Structure-reactivity studies of simple 4-hydroxyprolinamide organocatalysts in the asymmetric Michael addition reaction of aldehydes to nitroolefins

Article abstract of DOI:10.1002/adsc.201100028

A series of simple 4-hydroxyprolinamides was synthesised and they were found to act as organocatalysts for the asymmetric conjugate addition of aldehydes to nitroolefins in excellent yields (98%), with complete diastereoselectivity (99:1, syn:anti) and enantioselectivity (98% ee for syn). Furthermore, the use of low catalyst loadings (5mol%) and a low aldehyde molar excess (1.5equivalents) were achieved. Copyright

Full text of DOI:10.1002/adsc.201100028

FULL PAPERS
DOI: 10.1002/adsc.201100028
Structure-Reactivity Studies of Simple 4-Hydroxyprolinamide
Organocatalysts in the Asymmetric Michael Addition Reaction of
Aldehydes to Nitroolefins
John Watts,a Lien Luu,a Vickie McKee,b Ed Carey,a and Fintan Kellehera,*
a
Molecular Design and Synthesis Group, Department of Science, Institute of Technology Tallaght, Dublin 24, Ireland
Fax : (+353)-1-404-2700; phone: (+353)-1-404-42869; e-mail: Fintan.kelleher@ittdublin.ie
Chemistry Department, Loughborough University, Loughborough, Leicestershire, LE11 3TU, U.K.
b
Received: January 13, 2011; Revised: December 5, 2011; Published online: April 12, 2012
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.201100028.
Abstract: A series of simple 4-hydroxyprolinamides a low aldehyde molar excess (1.5 equivalents) were
was synthesised and they were found to act as orga- achieved.
nocatalysts for the asymmetric conjugate addition of
aldehydes to nitroolefins in excellent yields (98%),
with complete diastereoselectivity (99:1, syn:anti) Keywords: DFT calculations; Michael addition reac-
and enantioselectivity (98% ee for syn). Further- tion; organocatalysis; prolinamide; structure-reactivi-
more, the use of low catalyst loadings (5 mol%) and ty relationships
Introduction
compounds have found use as organocatalysts in the
asymmetric Michael addition reaction of aldehydes
The Michael addition reaction is one of the funda- and ketones to nitroolefins, with the products being
À
mental C C bond forming reactions in organic produced in high yields, with excellent diastereo- and
chemistry,[1] while the field of organocatalysis[2] has enantioselectivities (Figure 1).[2,4–6] More recently
seen an explosion of interest in the last decade, with highly efficient catalyst systems for this transforma-
just over 1000 journal papers being published in the tion have been developed and are the benchmark for
area in both 2010 and 2011.[3] Many l-proline-derived all new catalysts. Ma was able to achieve high yields
Figure 1. Proline and 4-hydroxyproline derived organocatalysts.[3–10]
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John Watts et al.
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and selectivities using only 0.5 mol% of 4 and of the structure-reactivity relationships of these cata-
1.5 equivalents of aldehyde in the presence of benzoic lytic systems.
acid as an additive.[4] However, Lombardo recently re-
ported the use of the ion-tagged diphenylprolinol silyl
ether 7 which achieves enantiomeric excesses of Results and Discussion
>99.5% at low catalyst loadings (0.25–5 mol%), and
uses only a slight excess of aldehydes (1.2–2 molar The starting material for the syntheses was trans-4-hy-
equivalents).[5] Ni achieved excellent yields and selec- droxy-l-proline which was fully protected as its
tivities with a water-soluble derivative of 4 using cata- TBDMS ether, methyl ester and N-Boc derivative 10,
lyst loadings of only 2–3%.[6] The most efficient cata- according to literature methods.[12] The best result for
lyst reported to date is the tripeptide 8 described by a-methylation was achieved using LiHMDS at
Wennemers.[7] This catalyst is highly efficient at levels À208C, and treatment of the resulting enolate with
of only 0.1–0.2 mol%, even with the nitroalkene in methyl iodide, which gave the fully separable diaste-
excess, giving high yields and selectivities for a range reoisomeric a-methyl esters 11 and 12, in a combined
of aldehydes and nitroalkenes. The usefulness of the isolated yield of 74% (Scheme 1). Separately each
products from these reactions resides in the potential ester was hydrolysed to give the free carboxylic acids
for further reaction or the transformation of both the 13 and 14. In order to compare directly with our pre-
nitro and carbonyl functionalities.
viously developed prolinamide catalysts,[8] the a-meth-
There is a continuing requirement for the develop- ylbenzylamine-derived 4-hydroxyprolinamides were
ment of new efficient catalysts for this and other im- prepared. Coupling of 13 separately with (R)- or (S)-
portant transformations, as well as their use in cas- N,a-dimethylbenzylamine in the presence of HATU
cade syntheses of complex products. An understand- gave the N-methylated prolinamides 15b and 16b, in
ing of the mechanisms[8] and structure-reactivity rela- low yields of 33 and 31% respectively, due to the
tionships of existing catalysts is also needed to help highly hindered nature of both coupling partners.
with the design and development of new catalytic sys- However, when similar couplings with the diastereo-
tems.
isomeric acid 14 were attempted no products were
Our group recently reported on the use of proline- isolated. This is most likely due to the fact that the
derived spirolactams, as well as more conformational- carboxylic acid and TBDMS ether groups are on the
ly flexible prolinamide analogues (e.g., 9), as asym- same side of the pyrrolidine ring, as well as the steri-
metric organocatalysts for the Michael addition of al- cally hindered nature of the amines being used. In
dehydes to nitrostyrenes.[9] High yields (98%) as well this case it was first necessary to remove the TBDMS
as excellent diastereoselectivities (49:1, syn:anti) were protecting group, with TBAF, to give the 4-hydroxy
achieved, for 9, while the enantiomeric excess (ee) carboxylic acid 21. Coupling with the (R)- or (S)-N,a-
was 81%. In this study it was found that a methyl dimethylbenzylamines was now successful with the
group in the pyrrolidine 2-position was detrimental to desired prolinamides 22b and 23b being isolated in 27
stereocontrol due to unfavourable steric interactions. and 31% yields, respectively. Deprotection of the
Thus there was a need to improve the enantioselectiv- TBDMS groups of 15b and 16b was achieved to give
ity of the spirolactam and prolinamide catalysts to 17b and 18b. The Boc group of all four diastereoiso-
give catalysts with full stereocontrol. In 2006, Palomo mers was removed using 50% TFA/DCM, where the
reported on the use of trans-4-hydroxyprolinamides isolation of the free amines 19b, 20b, 24b and 25b
(5, Figure 1) as a catalyst in the asymmetric Michael proved problematic with all isomers giving poor
addition reaction of aldhydes to nitroolefins.[10] The 4- yields of 20–25%. This was due to the high aqueous
hydroxy group was responsible for the high enantiose- solubility of the products and difficulty with their ex-
lectivity observed (98% ee) by directing the facial ap- traction.
proach of the b-nitrostyrene through a hydrogen-
The corresponding a-methyl N-H prolinamide ana-
bonding interaction. More recently Nakano used this logues were prepared in a similar manner by coupling
methodology to prepare an efficient catalyst (6, of acids 13 and 21 with the less hindered (R)- or (S)-
Figure 1) for both the asymmetric Michael addition N-methylbenzylamines giving the coupled products
and aldol reactions.[11] A study was thus undertaken 15a, 16a, 22a and 23a in slightly improved yields of
to examine the effect of a 4-hydroxy group on the 39–50%. Removal of the TBDMS groups of 15a and
enantioselectivity of our simple prolinamide catalysts. 16a gave 17a and 18a. Finally removal of all the Boc
Furthermore it was of interest to examine whether protecting groups, as before, gave the four diastereo-
the hydrogen-bonding ability of the 4-hydroxy group, isomeric N-H prolinamides 19a, 20a, 24a and 25a.
and its very efficient facial directing ability, would be Only compound 17a gave crystals suitable for X-ray
able to overcome the presence of a sterically hinder- crystal structure determination which clearly showed
ing methyl group in the pyrrolidine 2-position. This the (2S,4R,8S) configuration (Figure 2). This then al-
would therefore lead to an improved understanding
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Structure-Reactivity Studies of Simple 4-Hydroxyprolinamide Organocatalysts
Scheme 1. Synthesis of prolinamides 19, 20, 24 and 25. Reagents and conditions: a) i) LiHMDS, THF, À208C; ii) CH3I, THF,
18 h, À208C to room temperature; b) NaOH in MeOH/H2O, D; c) For 15a and 22a: (S)-1-phenylethylamine, HATU,
DIPEA, DMF, room tempearture; for 15b and 22b: (S)-N,a-dimethylbenzylamine, HATU, DIPEA, DMF, room tempera-
ture; d) For 16a and 23a: (R)-1-phenylethylamine, HATU, DIPEA, DMF, room temperature; for 16b and 23b: (R)-N,a-di-
methylbenzylamine, HATU, DIPEA, DMF, room temperature; e) 1M TBAF in THF, 08C; f) 50% TFA/DCM.
lowed for the assignment of the absolute configura-
tion of all the compounds prepared.
As the presence of the a-methyl group was previ-
ously found to be detrimental to efficient catalysis,[8]
the analogous simple 4-hydroxy prolinamide N-H and
N-methyl catalysts were prepared in a similar manner
to that outlined (vide supra), but using the N-Boc
TBDMS ether protected carboxylic acid 26, which
was prepared from the methyl ester 10 by hydrolysis
(Scheme 2). The N-H prolinamides 27 and 28 were
obtained in much improved yields of 68% and 72%,
respectively. N-Methylation was achieved by deproto-
nation with LiHMDS and methylation with methyl
iodide giving the desired compounds 29 and 31, with
both being obtained in a 58% yield. As before all pro-
tecting groups were removed giving the four simple 4-
hydroxy prolinamides 30, 32, 33 and 34.
All the prepared compounds were assessed as orga-
nocatalysts in the model reaction of valeraldehyde
with trans-b-nitrostyrene (Table 1). For comparison
with our previously published results[8] the reaction
Figure 2. X-ray crystal structure of 17a·H2O showing
conditions were kept constant, i.e., the solvent used
was DCM, with 5 mol% catalyst, 1.5 mole equivalents bond.
2S,4R,8S stereochemistry. The dashed line shows a hydrogen
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Scheme 2. Synthesis of prolinamides 30, 32-34 and 36–38. Reagents and conditions: a) (R)-1-phenylethylamine, EDC, DMAP,
DCM, 16 h, room temperature; b) i) LiHMDS, THF, À208C; ii) CH3I, THF, 18 h, À208C to room temperature; c) i) 1M
TBAF in THF, 0oC; ii) 50% TFA/DCM; d) (S)-1-phenylethylamine, EDC, DMAP, DCM, 16 h, room temperature.
Table 1. Optimisation of catalyst for Michael addition of va-
leraldehyde to trans-b-nitrostyrene.
of valeraldehyde, at room temperature for 48 h. The
two a-methyl compounds 19b and 20b with the N-
methyl amide trans to the 4-hydroxy group (entries 1
and 2) show good yields, poor diastereoselectivity, but
reasonable enantiomeric excesses of the major syn
product. However, the two a-methyl compounds 24b
and 25b with the N-methyl amide cis to the 4-hydroxy
group show much reduced yields, diastereoselectivi-
ties and enantioselectivities (entries 3 and 4). The
four corresponding N-H compounds (19a, 20a, 24a
and 25a) show similar results and trends (entries 5 to
8). Removal of the a-methyl group using the simple
N-methyl prolinamides 30 and 32 show improved re-
sults (entries 9 and 10) with 98% isolated yields,
hugely improved diastereoselectivity and enantiomer-
ic excesses back to 71% and 82%. The simplest hy-
droxyprolinamides 33 and 34 gave exceptional levels
of control with again isolated yields of 98%, excellent
diastereoselectivity (~99:1, syn:anti) and almost com-
plete enantioselectivity (98% ee).
Entry
Catalyst
Yield[a]
dr[b]
ee[c]
1
2
3
4
5
6
7
8
19b
20b
24b
25b
19a
20a
24a
25a
30
32
33
34
36
98
98
60
55
98
98
38
34
98
98
98
98
98
98
98
59:41
62:38
59:41
62:38
68:32
54:46
53:47
52:48
78:22
91:09
98:02
99:01
87:13
92:08
93:07
83[d]
77[d]
36
24
26[d]
58[d]
37
21
71
82
98
98
72
78
80
9
10
11
12
13
14
15
The results observed can be explained by looking
at the proposed transition state model for the reaction
(Figure 3). For catalysts 33 and 34 the hydroxy group
directs the Si face of the trans-b-nitrostyrene prefer-
entially to the Si face of the more stable E anti-enam-
ine (Si,Si-1 approach in Figure 3). The other Si,Si ap-
proach (Si,Si-2) is much less likely due to the steric
37
38
[a]
Isolated yield after column chromatography.
The syn:anti ratio was determined by H NMR spectros-
copy.
The ee of the syn isomer (R,S) as determined by Chiral
HPLC.
(S,R)-enantiomer of product.
[b]
[c]
[d]
1
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Structure-Reactivity Studies of Simple 4-Hydroxyprolinamide Organocatalysts
these compounds in the model reaction of valeralde-
hyde with trans-b-nitrostyrene are shown in Table 1,
entries 13–15. It can be seen that changing the proli-
namide side-chain to either a more, or less, sterically
hindered moiety is detrimental to the selectivity (dr
and ee) of the reaction. Thus the N-1-phenylethyl
side-chain is optimal in this catalyst system for the re-
action under study.
For a short-chain or branched aldehyde both cata-
lysts (33 and 34) show reduced diastereo- and enan-
tioselectivity (entries 3–6). For the substituted b-nitro-
styrenes the electron-donating methyl and methoxy
groups show reduced diastereo- and enantioselectivity
for both catalysts (entries 7–10). The results for the 4-
methyl case (entries 7 and 8) is surprising with
a much reduced yield along with very poor diastereo-
and enantioselectivities. In these cases the reactions
appeared slightly cloudy in appearance which may be
due to solubility issues which affected both the yield
and stereoselectivity. However, the 4-chloro analogue
retains high levels of diastereoselectivity, as well as
complete enantioselectivity (99% ee, entries 11 and
12). A preliminary result for the use of the catalysts
for the addition of cyclohexanone to trans-b-nitrostyr-
ene shows that they are also very reactive in these
cases (entries 13 and 14). It was however necessary to
use 20 molar equivalents of cyclohexanone, in the ab-
Figure 3. Proposed transition-state model for 4-hydroxypro-
linamide catalysts 33 and 34.
Table 2. Scope of catalysts 33 and 34 for Michael addition of
aldehydes to trans-b-nitrostyrenes.
interaction between the incoming b-nitrostyrene and
the amide side-chain of the enamine.
There are two probable approaches that would lead
to the minor enantiomeric product (Re,Re-1 and
Re,Re-2 in Figure 3). For Re,Re-2 the amide side-
chain sterically hinders approach of the b-nitrostyrene
to the Re face of the enamine. The Re,Re-1 trajectory
is the more likely but it is probable that the 4-hydroxy
group is too far away to direct the b-nitrostyrene.
Thus, it is likely that a combination of the effect of
the amide side-chain, the more likely enamine struc-
ture and the 4-hydroxy group which dictates the level
of stereocontrol stereocontrol observed. The optimal
combination of effects occurs for Si,Si-1 approach
giving the observed stereocontrol (see also computa-
tional studies below).
It was now of interest to examine whether the pro-
linamide N-1-phenylethyl side-chain was optimal for
reactivity. Three compounds with increased or de-
creased steric requirements were targeted so the N-1-
(1-naphthylethyl) (36 and 37) and N-benzyl (38) com-
pounds were also prepared (Scheme 2), by a similar
route to the N-1-phenylethyl derivatives except N-
Boc-trans-4-hydroxy-l-proline 35 was the starting ma-
terial (see Supporting Information). The results for
Entry Cat.
R
Ar
Yield[a] dr[b]
ee[c]
1
2
3
4
5
6
7
8
33
34
33
34
33
34
33
34
33
34
33
34
33
34
n-Pr Ph
n-Pr Ph
CH3 Ph
CH3 Ph
i-Pr
i-Pr
n-Pr p-Me-C6H4
n-Pr p-Me-C6H4
n-Pr p-MeO-C6H4 98
n-Pr p-MeO-C6H4 98
98
98
60
55
98
98
38
34
98:02 98
99:01 98
59:41 36
62:38 24
68:32 26[d]
54:46 58[d]
53:47 37
52:48 21
78:22 71
91:09 82
98:02 98
99:01 98
87:13 72
92:08 78
Ph
Ph
9
10
11
12
13
14
n-Pr p-Cl-C6H4
98
98
98
98
n-Pr p-Cl-C6H4
[e]
–
–
Ph
Ph
[e]
[a]
[b]
Isolated yield after column chromatography.
The syn:anti ratio was determined by H NMR spectros-
1
copy.
[c]
The ee of the syn isomer (R,S) as determined by Chiral
HPLC.
(S,R)-enantiomer of product.
Cyclohexanone used.
[d]
[e]
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Table 3. Energies of amide side-chain conformers (rotations
around the 4 rotatable bonds shown were examined).
Conformer[a]
E+ZPE (a.u.)
DACTHNGUTERNNUG
(E+ZPE) (kcalmolÀ1)
N-H trans 1
N-H trans 2
N-H cis 1
À961.094260
À961.091614
À961.083843
À961.074860
À1000.35997
À1000.36460
À1000.36260
À1000.36356
0.00
1.66
6.54
12.17
2.91
0.00
1.25
0.65
Figure 4. Relative energies of enamines (in kcalmolÀ1).
N-H cis 2
N-Me trans 1
N-Me trans 2
N-Me cis 1
N-Me cis 2
sence of solvent, and 10 mol% of the catalyst to ach-
ieve these results. This study is currently being ex-
tended in order to optimise the reaction conditions as
well as examining the scope of the catalysts with dif-
ferent ketones and b-nitrostyrenes, while the reactivi-
ty of the catalysts in aqueous solutions is also being
studied.
[a]
Refers to the cis and trans conformation around the
amide C N bond.
À
a number of low energy conformations possible de-
A closer examination of all the results in Table 1 pending on the position of the two methyl groups of
and Table 2, as well as the proposed transition state the isopropyl group, but a difference of 0.25 kcal
model, shows there are some discrepancies. For exam- molÀ1 was the smallest energy difference seen. Inter-
ple, if the amide side-chain is just acting as a steric estingly methylation of the amide side-chain nitrogen
blocking group (Figure 3) then it would be expected leads to a switch in the more stable enamine derived
that similar results should be obtained for the cata- from valeraldehyde (R=n-Pr), where the E-syn en-
lysts with either an N-H or N-Me group in the side- amine now is more stable by 0.14 kcalmolÀ1. From
chain (e.g., entry 9 versus entry 11 or entry 10 versus the transition state model outlined in Figure 3 the
entry 12 in Table 1). The presence of the N-Me group conformation of the enamine has a big influence on
clearly has a detrimental effect on the observed selec- the stereochemical outcome of the reaction and any
tivity. This begs the question as to whether there is change in the relative stability of the enamines would
some role, for example, hydrogen-bonding, for the lead to a reduction in the selectivity observed.
side-chain N-H which is not present for the N-Me
A more detailed study of the conformation of the
cases. A large drop in selectivity is also observed amide side was then undertaken, where the relative
when the aldehyde partner is changed. A shorter or energies of cis versus trans amides were examined de-
branched chain leads to a dramatic drop in the stereo- pending on whether the amide nitrogen atom was me-
control of the reaction (entries 3–6 in Table 2). It was thylated or not. The results show (see details in Sup-
therefore decided to use computational studies to ex- porting Information) that for the N-H cases there is
amine the relative energies of the different enamine a clear preference for the amide to assume the trans
structures, as well as possible transition states, in conformation (Table 3). However, when the corre-
order to explain the observed results.
sponding N-Me derivatives were examined the energy
The energies of the various enamines were calculat- differences between the cis and trans conformers
ed at the B3LYP/6-31G*[13] level of theory and the re- were much less. As part of these calculations con-
À
sults show that both the structure of the side-chain formers formed by rotation around the C C bond be-
amide and the aldehyde chain have an effect on the tween the pyrrolidine a-carbon and amide carbonyl
relative energies of the enamines. As expected, in all carbon were also examined, with the two lowest
cases the E rather Z enamines were more stable. For energy conformers being mentioned in each case
the amide side-chain containing an N-H the E-anti en- (e.g., N-H trans 1 and N-H trans 2 in Table 3).
amine derived from valeraldehyde (R=n-Pr) is more
One further suggestion for an explanation of the re-
stable by 0.13 kcalmolÀ1 (Figure 4). However, any duction in stereoselctivity in going from the N-H
change to the aldehyde chain (R=Me, Et or i-Pr) amide side-chain to a N-Me side-chain was that there
leads to the E-syn enamine being the more stable. For may be a H-bonding interaction between the N-H
the branched aldehyde (R=i-Pr) there were and the nitro group of the trans-b-nitrostyrene. The
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Structure-Reactivity Studies of Simple 4-Hydroxyprolinamide Organocatalysts
relative energies of transition states derived from the exact substrates used experimentally because very
reaction of the various enamines with trans-b-nitro- small changes in the structure of substrates can lead
styrene were next investigated, with trajectories from to profound differences in the stabilities of the enam-
above and beneath the enamine (both syn and anti) ines and transition states derived from them (see the
being examined, after a large number of individual Supporting Information). Attempts to use simplified
calculations (see Supporting Information). The activa- structures in order to speed up the calculations could
tion energy (15.43 kcalmolÀ1) for the Si,Si-1 trajectory lead to spurious results not comparable with the
(Figure 3) was 4.37 kcalmolÀ1 lower than the Re,Re- actual experimental results found. It is clear that fur-
1 trajectory (19.80 kcalmolÀ1). Furthermore, in all ther studies are required, not just for these catalysts,
cases involving a H-bond between the amide N-H but also for many other structural classes in order to
and the nitro group of the nitrostyrene, the energies improve the overall understanding of their structure-
of all such trajectories were much higher than the ap- reactivity relationships.
proach directed by the 4-hydroxy group, with the
lowest activation energy found being 21.43 kcalmolÀ1.
Similar activation energies were found when the Experimental Section
amide side-chain was N-methylated (21.45 kcalmolÀ1).
It seems that what is really important for this catalyst General Procedure for the Michael Addition
system is the structure of the amide sidechain and its Reaction of Aldehydes
effect on the relative stability of the E-enamines de-
To a solution of the b-nitrostyrene (1.00 mmol) in dry DCM
rived from each catalyst. A particular side-chain has
(1 mL) was added the relevant catalyst (0.05 mmol), fol-
an effect on the equilibria shown in the transition
lowed by the aldehyde (1.50 mmol). The reaction was stirred
state model in Figure 3 (i.e. which trajectory predomi-
nates) which in turn governs the selectivity observed
experimentally. We are currently undertaking further
computational studies to examine differences in the
relative energies between the transition states and ac-
tivation energies that lead to the syn and anti prod-
ucts being formed in this catalytic system. The results
of all these studies will be published in due course.
at ambient temperature for 2–3 days under nitrogen. It was
then diluted with chloroform (5 mL) and treated with 1N
HCl (4 mL) while stirring vigorously. The aqueous layer was
extracted with chloroform and the combined organic layers
were dried over MgSO4, and concentrated under vacuum.
The crude product was purified by column chromatography
using silica gel with 5% ethyl acetate: petroleum ether.
For the synthesis and characterisation of all new com-
pounds and products see the Supporting Information.
X-Ray Data
Conclusions
The data were collected at 150(2) K on a Bruker Apex II
CCD diffractometer. The structure was solved by direct
methods[13] and refined on F2 using all the reflections.[14] All
the non-hydrogen atoms were refined using anisotropic
atomic displacement parameters and hydrogen atoms
bonded to carbon and nitrogen were inserted at calculated
positions using a riding model. The H atoms bonded to
oxygen were located from difference maps and refined with
thermal parameters riding on the carrier atoms.
In conclusion we have prepared and studied a very
wide range of 4-hydroxyprolinamides as catalysts for
the asymmetric Michael addition reaction. It is appar-
ent from these studies that the trans-4-hydroxy group
is crucial for controlling the facial selectivity of the re-
actions. What is also apparent is that any compounds
with a methyl group in the 2-position of the pyrroli-
dine ring show much reduced reactivity and stereo-
control as catalysts, and even the presence of the
trans-4-hydroxy which directs the reaction electroni-
cally is unable to overcome the steric effect of the 2-
methyl group. The simplest trans-4-hydroxyprolina-
mides show the best reactivity with isolated yields of
98% being obtained using low catalyst loadings of
only 5 mol%, while they also demonstrate complete
stereocontrol. Within this subset of catalysts the re-
sults show that the exact structure of the prolinamide
side-chain is critical to a successful outcome. Very
small changes in the side-chain (e.g., N-H to N-Me or
a phenyl to a naphthyl group) led to large losses in
the efficient control of the reaction. A large number
of computational studies were undertaken to try to
understand the stereochemical results. All the compu-
Crystal data for 17a·H2O: C19H30N2O5.H2O, M=366.445
orthorhombic,
a=8.9076(7),
b=9.4253(7),
c=
23.1459(18) ꢁ, U=1943.3(3) ꢁ3, T=150(2) K, space group
P212121, Z=4, 19849 reflections measured, 2759 independent
reflections (Rint =0.0291). The final wR(F2) was 0.0819 (all
data) and R1 was 0.0302 for I>2s(I). CCDC 807941 con-
tains the supplementary crystallographic data for this paper.
These data can be obtained free of charge from The Cam-
bridge Crystallographic Data Centre via www.ccdc.cam.
ac.uk/data_request/cif or on application to CCDC, 12 Union
Road, Cambridge CB2 1EZ, UK [fax: +44-(0)1223-336033
or e-mail: deposit@ccdc.cam.ac.uk].
Acknowledgements
We are grateful to Strand I of the Irish Governmentꢀs Nation-
tational results show the importance of using the al Development Plan Technological Sector Research Pro-
Adv. Synth. Catal. 2012, 354, 1035 – 1042
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
1041

John Watts et al.
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Adv. Synth. Catal. 2012, 354, 1035 – 1042