
GowriSankar, S.; Kim, J. N. Tetrahedron Lett. 2004, 45, 5485–5488.
8. (a) Wierenga, W.; Skulnick, H. I. J. Org. Chem. 1979, 44, 310–311; (b) Sugino, T.;
Tanaka, K. Chem. Lett. 2001, 110–112.
9. Feringa, B. L.; Pineschi, M.; Arnold, L. A.; Imbos, R.; De Vries, A. H. M. Angew.
Chem., Int. Ed. 1997, 36, 2620–2623.
10. (a) Alexakis, A.; Benhaim, C.; Rosset, S.; Humam, M. J. Am. Chem. Soc. 2002, 124,
5262–5263; (b) Li, K.; Alexakis, A. Angew. Chem., Int. Ed. 2006, 45, 7600–7603.
11. Tissot-Croset, K.; Polet, D.; Gille, S.; Hawner, C.; Alexakis, A. Synthesis 2004,
2586–2590.
12. Albrow, V. E.; Blake, A. J.; Fryatt, R.; Wilson, C.; Woodward, S. Eur. J. Org. Chem.
2006, 2549–2557.