Synergistic effects within a C2-symmetric organocatalyst: The potential formation of a chiral catalytic pocket

Article abstract of DOI:10.1039/c3ob27250h

This study describes the synthesis of five novel C₂-symmetric organocatalysts that facilitate the on-water asymmetric aldol reaction at low catalyst loading (1 mol%) without the use of additives. Each catalyst is composed of two diprolinamide units joined by a symmetric alkyl bridging group allowing for systematic modulation of catalytic site proximity. Typically, catalysts in this manuscript which bear the catalytic units in close proximity gave the best reaction outcomes in terms of conversion (up to >99%), diastereomeric ratio (4/96, syn/anti) and enantiomeric excess (up to 97%). This effect has been attributed to the assembly of a chiral pocket, facilitated by hydrogen bonding at the oil-in-water interface. The Royal Society of Chemistry 2013.

Full text of DOI:10.1039/c3ob27250h

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Synergistic effects within a C2-symmetric
organocatalyst: the potential formation of a chiral
Cite this: DOI: 10.1039/c3ob27250h
catalytic pocket†
Joshua P. Delaney,a Hannah L. Brozinskia and Luke C. Henderson*a,b
This study describes the synthesis of five novel C2-symmetric organocatalysts that facilitate the on-water
asymmetric aldol reaction at low catalyst loading (1 mol%) without the use of additives. Each catalyst is
composed of two diprolinamide units joined by a symmetric alkyl bridging group allowing for systematic
modulation of catalytic site proximity. Typically, catalysts in this manuscript which bear the catalytic units
in close proximity gave the best reaction outcomes in terms of conversion (up to >99%), diastereomeric
ratio (4/96, syn/anti) and enantiomeric excess (up to 97%). This effect has been attributed to the assem-
bly of a chiral pocket, facilitated by hydrogen bonding at the oil-in-water interface.
Received 20th November 2012,
Accepted 15th February 2013
DOI: 10.1039/c3ob27250h
www.rsc.org/obc
Aside from the prominent use of steric influences, proper-
ties such as catalytic site proximity and catalyst pre-organi-
Introduction
Since the seminal work of List and Barbas, organocatalysis has sation are largely overlooked, thus spurring our interest in
experienced a dramatic increase in the intensity of investi- C2-symmetric organocatalysts. The use of C2-symmetric ligands
gation.1 Proline-derived organocatalysts have been the most is commonplace among transition metal catalysis but has
explored scaffold having been applied to a vast range of chiral been applied to organocatalysis only a few times.6 Embracing
bond forming reactions in a broad selection of solvents and C2-symmetric architectures provides a means to control spatial
conditions. In order to improve the activity, versatility and properties within an oligomeric catalyst, an aspect that has yet
chiral induction of proline based catalysts; the proline motif to be embraced as a significant aspect of organocatalyst
has been subjected to substantial modification and design.
elaboration.2
Recently, we reported the synthesis and evaluation of a
Rigorous modification of L-proline throughout the past novel C2-symmetric organocatalyst which demonstrated high
decade has seen a myriad innovations to the catalyst structure. catalytic activity for the asymmetric aldol reaction in an
Fundamental elaborations such as functionalization at the 4 ‘on-water’ reaction system (Fig. 1).7
position, as demonstrated by Hayashi et al.,3 have resulted in
vastly improved activity and chiral induction of proline cata-
lysts. Similarly, elaboration via the carboxyl group of proline
have seen great success.4 To this end, there has been an
increasingly broad range of organic transformations carried
out by highly derivatised, novel proline-based organocatalysts
such as small peptides, proline-thioamides and ionic liquid
tagged prolines are but a few.5 Despite the progress made
towards catalyst generality, organocatalysed asymmetric trans-
formations in water at low catalyst loadings remain a topic of
great interest in the synthetic chemistry community.
aStrategic Research Centre, Faculty of Science and Technology, Deakin University,
Geelong, Victoria 3216, Australia. E-mail: luke.henderson@deakin.edu.au;
Fax: (+613) 52271045; Tel: (+613) 52272767
bInstitute for Frontier Materials, Deakin University, Geelong, Victoria 3216, Australia
†Electronic supplementary information (ESI) available: 1H and 13C NMR of all
novel compounds and chiral HPLC traces and their corresponding racemates is
provided. See DOI: 10.1039/c3ob27250h
Fig. 1 Proposed catalytic conformation adopted by C2-symmetric organocata-
lysts, on-water (left) and organic (right) reaction medium. Diprolinamide sche-
matic is below.
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Based on this previous work, our hypothesis for this study
Organic & Biomolecular Chemistry
Table 1 Preliminary comparison of catalysts 1–5
was that the intramolecular distance of the prolinamide units
within the organocatalyst influences their cooperation and
therefore may lead to highly stereoselective aldol reactions. To
test this hypothesis several organocatalysts were synthesised
with sequentially increasing distance between the prolinamide
units. The rationale being that the shorter spacer lengths,
such as that present in catalysts 1 (4 methylene units) would
encourage prolinamide cooperation, while the larger intra-
molecular distances present in catalysts 4 and 5 (10 and
12 methylene units, respectively) would minimize the catalytic
site interaction and thus diminishing the cooperative potential
of each diprolinamide. Herein we present the comparison of
organocatalysts 1–5 using the asymmetric aldol reaction on-
water. Based on this experimental evidence we propose the
formation of a chiral catalytic pocket by this class of catalyst.
Entry
Catalyst
Conversiona (%)
dra (syn/anti)
eeb (%)
1
1
2
3
4
5
68
45
70
87
32
10/90
8/92
16/84
20/80
15/85
86
66
55
70
68
2c
3
4
5
a Determined by integration of key signals in the 1H NMR spectrum.
b Determined by Chiral HPLC, Chiralpak AD-H,
1 ,
mL min−1
2-propanol–n-hexane, 1 : 9. c Results obtained from a previous study
but provided here for clarity.7a
Results and discussion
chemistry.9 The on-water aldol reaction between cyclohexa-
The described organocatalysts are easily accessed via a four none 13 and benzaldehyde 14 (Scheme 1) was chosen as the
step synthesis utilizing affordable starting materials model reaction.
Employing diprolinamide 1 (Table 1, entry 1) at a catalyst
(Scheme 1). Incorporation of a tert-butyldiphenylsilyl moiety
onto trans-4-hydroxyproline 6 was achieved in excellent yield loading of 1 mol%, we were pleased to see that the aldol
(96%) following a protocol reported by McQuade et al.8 and product 15a was obtained in good yield and high stereopurity,
dr of 10/90 (syn-/anti-) and ee of 86%. Continuing the compari-
the crude product was directly N-protected using a tert-butoxy-
carbamate (Boc) group furnishing 7 in a high yield (82%) over son with the remaining catalysts (Table 1, entries 2–5) afforded
two steps. The protected proline unit was then tethered to inferior ee’s in all cases compared to 1, and similar sacrifices
were observed regarding dr. The general decline in stereo-
each end of a series of linear diamines via an EDCI mediated
peptide coupling to afford bis-prolinamides 8–12. Removal of chemical purity of the aldol products as prolinamide tether
the N-Boc protecting groups was obtained in moderate to excel- length increases supports our original hypothesis of potential
catalytic site cooperation.
lent yield using a TFA–CH2Cl2 (10% v/v) protocol furnishing
the desired organocatalysts 1–5.
Encouraged by these preliminary results our attention
By utilizing the well understood aldol reaction as a model turned to investigating each catalyst in combination with other
commonly employed benzaldehydes and a second ketone
system, variations in reaction outcome can be attributed to cata-
lyst structure with greater confidence. The clearer insight into (cyclopentanone) to see if catalyst 1 outperforming catalysts
potential transition states of each C2-symmetric diprolinamide 2–5 was indeed a general trend.
can be achieved. Additionally the aldol reaction is one of the
Employing cyclopentanone 16 as the donor ketone (Table 2,
most important C–C bond forming reaction in organic entries 1–5) demonstrated the same general trend with respect
Scheme 1
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Table 2 Reaction scope of organocatalysts 1–5
Catalyst→
1
2c
3
4
5
Con.a
(%)
dr (syn/
anti)a
eeb
(%)
Con.a
(%)
dra (syn/
anti)
eeb
(%)
Con.a
(%)
dra (syn/
anti)
eeb
(%)
Con.a
(%)
dra (syn/
anti)
eeb
(%)
Con.a
(%)
dra (syn/
anti)
eeb
(%)
Entry
n
R
15
1
2
3
4
5
6
5
6
7
8
9
10
11
0
0
0
0
0
0
0
1
1
1
1
1
1
H
4-Br
4-F
4-NO2
3-NO2
2-NO2
4-Ph
4-Br
15b
15c
15d
15e
15f
15g
15h
15i
15j
15k
15l
15m
15n
92
96
97
97
55
74
78
99
71
99
85
73
67
25/72
50/50
27/73
39/61
88/12
91/9
38/62
9/91
6/94
4/96
7/93
3/97
12/88
74
72
80
8
96
99
80
88
86
97
99
92
94
90
99
85
61
99
37
70
97
88
91
57
71
37
64/36
59/41
64/36
24/76
54/46
34/66
59/41
14/86
9/91
50
52
42
14
52
78
46
86
92
99
88
72
80
99
98
99
99
99
99
78
96
86
62
73
65
44
61/39
47/53
43/57
73/27
52/48
40/60
58/42
14/86
21/79
23/77
19/81
16/84
18/82
64
68
65
8
56
82
50
80
82
80
86
74
80
92
99
99
72
98
92
76
37
99
50
36
92
44
60/40
43/57
42/58
49/51
53/47
30/70
63/37
19/81
19/81
25/75
17/83
16/84
21/79
68
54
68
14
46
66
40
56
84
52
84
64
89
56
99
99
40
99
36
38
77
76
65
61
61
19
60/40
61/39
62/38
66/34
51/49
35/65
57/43
16/84
17/83
20/80
17/83
13/87
15/85
70
56
66
12
50
69
44
82
86
64
86
46
80
4-F
4-NO2
3-NO2
2-NO2
4-Ph
4/96
16/84
15/85
15/85
1
a Determined by integration of key signals in the H NMR spectrum, Chromatography was restricted to reaction mixtures showing conversions <20%, similar to such protocols employed by
groups such as Penhoat,11a Giacalone11b and Guellena11c in order to accurately quantify catalyst activity. b Determined by Chiral HPLC, Chiralpak AD-H, 1 mL min−1, IPA–Hexane, 1 : 9.
c Results obtained from a previous study but provided here for clarity of comparison.7a Results in bold were determined to be the best of the series by the authors.

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to catalyst 1 as was observed in Table 1 whereby the smallest
prolinamide linker furnishes the superior reaction outcomes.
In all cases the catalyst bearing the smallest intramolecular
distance between proline moieties exhibited the best optical
purity of aldol products obtained. In general, the reaction con-
versions were good to excellent, though no discernible trend
was obvious when comparing conversion values to catalyst
structure. When comparing the diastereomeric ratio of the pro-
ducts obtained from each of the catalysts examined, the predo-
minant diastereomer is syn, a stark contrast to those in
Table 1. Cyclopentanone has been reported to exhibit moder-
ate diastereoisomeric ratio in the aldol reaction and indeed
this was the case with catalysts 1–5.10 However, catalyst 1
displays behaviour which is countermand whereby in most
cases the anti diastereoisomer is preferred, while the aldol pro-
ducts furnished by 2–5 were primarily composed of the syn
diastereomer. This aberration in results suggests that there is
an important role being played by the intramolecular distance
between these prolinamide units that contributes to the
Fig. 2 Proposed conformation taken by catalysts 1–5 (left) and a proposed
catalyst 16 which is H-bond stabilized (right).
diastereomeric purity of the generated aldol products. We as a directing group for the first, and its degree of cooperation
that results in the observed discrepancies in catalytic ability.
To address the trends observed within each reaction outcome
across the catalysts 1–5, the formation of a chiral pocket has
been proposed (Fig. 2).
were further pleased as examination of the ees furnished by
catalyst 1 were superior to those in all cases to those shown by
catalysts 2–5.
Although, compound 15e (Table 2, entry 4) was deemed an
outlier due to a consistently poor compatibility among the cata-
It has been noted that on-water organocatalysis allows for
lysts series. In this instance we considered the superior con- particular advantages derived from abundant H-bonding inter-
actions at the oil–water interace.9,12 This participation of water
version demonstrated by catalyst 1 to be the optimal outcome.
has led to proposed transition states such as that by Pedrosa
6–9) gave a similar trend where the smallest organocatalyst 1 et al.13 who describe an on water organocatalysed aldol reac-
Repeating this series with cyclohexanone (Table 2, entries
tion by a prolinamide bearing multiple amide groups. This
transition state presents each amide as both a H-bond accep-
gave the best reaction outcomes. In this series of reaction
employing cyclohexanone 13, albeit the superiority of catalyst
1 to catalysts 2–5 was not as pronounced as it was when tor, leading to organization at the oil–water interface, and
H-bond donors which facilitate a controlled means of aldehyde
approach. Additionally, the concept of multiple hydrogen
employing cyclopentanone. It should be noted that in two
instances the results obtained for catalyst 1 and 2 were com-
parable in both conversion and stereochemical aspects. When bonding donors to facilitate the asymmetric aldol reaction
with high stereochemical outcome has been used previously
using 4-fluorobenzaldehyde as the reaction partner (Table 2,
entry 7) catalyst 2 was deemed superior to catalyst 1, though
by Gong et al.14 and Singh et al.15 who employed a prolina-
only by a marginal amount (17% higher yield and 6% mide based amino alcohol to assist in direct the approach of
the incoming aldehyde.
improved ee).
Through hydrogen bonding involving the amide groups at
These catalysts were also employed to catalyse the aldol
reaction using various ketones and electron rich aldehydes. the oil–water interphase, each diprolinamide could potentially
align along the surface of the oil droplet, a confirmation sup-
ported by lipophilic TBDPSO groups pointing into the oil
phase. The impact of this potential formation has dramatic
implications regarding both the catalytic activity and chiral
induction furnished by each catalyst.
Due to the symmetric nature of the proposed transition
state, each catalytic unit is situated equidistant to the
approaching aldehyde, and so the activity would be bolstered
due to a high relative concentration of the activated chiral
enamine. From a chiral standpoint, this symmetry ensures
that each enamine reacts with the appropriate Re or Si face of
the incoming aldehyde, furnishing the observed enantio-
enriched aldol product. This proximal advantage would
diminish as each catalytic unit is moved apart, reducing the
likelihood of cooperation between diprolinamide units and
Unfortunately, under these conditions the catalysts proved
ineffective at facilitating high levels of conversion or optical
purity. These data are presented in the ESI.†
A prominent trend becomes apparent when considering the
dr of each aldol product, with diastereochemical control
becoming markedly reduced among the larger catalysts 3–5.
This may be a result of a more flexible, and thus less stereo-
chemically defined, transition state allowing for multiple
approaches of the incoming aldehyde.
Based on the experimental evidence, it is apparent that the
transition state which is formed is significantly influenced by
catalytic site proximity. It was reasoned that each diprolina-
mide must adopt a transition state that allows for potential cata-
lytic site cooperation, be that via hydrogen bonding effects or
purely in a steric fashion i.e. the second prolinamide serving
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resulting in the poor stereochemical outcomes which were
observed for the larger diprolinamides.
Table 3 Examination of organocatalyst 6 in the asymmetric aldol reaction
This alignment at the interface also presents an opportu-
nity for the linking group to act as a sterically directing moiety,
restricting the approach of the aldehyde through the formation
of a chiral catalytic pocket – a stereochemically defined
environment. This further restricts the configuration by which
the reacting aldehyde may approach, significantly improving
the optical purity of the obtained products.
Considering the proposed catalytic pocket in Fig. 2 (left),
the alignment of the hydrocarbon linker along the oil–water
interface was considered to be an unfavourable interaction.
This effect would be minimal for catalysts bearing the smaller
hydrocarbon chains (such as catalysts 1 and 2). Though for the
larger catalysts, such as 3–5, this unfavourable interaction may
be responsible for the observed reductions in catalyst perform-
ance for catalysts bearing the larger, and thus more hydro-
phobic, alkyl chains.
Entry
n
Catalyst
R
Solvent Conv.a (%) dra (syn/anti) eeb
1
2
3
4
5
6
7
8
1
1
1
1
1
0
0
0
3
H
H
H
Neat
Neat
H2O
88
90
98
92
96
99
56
99
13/87
25/75
15/85
14/86
11/88
61/39
63/37
61/39
64
66
76
87
76
62
20
70
16
16
16
16
16
16
16
NO2 H2O
F
H
H2O
H2O
NO2 H2O
H2O
F
To address this unfavourable interaction, an oxygen rich
catalyst 16 (analogous in size to catalyst 3) was synthesised and
evaluated in the on-water asymmetric aldol system. It was
reasoned that the oxygenated linker between prolinamide
units would reinforce the chiral assembly, as proposed in
Fig. 2 (right), via H-bonding at the oil–water interface while
retaining the hydrophobic nature of the TBDPS groups on the
prolinamide units.
a Determined by integration of key signals in the 1H NMR spectrum.
b Determined by Chiral HPLC, Chiralpak AD-H, 1 mL min−1, IPA–
n-Hexane, 1 : 9.
Conclusions
In conclusion, this manuscript describes the synthesis of a
range of C2-symmetric organocatalysts 1–5 and 16 consisting
of multiple trans-TBDPS-prolinamides bearing systematically
increasing linker lengths. Each of these organocatalysts were
evaluated for their ability to facilitate the asymmetric aldol
reaction on-water at a low catalyst loading of 1 mol% without
the use of additives or co-solvents. It was observed that as the
distance between the prolinamide units increased, both the
conversion to the desired product and the optical purity
(dr and ee) decreased among each aldol reactions. Also
described is a new intramolecular organocatalytic interaction
between prolinamide moieties that allows for a cooperative
catalytic process. This effect was attributed to the formation of
a hypothesized chiral ‘catalytic pocket’ providing confor-
mational influences giving rise to aldol products of high
optical purity at low loadings.
It is important to note that the intramolecular distance
between prolinamide units in catalyst 16 is approximately the
same as that of catalyst 3. Thus a comparison could be drawn
between each catalysts and the effect of this ethereal linker.
To probe how the absence of H-bonding may impact the
activity of the oxygenated dimer, catalyst 16 was initially evalu-
ated in the absence of water by conducting the reaction in neat
cyclohexanone 13.
These experiments (Table 3, entries 1 and 2) show the simi-
larly sized catalysts 3 and 16 affect near identical reaction out-
comes, suggesting that without the presence of water, the
oxygenated linking chain has no bearing on catalytic ability.
Significant improvements to reaction outcome were
observed when water was added to the reaction vessel. With
respect to the cyclohexanone containing examples (Table 3,
entries 3–5), 16 shows a marked improvement in both conver-
sion, dr and ee compared to the purely alkyl bridged organo-
catalyst 3. Thus suggesting that there is some effect elicited by
the combination of oxygenated linker group and water at the
emulsion interface. In a similar trend observed throughout
this study, the use of cyclopentanone as the donor ketone
resulted in decreased enaniomeric excesses and only moderate
control over diastereomeric ratio.
The results obtained from this study will aid the rational
design of organocatalysts and introduces the concept of cata-
lytic site proximity within an oligomeric prolinamide system as
being a key property that contributes to the activity and chiral
induction of future novel catalysts.
Although not definitive, the experimental results presented
in this manuscript can be rationalised by the formation of a
chiral assembly at the oil-in-water interface. We believe that
Experimental section
General procedure for organocatalysed aldol reactions
full elucidation of this catalytic mechanism is beyond the Water (1.6 mL) was added to a round-bottom flask charge with
scope of this comparative study. Never-the-less the data pre- organocatalyst (0.002 g, 0.01 eq.) dissolved in ketone
sented herein will assist in the design of organocatalysts (0.127 mL, 1.22 mmol, 5 eq.). Benzaldehyde (0.244 mmol,
bearing multiple proline groups.
37 mg, 1 equiv.) was introduced to the emulsion and the
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reaction mixture was then stirred vigorously at room tempera-
1,4-Di(trans-N-Boc-4-tert-butyldiphenylsiloxy-L-prolinamide)
ture for 24 h. The emulsion was then extracted with CHCl3 (2 × butane 8. trans-N-Boc-4-tert-butyldiphenylsiloxy-L-proline
7
10 mL) and the combined organic phase was washed with 10% (0.295 g, 0.623 mmol) was dissolved in DCM (20 mL) and
citric acid (10 mL). The organic phase was then dried over cooled to 0 °C. HOBt (0.02 g, 0.015 mmol) was added to the
MgSO4 and the solvent was removed under vacuum to give the solution and the mixture was stirred for 5 min. EDCI (0.142 g,
crude product as a yellow solid. Analysis by 1H NMR spec- 0.074 mmol) was added to the mixture followed by 3 min
troscopy was used to determine the desired product, reaction additional stirring followed by the introduction of 1,4-diami-
conversion and the diastereomeric ratio. In cases where con- nobutane (0.03 mL, 0.297 mmol). The mixture was allowed to
version was determined to be <20%, the crude product was reach room temperature and stirred for 16 h. The final reaction
purified by silica gel column chromatography (1/3 EtOAc : Pet. mixture was diluted with additional DCM (30 mL) and washed
Spirits). The pure products were analysed by chiral HPLC with 10% citric acid (3 × 30 mL), saturated NaHCO3 (3 ×
(Chiral Pak AD-H, hexane : 2-propanol, 90 : 10, 1 mL min−1) to 30 mL) and brine (1 × 30 mL). The resulting organic phase was
determine the enantiomeric excess. All reactions were per- dried over MgSO4 and the solvent was removed in vacuo to give
formed a minimum of three times and the data presented was the crude boc protected diprolinamide 8 as a colourless oil.
considered representative of these results.
The crude mixture was purified via flash chromatography (1/3
trans-4-tert-Butyldiphenylsiloxy-N-Boc-L-proline-carboxylic EtOAc : Pet spirits → 1/1 EtOAc : Pet spirits) to give the pure
acid 7. trans-4-Hydoxy-L-proline (1.0 g, 0.763 mmol) was dimer as a viscous colourless oil (0.292 g, 0.254 mmol, 85%).
1
added to acetronitrile (20 mL) and stirred. TBDPS-Cl (6.94 mL, Rf = 8/33 (1 : 1 EtOAc : Pet. Spirits); H NMR (400 MHz, CDCl3)
0.026 mol) was added to the stirring solution and the reaction δ (ppm) = 7.62 (m, 8H), 7.40 (m, 12H), 4.40 (br, 4H), 3.72 (br,
was cooled to 0 °C. DBU (4.22 mL, 0.028 mol) was sub- 1H), 3.43 (br, 1H), 3.23 (br, 4H), 2.22 (br, 2H), 1.88–1.76 (br.
sequently added to the stirring solution and the mixture was m, 2H), 1.43 (br, 18H), 1.25 (br, 4H), 1.03 (br, 18H); 13C NMR
allowed to reach room temperature and stirred for 24 h. The (100 MHz, CDCl3) δ (ppm) = 172.0, 155.9, 135.7, 133.6, 129.9,
resulting reaction mixture was then quenched with hexane and 127.9, 71.0, 60.5, 59.1, 55.2, 40.2, 38.9, 37.7, 28., 26.9, 19.2;
the product was extracted into hexane (3 × 30 mL). The com- [α]2D2.2 = −30.8° (0.00089, CHCl3); IRmax λ = 2930 (m), 1660 (s),
+
bined hexane layers were combined and the solvent was 1105 (s), 700 (s); HRMS calculated for [C56H79N4O8Si2
]
removed in vacuo. The resulting oil was redissolved in a metha- M = 991.5431, found 991.5401.
nol (32 mL), THF (18 mL), water (16 mL) and 2 M NaOH
1,4-Di(trans-4-tert-butyldiphenylsiloxy-L-prolinamide) butane
(24 mL) mixture and allowed to stir for 90 min at room temp- 1. N-Boc protected diprolinamide 8 (0.394 g, 0.398 mmol) was
erature. The solution was then titrated to a pH of 6 with 2 M solvated in DCM (18 mL) and stirred. To the stirring solution
HCl before removing the organic solvents under reduced was added TFA (2 mL) to bring the solution to a 10 vol% con-
pressure. To the resulting water layer a 1 : 1 ratio of Et2O was centration of acid/DCM. The solution was stirred for 6 h under
added and the biphasic mixture was allowed to stand for 24 h, an inert atmosphere at room temperature. The final mixture
resulting in crystals forming in the organic phase. The solid was basified with saturated NaHCO3 (50 mL) and extracted
was filtered and washed with cold Et2O to give the silylated into DCM (3 × 30 mL). The combined organic phase was then
intermediate as white crystals (2.71 g, 0.733 mol, 96%). 1H washed with additional NaHCO3 (3 × 30 mL) and the organic
NMR (400 MHz, CD3OD) δ 7.67–7.64 (m, 4H), 7.45–7.42 (m, phase was dried over MgSO4. The solvent was removed in vacuo
6H), 4.59 (s, J = 0.27, 1H), 4.23 (1H, m), 3.30 (dd, J = 10.8, to give an opaque oil. Residual solvent was azeotroped with
5.4 Hz, 1H), 3.29 (dt, J = 13.5, 2.7 Hz, 1H), 2.31 (ddt, J = 13.5, Et2O to give the final organocatalyst 1 as an amorphous pale
7.56, 1.88 Hz, 1H), 1.93 (ddd, J = 13.5, 9.99, 4.05 Hz, 1H), 1.08 brown solid (0.309 g, 0.39 mmol, 98%). Rf = 4/33 (1 : 9 MeOH :
(s, 9H). Compound was identified by 1H NMR and was consist- EtOAc); Mp = 205.5–207 °C; 1H NMR (400 MHz, CDCl3) d
ent with literature values.8 Without further purification, (ppm) = 7.61 (m, 8H), 7.36 (m, 12H), 4.35 (br m, 2H), 4.00 (t,
TBDPSO-proline (2.71 g, 0.734 mmol) was dissolved in a 1 : 1 J = 8.4 Hz, 2H), 3.14 (m, 4H), 2.90 (d, J = 12.1, 2H), 2.58 (d, J =
ratio of THF–H2O (20 mL : 20 mL). To this mixture was added 2.94, 12.1, 2H), 2.26 (m, 2H), 1.70 (m, 2H), 1.45 (br, 4H), 1.04
NaOH (0.733 g, 0.018 mol) along with Boc2O (2.08 g, (br, 18H). 13C NMR (100 MHz, CDCl3) δ (ppm) = 173.7, 135.8,
0.953 mmol) and the solution was stirred for 16 h at room 133.2, 129.9, 127.9, 71.8, 65.9, 59.4, 51.9, 38.9, 26.7, 19, 15.4;
temperature. The resulting solution was then acidified with [α]2D3.3 = −37.6° (c = 0.0025, CHCl3); IR νmax = 2925 (m), 1624 (s)
+
2 M HCl and extracted into diethyl ether (3 × 20 mL). The com- 698 (s); HRMS calculated for [C46H63N4O4Si2 ] M = 791.4382,
bined organic phase was dried over MgSO4 and the solvent was found 791.4395.
removed in vacuo to afford clear viscous oil. The crude mixture
1,6-Di(trans-N-Boc-4-tert-butyldiphenylsiloxy-L-prolinamide)
was purified via flash chromatography (1/4 EtOAc : Pet spirits) hexane 9. trans-N-Boc-4-tert-butyldiphenylsiloxy-L-proline
7
to give the pure N-Boc protected monomer as a colourless oil (0.714 g, 1.52 mmol) was dissolved in DCM (20 mL) and
(2.82 g, 0.6 mol, 86%). 1H NMR (400 MHz, CDCl3) δ (ppm) cooled to 0 °C. HOBt (0.042 g, 0.36 mmol) was added to the
7.64 (m, 4H), 7.39 (m, 6H), 4.56 (t, J = 8 Hz, 1H), 4.43 (m, 1H), solution and the mixture was stirred for 5 min. EDCI (0.271 g,
3.59–3.29 (m, 2H), 2.28–2.04 (m, 2H), 1.47 (m, 9H), 1.07 (m, 1.41 mmol) was added to the mixture followed by 3 min
1
9H). Compound was identified by H NMR and was consistent additional stirring followed by the introduction of 1,6-diamino-
with literature values.8
hexane (0.084 g, 0.72 mmol) was introduced. The mixture
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was allowed to reach room temperature and stirred for 16 h.
1,8-Di(trans-4-tert-butyldiphenylsiloxy-L-prolinamide) octane
The final reaction mixture was diluted with additional DCM 3. N-Boc protected diprolinamide 10 (568 mg) was solvated in
(30 mL) and washed with 10% citric acid (3 × 30 mL), saturated DCM (18 mL) and stirred. To the stirring solution TFA (2 mL)
NaHCO3 (3 × 30 mL) and brine (1 × 30 mL). The resulting was added to bring the solution to a 10 vol% concentration of
organic phase was dried over MgSO4 and the solvent was acid/DCM. The solution was stirred for 7 h under an inert
removed in vacuo to give the crude boc protected diprolina- atmosphere at room temperature. The final mixture was basi-
mide 8. The crude mixture was purified via flash chromato- fied with saturated NaHCO3 (50 mL) and extracted into DCM
graphy (1/3 EtOAc : Pet spirits) to give the pure dimer as a (3 × 30 mL). The combined organic phase was then washed
1
white amorphous solid (0.484 g, 0.475 mmol, 66%). H NMR with additional NaHCO3 (3 × 30 mL) and the organic phase
(270 MHz, CDCl3) δ (ppm) = 7.59–7.25 (m, 20H), 4.39 (m, 4H), was dried over MgSO4. The solvent was removed in vacuo to
3.69–3.42 (m, 4H), 3.17 (br s, 4 H), 2.39–1.97 (br m, 4H), 1.43 give an opaque oil. Residual solvent was azeotroped with Et2O
(s, 18H), 1.40 (br, 4H), 1.24 (br, 4H), 1.02 (s, 18H). The com- to give the final organocatalyst 3 as pale brown solid (0.248 g,
pound was confirmed by correlation to published spectra.7
0.29 mmol, 54%). Rf = 20/33 (1 : 9 MeOH–EtOAc); M.p. =
1
1-6-Di(trans-4-tert-butyldiphenylsiloxy-L-prolinamide) hexane 88.9–90 °C; H NMR (400 MHz, CDCl3) δ (ppm) = 7.6 (m, 8H),
2. N-Boc protected diprolinamide 9 (0.318 g, 0.312 mmol) was 7.38 (m, 12H), 4.36 (br, 2H), 4.08 (t, J = 8 Hz, 2H), 3.15 (q, J = 4
solvated in DCM (18 mL) and stirred. To the stirring solution Hz, 4H), 2.95–2.91 (dt, J = 12, 1.6 Hz, 2H), 2.62 (dd, J = 12, 3.2
was added TFA (2 mL) to bring the solution to a 10 vol% con- Hz, 2H), 2.29 (m, 2H), 1.74 (ddd, J = 13.2, 8.4, 4.4 Hz, 2H), 1.42
centration of acid/DCM. The solution was stirred for 6 h under (m, 8H), 1.23 (m, 4H), 1.04 (m, 18H); 13C NMR (100 MHz,
an inert atmosphere at room temperature. The final mixture CDCl3) δ (ppm) 174.37, 135.74, 135.69, 134.03, 133.73, 129.90,
was basified with saturated NaHCO3 (50 mL) and extracted 129.86, 127.84, 127.82, 77.49, 77.17, 76.86, 74.81, 59.93, 55.62,
into DCM (3 × 30 mL). The combined organic phase was then 40.03, 38.86, 29.61, 29.15, 27.00, 26.82, 19.17; [α]2D2.5 = −16.0°
washed with additional NaHCO3 (3 × 30 mL) and the organic (c = 0.001, CHCl3); IR νmax = 2929 (s), 1657 (s), 702 (s); HRMS
+
phase was dried over MgSO4. The solvent was removed in vacuo calculated for [C50H71N2O4Si2 ] M = 847.5008, found 847.5016.
to give an opaque oil. Residual solvent was azeotroped with
1,10-Di(trans-N-Boc-4-tert-butyldiphenylsiloxy-L-prolinamide)
Et2O to give the final organocatalyst 1 as an amorphous pale decane 11. trans-N-Boc-4-tert-butyldiphenylsiloxy-L-proline
7
brown solid (0.252 g, 0.31 mmol, 99%). 7.608 (br m, 8H), 7.38 (0.296 g, 0.63 mmol) was dissolved in DCM (15 mL) and
(br m, 12H), 4.35 (br, 2H), 3.99 (t, J = 8.4 Hz, 1H), 3.14 (sept, cooled to 0 °C. HOBt (0.016 g, 0.012 mmol) was added to the
4H), 2.89 (d, J = 12.1 Hz, 2H), 2.56 (dd, J = 4.45, 7.7 Hz, 2H), solution and the mixture was stirred for 5 min. EDCI (0.127 g,
2.24 (m, 2H), 1.7 (m, 2H), 1.41 (m, 4H), 1.27 (m, 4H), 1.03 (br 0.66 mmol) was added to the mixture followed by 3 min
s, 18H). Product was confirmed by 1H NMR spectroscopy.7
additional stirring followed by the introduction of 1,10-diamino-
1,8-Di(trans-N-Boc-4-tert-butyldiphenylsiloxy-L-prolinamide) decane (0.051 g, 0.30 mmol). The mixture was allowed to
octane 10. trans-N-Boc-4-tert-butyldiphenylsiloxy-L-proline reach room temperature and stirred for 16 h. The final reaction
7
(0.565 g, 1.20 mmol) was dissolved in DCM (15 mL) and mixture was diluted with additional DCM (30 mL) and washed
cooled to 0 °C. HOBt (0.030 g, 0.022 mmol) was added to the with 2 M HCl (2 × 30 mL), saturated NaHCO3 (2 × 30 mL) and
solution and the mixture was stirred for 5 min. EDCI (0.241 g, brine (2 × 30 mL). The resulting organic phase was dried over
1.25 mmol) was added to the mixture followed by 3 min MgSO4 and the solvent removed in vacuo to give the crude Boc
additional stirring followed by the introduction of 1,8-diamino- protected diprolinamide as a colourless oil. The crude mixture
octane (0.082 g, 0.57 mmol). The mixture was allowed to was purified via flash chromatography (1/4 EtOAc : Pet spirits)
reach room temperature and stirred for 16 h. The final reaction to give the pure dimer 11 as a viscous colourless oil (0.246 g,
1
mixture was diluted with additional DCM (30 mL) and washed 0.23 mmol, 36%). Rf = 18/31 (1/3 EtOAc : Pet. Spirits); H NMR
with 2 M HCl (2 × 30 mL), saturated NaHCO3 (2 × 30 mL) and (400 MHz, CDCl3) δ (ppm) 7.59 (m, 8H), 7.37 (m, 12H), 4.39 (s,
brine (2 × 30 mL). The resulting organic phase was dried over 4H), 3.64–3.44 (m, 4H), 3.17 (br, 4H), 2.60 (dd, J = 12, 4 Hz,
MgSO4 and the solvent removed in vacuo to give the crude boc 2H), 2.28 (m, 2H), 1.73 (m, 2H), 1.43 (m, 4H), 1.28–1.90 (m,
protected diprolinamide as a colourless oil. The crude mixture 4H), 1.44 (br, 18H), 1.4 (br, 4H), 1.2 (br, 12H), 1.02 (s, 18H);
was purified via flash chromatography (1/9 EtOAc : Pet spirits) 13C NMR (100 MHz, CDCl3) δ (ppm) = 173.66, 153.91, 135.69,
to give the pure dimer 10 as a viscous colourless oil (0.507 g, 133.62, 129.99, 127.87, 70.85, 58.28, 57.78, 54.90, 54.56, 52.21,
0.544 mmol, 45%). Rf = 11/31 (1/3 EtOAc : Pet. Spirits); 1H NMR 52.01, 39.66, 38.88, 28.48, 28.35, 26.90, 19.14; [α]D23.6 = −29.4°
(270 MHz, CDCl3) δ (ppm) = 7.69–7.36 (m, 20H), 4.52–4.36 (c = 0.001, CHCl3); IR νmax = 2929 (s), 1700 (s), 1162 (s), 702 (s);
(m, 4H), 3.67–3.65 (m, 4H), 3.52–3.37 (m, 4H), 2.29–1.79 HRMS calculated for [C62H91N4O8Si2] M+ = 1075.6370, found
(m, 4H), 1.57 (s, 4H), 1.43 (s, 18H), 1.24 (s, 8H), 1.03 (s, 18H); 1075.6345.
13C NMR (100 MHz, CDCl3) δ (ppm) = 173.7, 153.9, 135.7,
1,10-Di(trans-4-tert-butyldiphenylsiloxy-L-prolinamide) decane
133.6, 123.0, 127.7, 71.6, 70.8, 58.3, 57.8, 54.9, 54.6, 52.2, 4. N-Boc protected diprolinamide 11 (253 mg) was solvated in
52.0, 39.7, 38.9, 28.5, 28.4, 26.9, 19.4. [α]2D1.2 = −89.2° DCM (18 mL) and stirred. To the stirring solution TFA (2 mL)
(c = 0.001, CHCl3); IR νmax = 2928 (s), 1664 (s), 1162 (s), 702 (s); was added to bring the solution to a 10 vol% concentration of
+
HRMS calculated for [C60H87N4O8Si2 ] M = 1047.6057, found acid/DCM. The solution was stirred for 6 h under an inert
1047.6075.
atmosphere at room temperature. The final mixture was
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1
basified with saturated NaHCO3 (50 mL) and extracted into MeOH : EtOAc); H NMR (270 MHz, CDCl3) δ (ppm) = 7.59 (br
DCM (3 × 30 mL). The combined organic phase was then m, 8H), 7.38 (m, 12H), 4.36 (br, 1H), 4.09 (t, J = 8.4 Hz, 1H),
washed with additional NaHCO3 (3 × 30 mL) and the organic 3.14 (m, 4H), 2.94 (d, J = 11.9 Hz, 2H), 2.65 (dd, J = 11.9, 3.32
phase was dried over MgSO4. The solvent was removed in vacuo Hz, 2H), 2.27 (m, 2H), 1.76 (m, 2H), 1.41 (br, 4H), 1.21 (br,
to give an opaque oil. Residual solvent was azeotroped with 16H), 1.03 (br, 18H); 13C NMR (100 MHz, CDCl3) δ (ppm) =
Et2O to give the final organocatalyst 4 as pale brown oil 173.9, 135.7, 133.9, 133.6, 129.1, 127.8, 74.6, 65.9, 59.8, 55.5,
1
(0.136 g, 0.15 mmol, 66%). Rf = 21/33 (1 : 9 MeOH–EtOAc); H 39.7, 39.03, 29.78, 29.62, 29.52, 29.24, 26.7, 19.1, 15.4;
NMR (400 MHz, CDCl3) δ (ppm) = 7.62 (m, 8H), 2.38 (m, 12H), [α]2D4.3 = −12.8° (0.00113, CHCl3); IR νmax = 2927 (s), 1658 (s),
+
4.36 (s, 2H), 4.03 (t, J = 8.4 Hz, 2H), 3.15 (m, 4H), 2.92 (d, J = 1105 (s), 700 (s); HRMS calculated for [C54H79N4O4Si2
]
12 Hz, 2H), 2.60 (dd, J = 12, 3.2 Hz, 2H), 2.32–2.26 (m, 2H), M = 903.5634, found 903.56196.
1.73 (ddd, J = 12.8, 8, 4.4 Hz, 2H), 4.13 (br m, 4H), 1.22 (br s,
Di-tert-butyl 5,5′-(5,8-dioxa-2,11-diazadodecane-1,12-dioyl)-
12H), 1.04 (s, 18H); 13C NMR (125 MHz, CDCl3) δ (ppm) = bis(3-((tert-butyldiphenylsilyl)oxy)pyrrolidine-1-carboxylate).
174.3, 135.7, 134.0, 133.6, 129.8, 121.8, 59.9, 55.5, 47.9, 40.0, trans-4-tert-Butyldiphenylsiloxy-N-Boc-L-proline (7) (0.250 g,
38.8, 29.6, 29.4, 29.2, 26.9, 26.85, 19.0; [α]2D4.1 = −49.4° (c = 0.533 mmol) was dissolved in DCM (15 mL) and cooled to
0.001, CHCl3); IR νmax = 2928 (s), 1662 (s), 702 (s); HRMS calcu- 0 °C. HOBt (0.014 g, 0.101 mmol) was added to the solution
lated for [C52H75N4O4Si2+] M = 875.5321, found 875.5337.
and the mixture was stirred for 5 min. EDCI (0.107 g,
1,12-Di(trans-N-Boc-4-tert-butyldiphenylsiloxy-L-prolinamide) 0.558 mmol) was added to the mixture followed by 3 min
dodecane 12. trans-N-Boc-4-tert-butyldiphenylsiloxy-L-proline 7 additional stirring followed by the introduction of 1,8-
(0.3 g, 0.64 mmol) was dissolved in DCM (25 mL) and cooled diamino-3,6-dioxaoctane (0.037 mL, 0.253 mmol). The mixture
to 0 °C. HOBt (0.021 g, 0.015 mmol) was added to the solution was allowed to reach room temperature and stirred for 16 h.
and the mixture was stirred for 5 min. EDCI (0.129 g, The final reaction mixture was diluted with additional DCM
0.67 mmol) was added to the mixture followed by 3 min (30 mL) and washed with 2 M HCl (2 × 30 mL), saturated
additional stirring followed by the introduction of 1,12-diami- NaHCO3 (2 × 30 mL) and brine (2 × 30 mL). The resulting
nododecane (0.061 g, 0.305 mmol) was introduced. The organic phase was dried over MgSO4 and the solvent removed
mixture was allowed to reach room temperature and stirred for in vacuo to give the crude boc protected diprolinamide as a col-
16 h. The final reaction mixture was diluted with additional ourless oil. The crude mixture was purified via flash chromato-
DCM (30 mL) and washed with 10% citric acid (3 × 30 mL), graphy (99/1 EtOAc : EtOH) to give the pure dimer as a viscous
saturated NaHCO3 (3 × 30 mL) and brine (1 × 30 mL). The colourless oil (0.165 g, 0.157 mmol, 29%). Rf = 20/37 (99/1
1
resulting organic phase was dried over MgSO4 and the solvent EtOAc : EtOH); H NMR (400 MHz, CDCl3) δ (ppm) = 7.62–7.36
was removed in vacuo to give crude boc protected diprolina- (m, 20H), 4.39 (m, 4H), 3.66 (m, 4H), 3.51 (m, 6H), 3.36 (m,
mide as colourless oil. The crude compound was purified via 6H), 2.29–1.90 (m, 4H), 1.47 (s, 18H), 1.08 (s, 18H); 13C NMR
flash chromatography (1/3 EtOAc : Pet spirits) to give the pure (100 MHz, CDCl3) δ (ppm) = 135.73, 135.66, 133.56, 129.95,
dimer 12 as a viscous colourless oil (0.14 g, 0.127 mmol, 42%). 127.86, 70.29, 55.23, 53.73, 28.42, 26.89, 19.15; [α]2D1.1 = −1.70°
1
Rf = 1/3 (1 : 1 EtOAc : Pet. Spirits); H NMR (400 MHz, CDCl3) δ (c = 0.002, CHCl3); IR νmax = 2930 (s), 1701 (s), 1162 (s), 703 (s);
+
(ppm) = 7.62 (m, 8H), 7.38 (m, 12H), 4.41–4.32 (br m, 4H), HRMS calculated for [C58H83N4O10Si2 ] M = 1051.5642, found
3.71 (br, 2H), 3.44 (br, 2H), 3.16 (m, 4H), 2.31 (br, 2H), 1051.5623.
2.06–1.94 (br m, 2H), 1.42 (br, 18H), 1.25 (br, 20H), 1.04 (br,
N,N′-((Ethane-1,2-diylbis(oxy))bis(ethane-2,1-diyl))bis(4-((tert-
18H); 13C NMR (100 MHz, CDCl3) δ (ppm) = 171.4, 156.5, butyldiphenylsilyl)oxy) pyrrolidine-2-carboxamide) 16. N-Boc
135.7, 133.6, 129.9, 127.9, 71.0, 60.6, 58.9, 55.2, 40.2, 39.4, protected oxygenated diprolinamide (0.166 g, 0.158 mmol) was
36.9, 32.0, 29.8, 29.6, 29.34, 28.4, 26.9, 19.2; [α]2D4.6 = −46.7° solvated in DCM (18 mL) and stirred. To the stirring solution
(0.00033, CHCl3); IR νmax = 2927 (s), 11 656 (s), 700 (s); HRMS TFA (2 mL) was added to bring the solution to a 10 vol% con-
+
calculated for [C64H95N4O8Si2 ]
1103.6698.
M
=
1103.6683, found centration of acid/DCM. The solution was stirred for 7 h under
an inert atmosphere at room temperature. The final mixture
1,12-Di(trans-4-tert-butyldiphenylsiloxy-L-prolinamide) was basified with saturated NaHCO3 (50 mL) and extracted
dodecane 5. N-Boc protected diprolinamide 12 (0.16 g, into DCM (3 × 30 mL). The combined organic phase was then
0.0145 mmol) was dissolved in (18 mL) and stirred. To the stir- washed with additional NaHCO3 (3 × 30 mL) and the organic
ring solution was added TFA (2 mL) to bring the solution to a phase was dried over MgSO4. The solvent was removed in vacuo
10 vol% concentration of acid/DCM. The solution was stirred to give a yellow oil. Residual solvent was azeotroped with Et2O
for 6 h under an inert atmosphere at room temperature. The to give the final organocatalyst as an orange solid (0.097 g,
final mixture was basified with saturated NaHCO3 (50 mL) and 0.114 mmol, 72%). Rf = 21/32 (1 : 9 MeOH–EtOAc); M.p. =
1
extracted into DCM (3 × 30 mL). The combined organic phase 61–62.5 °C; H NMR (400 MHz, CDCl3) δ (ppm) = 7.6 (m, 8H),
was then washed with additional NaHCO3 (3 × 30 mL) and the 7.37 (m, 12H), 4.38 (br s, 2H), 4.14 (t, J = 8 Hz, 2H), 3.47 (m,
organic phase was dried over MgSO4. The solvent was removed 12H), 2.97 (d, J = 12 Hz), 2.71 (dd, J = 12, 4 Hz), 2.26 (m, 2H),
in vacuo to give a pale yellow oil. Residual solvent was azeo- 1.79 (m, 2H), 1.02 (m, 18H); 13C NMR (100 MHz, CDCl3) δ
troped with Et2O to give the final organocatalyst 5 as a viscous (ppm) = 135.75, 135.73, 135.72, 135.69, 133.84, 133.61, 129.93,
pale yellow oil (0.13 g, 0.144 mmol, 99%). Rf = 20/33 (1 : 9 129.91, 127.88, 127.86, 127.84, 127.83, 74.38, 70.27, 69.94,
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65.94, 59.83, 55.34, 39.80, 38.88, 26.96, 19.15, 19.14, 19.13,
19.08, 15.36; [α]D22.5 = −0.17° (c = 0.01, CHCl3); IR νmax = 2929
(s), 1662 (s), 1111 (s), 703 (s); HRMS calculated for
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and S. Chow, Eur. J. Org. Chem., 2006, 4578–4584;
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+
[C48H67N4O4Si2 ] M = 851.4594, found 851.4569.
Representative syntheses for aldol product racemates
(benzaldehyde)
3 (a) S. Aratake, T. Itoh, T. Okano, N. Nagae, T. Sumiya,
M. Shoji and Y. Hayashi, Chem.–Eur. J., 2007, 13, 10246–
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Procedure A: A stirred solution of water (15 mL) was charged
with 10 M NaOH (1 mL). Ketone (0.28 mL, 2.7 mol, 5 equiv.)
was added and the solution was stirred for 1 min. To the
mixture was added aryl aldehyde (0.6 mL, 0.54 mmol, 1 equiv.)
and the solution was stirred for 3 h. The mixture was extracted
into CHCl3 (3 × 20 mL) and the combined organic phase was
dried with MgSO4. The racemic mixture was isolated via flash
chromatography (1/3 EtOAc/Petroleum spirits).
Procedure B: Pyrrolidine (0.44 mL, 0.53 mmol, 1 equiv.) was
added to a stirred solution of CHCl3. To the stirred mixture
was added ketone (0.223 mL, 2.65 mmol, 5 equiv.) and alde-
hyde (80 mg, 0.53 mmol, 1 equiv.). Benzoic acid (20 mg,
0.16 mmol, 0.3 equiv.) was added to the mixture and the reac-
tion was stirred at room temperature for 16 h. The reaction
mixture was taken up in additional CHCl3 and washed with
2 M HCl (2 × 20 mL). The organic phase was dried with
MgSO4. The racemic mixture was analysed by chiral HPLC
without purification.
Acknowledgements
We would like to thank the Deakin University Central Research
Grants Scheme. The Institute for Frontier Materials and the
Strategic Research Centre for Chemistry and biotechnology
for Funding. We would also like to thank Simren Khosa for
manuscript preparation and the Australian Government for an
Australian Postgraduate Award for JD.
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