Catalyst, additive and counterion effects on the efficiency and enantioselectivity of copper-catalysed C-H insertion reactions of α-diazosulfones

Article abstract of DOI:10.1016/j.tet.2012.12.003

Asymmetric copper-catalysed intramolecular C-H insertion reactions of α-diazosulfones in the presence of various group I salts are reported leading to substantial variation in reaction efficiencies and enantioselectivities. The borate additives NaBARF and

Full text of DOI:10.1016/j.tet.2012.12.003

Tetrahedron 69 (2013) 1297e1301
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Catalyst, additive and counterion effects on the efficiency and
enantioselectivity of copper-catalysed CeH insertion reactions
of a-diazosulfones
,
Catherine N. Slattery a, Leslie-Ann Clarke a, Alan Ford a, Anita R. Maguire b
*
a Department of Chemistry and Analytical and Biological Chemistry Research Facility, University College Cork, Ireland
b Department of Chemistry and School of Pharmacy, Analytical and Biological Chemistry Research Facility, University College Cork, Cork, Ireland
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 14 June 2012
Received in revised form 13 November 2012
Accepted 3 December 2012
Available online 7 December 2012
Asymmetric copper-catalysed intramolecular CeH insertion reactions of a-diazosulfones in the presence
of various group I salts are reported leading to substantial variation in reaction efficiencies and enan-
tioselectivities. The borate additives NaBARF and KBARF were found to be the most effective additives for
permitting highly enantioselective syntheses with short reactions times and high efficiency. Significantly,
direct evidence of the critical role of the additive in enantioselective carbenoid reactions has been
secured.
Keywords:
Diazo
Ó 2012 Elsevier Ltd. All rights reserved.
CeH insertion
Copper catalysis
Bis(oxazoline)
NaBARF
1. Introduction
insertion employing chiral copper catalysts. Examples of copper
catalysis in CeH insertion chemistry have been reported, however,
a
-Diazocarbonyl compounds are synthetically versatile in-
until recently the levels of asymmetric induction attained have
been generally poor, with limited good results for both intra-
molecular11 (up to 60% ee) and intermolecular12 (up to 88% ee)
reactions.
termediates, capable of producing a diverse range of products upon
transition metal-catalysed decomposition.1 Carbenoid CeH in-
sertion processes are particularly powerful transformations and
while early studies were effected with copper catalysts, efficiencies
and stereoselectivities were low and these reactions were of lim-
ited synthetic utility as a result. With the advent of rhodium acetate
and other rhodium carboxylate catalysts in the 1970s and 1980s,2
Recently, we reported that CeH insertion reactions of a-diazo-
sulfones in the presence of copperebis(oxazoline) complexes pro-
vide access to highly enantioenriched thiopyran13 (up to 98% ee) and
cyclopentanone14 (up to 82% ee) products. Enantioselectivities ob-
tained for these reactions represent the highest levels of asymmetric
induction recorded to date for copper-catalysed CeH insertion,
thereby establishing the synthetic utility of chiral copper catalysts in
enabling highly enantioselective CeH insertion reactions.
intramolecular CeH insertion reactions of
a-diazo-b-keto esters
became synthetically useful leading to very efficient synthesis of
cyclopentanone derivatives with excellent regiocontrol.3e6 The first
report of asymmetric catalysis in CeH insertion chemistry in 1990
employed a chiral rhodium carboxylate catalyst and led to just 12%
ee.7 Since this time enantioselective rhodium-catalysed CeH in-
sertion has attracted enormous attention with excellent enantio-
control achieved in many cases using a range of carboxylate and
carboxamidate catalysts.8e10
The borate anion BARFꢀ {BARF¼tetrakis[3,5-bis (trifluoromethyl)
phenyl] borate} was first utilised in 1981 by Kobayashi and co-
workers as a negatively charged phase transfer catalyst.15 This an-
ionic species behaves as an extremely weakly-coordinating anion
owing to distribution of the negative charge over a large area of non-
nucleophilic and chemically stable functional groups.16 Salts of
BARFꢀ, including sodium, potassium, silverandthallium compounds,
have been employed in several transition metal-catalysed trans-
formations, such as hydrogenation17,18 and hydrovinylation19,20 re-
actions, where they have been shown to enhance the activity of
cationic catalyst species resulting in improvements in reaction effi-
ciencies and selectivities.
In contrast, while enantioselective copper catalysis has proven
successful in asymmetric cyclopropanations and ylide formations,
limited success has been achieved in enantioselective CeH
* Corresponding author. Tel.: þ353 21 4901693; fax: þ353 21 4901770; e-mail
address: a.maguire@ucc.ie (A.R. Maguire).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.12.003

1298
C.N. Slattery et al. / Tetrahedron 69 (2013) 1297e1301
In our previous study, the addition of NaBARF to the catalytic
copper complexes was shown to be critical for achieving high
enantioselectivity in the insertion reactions of -diazo- -keto sul-
and methyl 2-diazo-2-(4-phenylbutylsulfonyl)acetate 6 were per-
formed in refluxing dichloromethane with a copper catalyst gen-
erated in situ from 5 mol % CuCl2, 6 mol % bis(oxazoline) ligand and
6 mol % group I salt. Three chiral bis(oxazoline) ligands 1e3 (Fig. 1)
were employed in this study. In general, trans-cyclopentanone 5
and cis-thiopyran 7 were the major products for the insertion re-
actions of 4 and 6, respectively.
a
b
fones,14 with a dramatic decrease in enantiocontrol being observed
in the absence of this borate additive. A similar effect had pre-
viously been reported by Zhou and co-workers for carbenoid in-
sertion into OeH and NeH bonds,21,22 however, the mechanistic
role that NaBARF plays in enhancing asymmetric induction in car-
benoid insertion reactions has not been discussed in these previous
reports. Recently, we reported a preliminary investigation of ad-
ditive effects in enantioselective copper-catalysed CeH insertion
While our previous study examining asymmetric copper-
catalysed intramolecular CeH insertion reactions of
a-diazo-b-
keto sulfones employed CuCl,14 CuCl2 was the chosen copper source
in this study. Such a change was found to have little effect on the
levels of enantioselectivity achieved in the insertion reactions,
however, significantly shorter reaction times were recorded in the
presence of CuCl2 and NaBARF. As was previously observed for re-
and aromatic addition reactions of a
-diazocarbonyl compounds.23
Building on the preliminary study, we report herein a more com-
prehensive investigation on the effect of NaBARF and a range of
other group I salts on the efficiency and enantioselectivity of CeH
actions in the presence of CuCl,14 CeH insertion of
a-diazo-b-keto
insertion reactions of
a
-diazosulfones, extending our preliminary
sulfone 4 in the presence of CuCl2 and bis(oxazoline) ligand resul-
ted in very low levels of enantioselectivity (Table 1, entry 1). A large
improvement in enantiocontrol was recorded for reactions
employing the weakly-coordinating counterion BARFꢀ (Table 1,
entry 2), with up to 89% ee observed for cyclisation with the
indane-derived bis(oxazoline) 1. In addition to enhanced enantio-
control, the addition of NaBARF also results in a dramatic decrease
in the time taken to achieve reaction completion.
study to include a wider range of bis(oxazoline) ligands. A detailed
discussion of the key role of the alkali metal cation in producing
highly enantioenriched products and an examination of additive
effects on chemoselectivity is included.
2. Results and discussion
The addition of a variety of other sodium salts (displaying
varying solubilities in dichloromethane) was explored to de-
termine their effects on enantioselectivity in the cyclisations of a-
The role of the additive in the cyclisation of two a-diazosulfones
was explored to determine the impact of the variation of both the
additive metal ion and counteranion. The intramolecular insertion
diazosulfone 4. Enantioselectivities obtained in the presence of
sodium hexafluorophosphate were found to largely parallel those
achieved with NaBARF, although increased reaction times were
recorded (Table 1, entry 3). Reactions with the remaining sodium
salts, sodium tetraphenylborate and sodium tetrafluoroborate,
displayed significantly decreased enantiocontrol and considerably
longer reaction times were required (Table 1, entries 4 and 5).
reactions of 1-diazo-1-phenylsulfonyl-5-phenylpentan-2-one
4
From the results obtained for the CeH insertion reactions of
a-
diazosulfone 4 the following order of effect on enantioselectivity
may be defined: NaBF4<NaB(C6H5)4<<NaPF6<NaBARF. This pat-
tern is in line with results reported by Pfaltz and co-workers for
studies of anion effects in asymmetric hydrogenation reactions
employing iridium-phosphinooxazoline catalysts, in which in-
creased reaction rates and catalyst stability were observed in the
Fig. 1. Bis(oxazoline) ligands.
Table 1
Copper-catalysed CeH insertion reactions of 1-diazo-1-phenylsulfonyl-5-phenylpentan-2-one 4
Entry
Cu
Additive
L*
Time (h)
Yielda (%)
eeb,c (%)
1
2
3
1
2
3
1
2
3
1
2
3
4
5
6
7
8
9
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
d
21
2
4
5
20
2
20
5
4
21
2
8
36
35
2
25
5
30
2
5
20
20
2
29
5
62
87
66
77
63
59
43
78
56
66
57
65
75
77
56
67
36
83
83
79
48
69
43
71
53
80
42
59
90
90
14 (2R, 3R)
89 (2R, 3R)
83 (2R, 3R)
25 (2R, 3R)
11 (2R, 3R)
91 (2R, 3R)
35 (2R, 3R)
71 (2R, 3R)
60 (2R, 3R)
57 (2R, 3R)
9 (2S, 3S)
0
NaBARF
NaPF6
NaB(C6H5)4
NaBF4
KBARF
KPF6
79 (2S, 3S)
76 (2S, 3S)
46 (2S, 3S)
22 (2S, 3S)
78 (2S, 3S)
56 (2S, 3S)
78 (2S, 3S)
71 (2S, 3S)
76 (2S, 3S)
57 (2S, 3S)
55 (2S, 3S)
15 (2S, 3S)
7 (2S, 3S)
49 (2S, 3S)
37 (2S, 3S)
51 (2S, 3S)
52 (2S, 3S)
46 (2S, 3S)
LiPF6
d
Cu(MeCN)4PF6
Cu(OTf)2
2
2
3
5
10
d
4
a
Isolated after flash chromatography.
b
c
Determined by chiral HPLC (see Supplementary data for details).
Stereochemical assignments are in agreement with previously reported data.31

C.N. Slattery et al. / Tetrahedron 69 (2013) 1297e1301
1299
presence of BARFꢀ compared to other anionic species, such as
insertion do not possess any clear steric interaction that allows for
discrimination between the two prochiral faces of the carbe-
neecarbon. It has been suggested in earlier reports that the primary
function of NaBARF is the abstraction of chloride from the catalytic
structure.27e29 It is therefore envisaged that complete or partial
abstraction of chloride by the naked sodium ion of NaBARF occurs
in the CeH insertion reactions of 4, thereby altering the geometry
of the catalytic complex resulting in higher levels of enantiocontrol.
The observation of small amounts of an insoluble white solid in the
reaction flask following reaction completion, found to be sodium
chloride by PXRD analysis, supports this theory.
ꢀ
ꢀ
17,18
PF6 and BF4
.
Indeed a similar effect was also observed by
Zhou and co-workers for asymmetric hydrovinylation reactions
employing catalytic palladium complexes of chiral phosphor-
amidite and phosphate ligands.19 In this previous work, improving
reactivity and enantioselectivity were recoꢀrded for various coun-
teranions in the order: OTfꢀ<BF4ꢀ<<SbF6 <BARFꢀ.
Reactions employing KBARF as an additive (Table 1, entry 6),
were found to result in similar levels of enantioselectivity in com-
parison to CeH insertions in the presence of NaBARF (Table 1, entry
2), with reaction times and yields also seen to be generally in
agreement. A slight increase in the level of enantioinduction ach-
ieved (91% ee) was recorded for the KBARF reaction with ligand 1.
Notably, this result represents the highest level of asymmetric in-
duction recorded to date for cyclopentanone synthesis via CeH
insertion, proving superior to previous rhodium-catalysed enan-
The results in Table 1 indicate that the nature of the counterion
in the alkali metal (Na, K, Li) salts only plays a role in terms of
enantioselectivity in so far as it enables solubility of the group I
cations. Thus, the key role of the additives is in generating a poorly-
solvated naked alkali metal cation in the dichloromethane solution.
Taking the above findings into account, the replacement of CuCl2
with a copper source possessing a more weakly-coordinating anion
was envisioned to lead to increased levels of enantioselectivity
for our CeH insertion reactions. Such an effect has been previously
observed by Zhou and co-workers for copper-catalysed carbenoid
insertions into SieH bonds in which enantioselectivites in excess
of 90% ee were recorded for reactions in the presence of
Cu(MeCN)4PF6 and Cu(OTf)2 without addition of NaBARF.30 In this
study, insertion reactions of diazosulfone 4 with the weakly-co-
ordinating Cu(MeCN)4PF6 and Cu(OTf)2 salts (Table 1, entries 9 and
10) were found to result in significantly higher levels of enantio-
control compared to CuCl2/bis(oxazoline)-catalysed reactions
(Table 1, entry 1), although failing to reach the levels recorded for
CuCl2/NaBARF cyclisations. This outcome is consistent with BARFꢀ
tioselective cyclisations employing
a-diazo-b-keto esters in which
up to 80% ee was achieved.24,25
In contrast to reactions employing NaBARF and NaPF6 as addi-
tives in which similar levels of enantioselectivity were recorded,
a significant falloff in enantioselectivity was recorded for cyclisa-
tions in the presence of KPF6 relative to the corresponding KBARF
reactions (Table 1, entries 7 vs 6). This decrease in asymmetric in-
duction, as well as the considerable increase in reaction times, is
believed to be a related to poor solubility of KPF6 in the reaction
solvent, which may limit its effect in the CeH insertion process.
Despite a slight increase in reaction times, high levels of
asymmetric induction were again observed for CeH insertions in
the presence of LiPF6 (Table 1, entry 8). Enantioselectivities ob-
tained for these cyclisations were largely in line with those pre-
viously observed for reactions employing NaBARF, however,
a decrease in enantioselectivity was recorded for insertion with the
indane-derived ligand 1 (Table 1, entries 2 vs 8).
being much less coordinating than both PF6 and OTfꢀ.16
ꢀ
CeH insertion reactions with methyl 2-diazo-2-(4-pheny-
lbutylsulfonyl)acetate 6 were also conducted (Table 2). As was
In studies examining the role of the counterion in copper/
bis(oxazoline)-catalysed enantioselective cyclopropanation re-
actions, the presence of the chloride counteranion was shown to
dramatically decrease enantioselectivity compared to reactions
with the more weakly-coordinating triflate anion.26 Theoretical
calculations conducted in this previous study revealed that the
presence of the strongly-coordinating chloride ion results in sig-
nificant geometric changes in the catalyst structure, with the result
that the diastereomeric transition structures for the carbenoid
previously observed for cyclisation of a-diazosulfone 4, achieve-
ment of high levels of enantioselectivity was possible for reactions
employing NaBARF, KBARF, NaPF6 and LiPF6 (Table 2, entries 2, 3, 6
and 8). In this instance, maintenance of enantiocontrol was ob-
served for insertions in the presence of KPF6 (Table 2, entry 7)
despite long reaction times being required. This observation is in
contrast with results recorded for insertion with
a-diazo-b-keto
sulfone 4 in which a decrease in ee was noted for insertion in the
presence of KPF6 (Table 1, entry 7). Bis(oxazoline) 3, which
Table 2
Copper-catalysed CeH insertion reactions of methyl 2-diazo-2-(4-phenylbutylsulfonyl)acetate 6
Entry
Additive
L*
Time (h)
Yielda (%)
eeb,c (%)
2
3
2
3
2
3
1
2
3
4
5
6
7
8
d
d
2.5
6
56
48
2
98
1.5
6
56
24
3
d
67
48
0
22
51
48
35
48
61
68
4
43
46
45
47
d
dd
NaBARF
NaPF6
NaB(C6H5)4
NaBF4
KBARF
KPF6
60 (2S, 3S)
73 (2S, 3S)
dd
95 (2S, 3S)
96 (2S, 3S)
dd
dd
dd
62 (2S, 3S)
70 (2S, 3S)
69 (2S, 3S)
95 (2S, 3S)
93 (2S, 3S)
85 (2S, 3S)
48
21
30
21
LiPF6
a
Isolated after flash chromatography.
b
c
Determined by chiral HPLC (see Supplementary data for details).
Stereochemical assignments are in agreement with previously reported data.13
No analytically pure sample isolated.
d

1300
C.N. Slattery et al. / Tetrahedron 69 (2013) 1297e1301
displayed only moderate asymmetric induction for reactions with
4, was found to be the best performing ligand for reactions with
diazosulfone 6, providing in excess of 90% ee for cyclisations in the
presence of NaBARF, KBARF, NaPF6 and KPF6. Notably, high levels of
enantioselectivity (94% ee) have also previously been observed for
CeH insertion reactions of 6 in the presence of Cu(MeCN)4PF6 and
ligand 3.13 Cyclisation of 4 in the presence of CuCl, ligand 1 and
NaBARF provided thiopyran 7 in 57% yield and 54% ee.
4. Experimental
4.1. General
DCM was distilled from phosphorous pentoxide and was further
distilled from calcium hydride. All CeH insertion reactions were
performed in oven-dried or flame-dried glassware under an at-
mosphere of dry N2. Thin layer chromatography (TLC) was carried
out on precoated silica gel plates. Visualisation was achieved by UV
light detection (254 nm) and vanillin staining. Infra red spectra
were recorded as thin films on sodium chloride plates for oils or as
potassium bromide (KBr) discs for solids on a 1000 FT-IR spec-
trometer. 1H (300/400 MHz), 13C (75.5 MHz) and 1H COSY NMR
spectra were recorded on a 300/400 NMR spectrometer. All spectra
were recorded at 20 ꢁC in deuterated chloroform (CDCl3) using
tetramethylsilane (TMS) as an internal standard unless otherwise
stated. Chemical shifts (dH and dC) are reported in parts per million
(ppm) relative to TMS and coupling constants are expressed in
Hertz (Hz). Splitting patterns in 1H spectra are designated as s
(singlet), d (doublet), t (triplet), q (quartet), qu (quintet), dd (dou-
blet of doublets), m (multiplet) and sym m (symmetrical multiplet).
13C NMR spectra were calibrated using the solvent signals, i.e.,
CDCl3: dC 77.0 ppm. Low resolution mass spectra were recorded in
electrospray ionisation (ESI) mode using 50% acetonitrile/water
containing 0.1% formic acid as eluent; samples were made up in
acetonitrile. High resolution precise mass spectra (HRMS) were
recorded in electrospray ionisation (ESI) mode using 50% acetoni-
trile/water containing 0.1% formic acid as eluent; samples were
made up in acetonitrile. Melting points were measured on a capil-
lary melting point apparatus. Enantiopurity of the chiral com-
pounds were determined by chiral HPLC performed on a Chiralpak
AS-H, Chiralpak OJ-H or Chiralcel OD-H column.
In addition to the observed benefits in terms of enantiocontrol,
the use of the additive species in this study was also found to lead to
increased chemoselectivity towards CeH insertion. In particular,
reactions conducted in the presence of NaBARF or KBARF provided
5 and 7 with very high levels of efficiency relative to reactions
without additives present, where increased evidence of side re-
actions, for example, with adventitious water or oxygen, is
observed.
In order to confirm the key role that the metal ion (Naþ, Kþ, Liþ)
plays in enhancing the efficiency and enantioselectivity of the CeH
insertion reactions of a-diazosulfones 4 and 6, a number of exper-
iments were conducted with NaBARF in the presence of 15-crown-5
(Table 3). Crown ethers are widely recognised as strong binding
agents for metal ions, with 15-crown-5 known to have a particular
high affinity for sodium cations.32 Addition of 15-crown-5 to our
catalytic system comprising CuCl2, bis(oxazoline) ligand and
NaBARF was found to have a significant detrimental effect on both
the time required to achieve reaction completion and the level of
enantioselectivity obtained (Table 3, entries 1e3 vs Table 1, entry 2).
Through crown ether-mediated complexation of the sodium cation,
chloride abstraction is prevented with the result that the cop-
perebis(oxazoline) complex can no longer adopt a geometry lead-
ing to efficient asymmetric induction. Thus, the presence of the
crown ether negates the enhancement of enantioselectivity pre-
viously observed for insertions employing NaBARF, thereby con-
firming the key role of the sodium cation in this effect.
4.2. General procedure for CeH insertion reactions of 1-diazo-
1-phenylsulfonyl-5-phenylpentan-2-one 4
Table 3
CeH insertion in the presence of 15-crown-5
The CuCl2-L*-(NaBARF) catalyst was generated in situ from
a mixture of CuCl2 (5 mol %) and bis(oxazoline) ligand (6 mol %) in
CH2Cl2 (15 mL), with or without NaBARF (6 mol %). This catalytic
mixture was stirred under nitrogen at 40 ꢁC for 1.5 h.
a-Diazo-b-
keto sulfone 4 (150 mg,1 equiv) was then added dropwise in CH2Cl2
(15 mL) over 0.5 h to the refluxing solution. The progress of the
reaction was monitored by TLC and IR spectroscopy, where reaction
completion was indicated by the disappearance of the character-
istic diazo peak at 2122 cmꢀ1. Upon reaction completion, evapo-
ration of the reaction solvent at reduced pressure gave the crude
product. Purification by flash chromatography on silica gel,
employing ethyl acetate/hexane as eluent, gave the pure cyclo-
pentanone product as a white solid.
Entry
L*
Time (h)
Yielda (%)
eeb (%)
1
2
3
1
2
3
20
48
20
63
50
62
25 (2R, 3R)
28 (2S, 3S)
20 (2S, 3S)
a
Isolated after flash chromatography.
Determined by chiral HPLC (see Supplementary data for details).
b
4.2.1. trans-2-Phenylsulfonyl-3-phenylcyclopentanone (5).31 White
solid, (found C, 67.59; H, 5.43. C17H16O3S requires C, 67.98; H,
5.37%); mp 96e99 ꢁC; nmax (KBr)/cmꢀ1 1743 (C]O), 1306, 1150
(SO2), dH (400 MHz, CDCl3) 1.92e2.07 [1H, m, one of C(4)H2],
2.49e2.70 [3H, m, C(5)H2, one of C(4)H2], 3.91 [1H, d, J 7.5, C(2)
HSO2], 4.05e4.17 [1H, m, C(3)HPh], 7.12e7.16 (2H, m, aromatic H),
7.20e7.32 (3H, m, aromatic H), 7.47e7.53 (2H, m, aromatic H),
7.59e7.65 (1H, m, aromatic H), 7.77e7.83 (2H, m, aromatic H).
3. Conclusion
In conclusion, copper bis(oxazoline)-catalysed CeH insertion
reactions of two -diazosulfones in the presence of various group I
a
salts have been carried out. We have demonstrated that variation of
the group I additive can have a significant effect on reaction time,
yield and enantioselectivity. The borate additives NaBARF and
KBARF were found to be the most effective for permitting highly
enantioselective cyclopentanone and thiopyran syntheses with
short reaction times and minimal side product formation. Signifi-
cantly, direct experimental evidence providing insight into the role
of NaBARF as an additive in carbenoid chemistry has been estab-
lished. It is clear that the key factor is generation of a highly reactive
naked alkali metal cation, which alters the nature of the copper
catalyst through partial or complete chloride abstraction.
4.3. General procedure for CeH insertion reactions of methyl
2-diazo-2-(4-phenylbutylsulfonyl)acetate 6
CuCl2 (5 mol %), L* (6 mol %), and NaBARF (6 mol %) were
weighed out and added to CH2Cl2 (8 mL). The required diazo ma-
terial (200 mg) was added as a CH2Cl2 solution (2 mL) and the
mixture was brought to reflux conditions. The reaction was

C.N. Slattery et al. / Tetrahedron 69 (2013) 1297e1301
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monitored by IR spectroscopy and kept at reflux until the diazo
absorbance in the IR spectrum had disappeared. The solvent was
removed under reduced pressure and the crude product was pu-
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boxylate (7).13 White solid, mp 116e118 ꢁC; (found C, 58.11; H, 6.19;
S, 11.94, C13H16O4S requires C, 58.19; H, 6.02; S, 11.93%); nmax/cmꢀ1
(KBr) 1727 (CO), 1323, 1118 (SO2); dH (300 MHz, CDCl3) 1.86 [1H,
dddd, appears as dq, J 13.8, 3.3, HA of C(4)H2], 2.11e2.36 [2H, m, C(5)
H2], 2.61 [1H, dddd, appears as qd, 13.3, 4.0, HB of C(4)H2], 3.05 [1H,
dddd, appears as dq, J 14.0, 3.2, HA of C(6)H2], 3.54 (3H, s, OCH3),
3.62e3.75 [2H, m, HB of C(6)H2 and C(3)H], 3.99 [1H, dd, J 4.5, 3.0,
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Acknowledgements
Financial support from the Irish Research Council for Science,
Engineering and Technology, and Eli Lilly is gratefully acknowl-
edged. The authors would like to thank Dr. Kevin Eccles and Dr.
Simon Lawrence for PXRD analysis.
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Supplementary data (chiral HPLC analysis and PXRD analysis).
Supplementary data related to this article can be found at http://
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