Direct asymmetric aldol reactions in water catalysed by a highly active C2-symmetrical bisprolinamide organocatalyst

Article abstract of DOI:10.1002/adsc.201100667

A novel C₂-symmetrical bisprolinamide organocatalyst was synthesised and used to facilitate asymmetric direct aldol reactions in a water emulsion. Reactions were performed at room temperature with very low catalyst loadings (1-2.5 mol%) without the required use of additives, co-catalysts or extended reaction times (24 h). This catalyst system was then used with a variety of aldehyde substrates showing good reaction generality for benzaldehydes with cyclohexanone (dr range 77/23 to <99/1, anti/syn; ee range 33% to <99%) and moderate scope with cyclopentanone (dr range 45/55 to 76/24, anti/syn; ee range 14% to 68%). Ultra-low catalysts loadings (0.1 and 0.05 mol%) were also investigated demonstrating catalyst turnover numbers in the order of 1000.

Full text of DOI:10.1002/adsc.201100667

FULL PAPERS
DOI: 10.1002/adsc.201100667
Direct Asymmetric Aldol Reactions in Water Catalysed by a
Highly Active C2-Symmetrical Bisprolinamide Organocatalyst
Joshua P. Delaneya and Luke C. Hendersona,*
a
School of Life and Environmental Sciences, Deakin University, Geelong, Victoria, Australia 3216
Fax : (+61)-352-271-040; e-mail: luke.henderson@deakin.edu.au
Received: August 23, 2011; Revised: October 11, 2011; Published online: January 12, 2012
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.201100667.
Abstract: A novel C2-symmetrical bisprolinamide or- cyclohexanone (dr range 77/23 to >99/1, anti/syn; ee
ganocatalyst was synthesised and used to facilitate range 33% to >99%) and moderate scope with cy-
asymmetric direct aldol reactions in a water emul- clopentanone (dr range 45/55 to 76/24, anti/syn; ee
sion. Reactions were performed at room temperature range 14% to 68%). Ultra-low catalysts loadings (0.1
with very low catalyst loadings (1–2.5 mol%) without and 0.05 mol%) were also investigated demonstrat-
the required use of additives, co-catalysts or extend- ing catalyst turnover numbers in the order of 1000.
ed reaction times (24 h). This catalyst system was
then used with a variety of aldehyde substrates show- Keywords: aldol reaction; organocatalysts; prolin-
ing good reaction generality for benzaldehydes with
ACHTUNGERTNaNUNG mides; prolines; water
Introduction
been put under the spotlight as concerns over both
the cost and environmental implication of solvent
Since the seminal work by List and Barbas published waste is becoming increasingly scrutinised by the gen-
in 2000,[1] proline-based organocatalysis has seen an eral community. Water serves as an ideal solvent as it
incredible increase in research focus.[2] Proline-de- is cheap, readily available, non-toxic and has been
rived organocatalysts (related pyrrolidines/pyrrolidi- shown to enhance both reaction rate and stereochemi-
nones) have been used extensively to carry out a cal outcome of organocatalysed reactions. The use of
myriad of asymmetric reactions including the direct low organocatalyst loadings (1–5 mol%) within aque-
aldol, Baylis–Hillman and Mannich reactions, as well ous systems is still very limited with many examples
as a range of other cycloaddition reactions.[3]
employing organic additives or cocatalysts to increase
Though recognised as a legitimate and effective reaction rate and/or enhance optical purity of reaction
means to install stereochemistry within complex or- products.[3a,o,4d,i,o,5]
ganic scaffolds, organocatalysts are not without limita-
While there has been significant investigation into
tions, namely the typical requirement for relatively the direct modification of proline to bolster catalytic
high catalyst loadings (10–30 mol%). This shortcom- activity, there has been surprisingly little research into
ing has been mitigated to a small extent by the exten- the incorporation of multiple proline units into larger
sive modification of the proline scaffold to afford organic scaffolds. Some excellent examples include
novel organocatalysts which demonstrate very high the work of Najera et al.[6] and Zhou et al.[7] both
levels of enantioselective induction and acceptable using C2-symmetrical bisprolinamides in Binam and
catalytic loading (5–10 mol%) among a diverse range trans-1,2-cyclohexandiamine scaffolds, respectively. In
of reaction partners.[3]
these instances the incorporation of two proline units
The major advantages of organocatalysts are their into one scaffold gave both improved yield and opti-
robust nature (for the most part, they are not air- or cal purity of reaction products compared to simply
moisture-sensitive) and recently, several groups have doubling the catalyst loading of the monoprolinamide
reported organocatalysed reactions in or on water, alternative. In both of these cases the prolinamide
further enhancing the ꢀgreenꢁ alignment of organoca- groups are held in relatively close proximity to each
talysts.[4] The use of aqueous environments as a other due to their rigid scaffold.
medium to carry out organic transformations has
Adv. Synth. Catal. 2012, 354, 197 – 204
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197

Joshua P. Delaney and Luke C. Henderson
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Scheme 1. Synthesis of organocatalyst 5.
Our interest in the development of a novel organo- clean and quantitative deprotection of both tert-bu-
catalyst was to tether multiple 4-substituted proline toxycarbamate groups giving our desired organocata-
units to a flexible hydrocarbon linking group. Doing lyst 5.
so provides the opportunity for each catalytic site to
Our initial investigations into catalyst activity ap-
either: (i) operate independently as individual catalyt- plied to the direct aldol reaction of cyclohexanone 6
ic units or (ii) allow potential interaction units (be and 4-nitrobenzaldehyde 7, commonly employed for
that interaction synergistic or competitive) between catalyst optimisation, organocatalyst evaluation and
the prolinamides. We chose the aldol reaction as a optimisation.[3a] We chose water as our reaction media
model reaction as it has not only become a bench- as Hayashi et al.[3l] have shown great success using the
mark by which organocatalysts can be compared, but N-deprotected version of Boc-proline 3 as an organo-
ꢀ
it is also one of the most fundamental C C bond catalyst in aqueous solution.
forming reactions in organic chemistry.[8]
Initial testing using l-proline under the desired re-
action conditions returned only starting materials
(entry 1, Table 1), as has been observed in other re-
ported instances.[3a] Not surprisingly, the exclusion of
any catalyst from the reaction mixture also returned
Results and Discussion
The protection of the carboxyl group of Boc-proline 1
was carried out using benzyl bromide to give 2 under
basic conditions in good yield (67%, Scheme 1). With
the amine and carboxyl groups orthogonally protected
the 4-hydroxy group was converted to the tert-butyldi-
phenylsilyl derivative. The carboxyl protection step
was required as previous attempts to introduce the
silyl group to the 4-hydroxy moiety in the presence of
the free acid proved problematic. Subsequent hydro-
genolysis of the benzyl ester gave the 4-substituted
proline monomer 3 in excellent yield over two steps
(72%).
Table 1. Optimization of organocatalyst conditions.
Entry Loading
[mol%]
Time
[h]
Yield
[%][b]
dr anti/
syn[b]
ee
[%][c]
1
2
3
4
5
6
7
20[a]
0
5
24
24
24
24
24
24
6
0
0
–
–
–
–
Bisprolinamide 4 was then obtained by EDCI-
mediated coupling of 3 with 0.5 equivalents of 1,6-di-
ACHTUNGTRENNUNG
99
91
49
11
47
77/23
96/4
95/5
>99/1
92/8
97
>99
98
98
87
1
0.5
0.1
20
ACHTUNGTRENNUNGoxycarbamate under standard literature conditions
(20% TFA/CH2Cl2, 16 h)[9] resulted in complete deg-
radation of 4 to a complex mixture of unidentified
products. A similar result was observed when the re-
action time was reduced to 2 h. Interestingly, a more
dilute CH2Cl2 solution of TFA (10% v/v) resulted in
[a]
[b]
[c]
l-Proline used as the organocatalyst.
Determined via H NMR.
Determined via chiral HPLC using a Chiralpak AD-H
1
column
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Direct Asymmetric Aldol Reactions in Water Catalysed by a Highly Active C2-Symmetrical Bisprolinamide
starting materials (entry 2, Table 1). Employing bis- low conversion was observed, the reaction was repeat-
prolinamide 5 under identical reaction conditions at ed with a slightly higher catalyst loading (2.5 mol%)
5 mol% loading gave an excellent yield (99%) of the to facilitate a greater yield while still maintaining a
desired product 8 in a good diastereochemical ratio, very low catalyst loading for an aqueous system.
77/23 (anti/syn), and very high optical purity (97% ee)
(entry 3, Table 1).
Employing a higher catalyst loading with benzalde-
hyde gave the desired product in much higher yield
We endeavoured to determine the minimal catalyst (75%) with a minor loss of diastereomeric purity (82/
loading required to achieve very high (>90%) reac- 18 anti/syn) but a substantial depression in enantio-
tion progression without sacrificing the optical purity meric excess (36% ee) was observed (entry 2,
of the aldol products. Lowering the catalyst loading to Table 2). When employing 4-bromobenzaldehyde (en-
1, 0.5 and 0.1 mol% (entries 4–6, Table 1) showed tries 3 and 4, Table 2), a remarkable increase in yield
1 mol% catalyst loading (entry 4, Table 1) to be opti- was observed from 2% to 96% when the catalyst
mal, giving very high yield (91%) of the desired prod- loading was increased from 1 mol% to 2.5 mol% re-
ucts possessing exceptionally high optical purity (96/4 spectively. To complement this high yield, when the
dr anti/syn, >99% ee). Organocatalyst loadings of 0.5 latter catalytic loading was employed, the optical
and 0.1 mol% showed excellent potential and investi- purity of the obtained products was high [86/14 (anti/
gations into these ultra-low catalyst loadings will be syn) dr and 71% ee].
discussed in full later.
2-Nitrobenzaldehyde gave moderate yield (44%,
Employing ꢀtypicalꢁ organocatalytic reaction condi- entry 5, Table 2) but in excellent diastereomeric ratio
tions (20 mol%) showed moderate reaction conver- (99/1, anti/syn) and very high enantiomeric excess
sion (47%) within a shorter timeframe (6 h) but with (91%).
Also,
2,4-trifluoromethylbenzaldehdye
reduced stereoselectivity (92/8 dr and 87% ee). (entry 6, Table 2) gave excellent yield (96%) using
With optimal reaction conditions determined 1 mol% of 5 in addition to very high diastereomeric
(1 mol% 5, H2O, 24 h) we set out to investigate the purity (96/4 anti:syn) and enantiomeric excess (86%
generality of organocatalyst 5 with respect to benzal- ee) of the direct aldol product.
dehyde reaction partners. The aldol addition of cyclo-
Interestingly, 4-fluorobenzaldehyde gave the direct
hexanone to benzaldehyde (entry 1, Table 2) showed aldol products in excellent diastereomeric ratio (90/
moderate yield (45%) but gave products with excel- 10, anti/syn) and excellent enantiomeric purity (92%)
lent diastereomeric ratio but only moderate enantio- but in a low yield (21%) when employing 1 mol% of
purity (92/8 anti/syn, 66% ee). In those cases where organocatalyst 5. Increasing the amount of organoca-
talyst 5 to 2.5 mol% (entry 8, Table 2) afforded the
desired product in excellent yield (91%) and diaster-
eochemical purity (90/10, anti/syn) but with a signifi-
Table 2. Reaction scope of oganocatalyst 5.
cant loss of enantiomeric excess (72% ee).
The reason for the loss in enantiomeric excess is
unknown but, in general, the enantiomeric excess in
this system tends to decrease as the catalyst loading
of organocatalyst 5 increases (examples include,
entry 7, Table 1; entry 2, Table 2; entry 8, Table 2).
The final example utilising cyclohexanone as the
ketone reaction partner employed pentafluorobenzal-
dehyde (entry 9, Table 2). The direct aldol product at
1 mol% catalyst loading of 5 was isolated in quantita-
tive yield and diastereomeric purity (>99/1, anti/syn)
while maintaining a very high enantiomeric excess
(81% ee).
With a broad scope of arylaldehydes examined, our
attention turned to using cyclopentanone in a selec-
tion of aldol reactions. In general, organocatalyst 5
demostrated higher reaction progression with cyclo-
pentanone compared to cyclohexanone, but products
consistently showed a significant reduction in optical
purity. The aldol reaction of cyclopentanone and 4-ni-
trobenzaldehyde (entry 10, Table 2) catalyzed by
1 mol% of 5 gave the desired product in moderate
yield (61%) and diastereomeric ratio (76/24, anti/syn)
Entry n R
Yield [%][a] dr[a] anti/syn ee [%][b]
1
2
3
4
5
6
7
8
1
1
1
1
1
1
1
1
1
0
0
0
0
0
0
C6H5[c]
45
75
2
96
44
92/8
66
36
–
C6H5
82/18
82/18
86/14
99/1
4-BrC6H4[c]
4-BrC6H4
2-NO2C6H4
71
91
86
92
72
81
14
50
42
52
64
68
2,4-CF3C6H3 96
96/4
4-FC6H4[c]
21
91
91/9
4-FC6H4
90/10
>99/1
76/24
36/64
36/64
41/59
55/45
31/69
9
2,3,4,5,6-F5C6 >99
4-NO2C6H4
C6H5
4-FC6H4
4-BrC6H4
2,4-CF3C6H3 >99
10
11
12
13
14
15
61
90
85
>99
2-NO2C6H3
51
[a]
[b]
1
Determined via H NMR.
Determined via chiral HPLC using a Chiralpak AD-H
column.
[c]
Reaction carried out with 2.5 mol% of catalyst 5.
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Joshua P. Delaney and Luke C. Henderson
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but with almost no enantiomeric enrichment (14% obtained in acceptable yield by employing
a
ee). 2.5 mol% of 5, we thought using a 1 mol% catalyst
When employing benzaldehyde, 4-fluorobenzalde- loading in this instance provided the best basis to
hyde, 4-bromobenzaldehyde (entries 11–13, Table 2) a compare results.
reversal in the major diastereoismer was observed
Interestingly, the addition of 0.1 equivalent TFA
whereby the syn isomer became the major product. In (with respect to the aldehyde) had highly variable ef-
all three cases yields were good to excellent but the fects on the reaction outcome and was seemingly sub-
aldol products obtained posessed very poor optical strate dependent. The addition of TFA to the aldol
purity. Pairing cyclopenanone with 2,4-trifluorome- partnering of 4-bromobenzaldehyde and cyclohexa-
thylbenzaldehyde (entry 14, Table 2) gave the desired
product in quantitative yield, but the product pos-
sessed minimal diastereomeric ratio (55/45, anti/syn)
and moderate enantiomeric purity (64% ee). The
Table 3. Investigation of trifluoroacetic acid as a catalytic
additive.
lowest yield (51%) was observed when 2-nitrobenzal-
dehyde was combined with cyclopentanone (entry 15,
Table 2) again showing a preference for the syn
isomer and displaying only moderate optical purity
(31/69, anti/syn, 68% ee).
It is important to note that organocatalysed direct
aldol reactions often give products which (on a sub-
strate to substrate basis) are highly varied in yield
and optical purity. Given that the catalytic system
used in this study employs low catalyst loadings (both
1 mol% and 2.5 mol%), a reasonable timeframe
(24 h) and do not require low temperatures and/or
the use of additives these outcomes, with respect to
cyclohexanone, were extremely pleasing.
Entry n R
Yield [%][a] dr[a] anti/syn ee [%][b]
1
2
3
4
1
1
0
0
4-BrC6H4
4-FC6H4
4-NO2C6H4 74 (61)
2-NO2C6H4 7 (51)
35 (2)
21 (21)
96/4 (82/18) 98 (–)
94/6 (91/9) 80 (92)
84/16 (76/24) >99 (14)
59/41 (31/69) – (68)
[a]
[b]
1
Determined via H NMR.
Determined via chiral HPLC using a Chiralpak AD-H
column. Numbers in parentheses indicate results ob-
tained without the use of TFA.
The reason for the very high catalytic activity of or-
ganocatalyst 5 may be contributed to by the use of
water as the reaction medium. The subject of “in- none induced a significant increase in catalyst activity
water” versus “on-water” has been the subject of de- (entry 1, Table 3), promoting a yield 16 times greater
tailed analysis in the literature.[11] In 2007 Jung and than when treated with organocatalyst 5 alone. In ad-
Marcus[11a] proposed that at the oil-and-water inter- dition the optical purity of the products obtained was
face there exist free OH groups which protrude into very high. Alternatively, 4-fluorobenzaldehyde
the organic phase (in this case droplets of the donor (entry 2, Table 3) displayed minimal changes in both
ketone). It is thought that these free OH groups from conversion and diasteromeric ratio, but a slight de-
the water phase elicit very strong hydrogen bonding crease in enantiomeric excess. Additional differences
character and, by stabilising polar transition states, were observed when TFA was used to promote the
play a very important role in catalysis. As a result of aldol coupling of 4-nitrobenzaldehyde with cyclopen-
this action the decrease in transition state energy re- tanone (entry 3, Table 3). The catalyst alone gave an
sults in a substantial increase in rate of reaction. acceptable yield of 61% with an almost racemic prod-
More considerations in regard to stereochemical in- uct. In the presence of TFA, a modest improvement
duction by organocatalyst 5 caused by the oil-in-water in conversion (74%) was noted. This mild increase in
emulsive nature of these reactions will be discussed at activity coincided with a small increase in diastereo-
the end of this manuscript.
meric ratio (84/16, anti/syn) and a dramatic improve-
In the interest of thoroughness our attention turned ment of enantiomeric excess (>99% ee). Finally, em-
to examining selected direct aldol reactions in the ploying 2-nitrobenzaldehyde (entry 4, Table 3) in the
presence of a catalytic additive, as is commonly used presence of TFA depressed the yield to 7% while re-
in aqueous systems. Organic acids are routinely em- sulting in a preference for the anti diastereomer in a
ployed as additives for organocatalysed direct aldol low dr (59/41). Due to the low yield of this reaction a
reactions, especially in water, and as such we consid- reliable enantiomeric excess was unable to be deter-
ered trifluoroacetic acid as an ideal additive to inves- mined. Given the inconsistent nature of these results
tigate in our system.
we concluded that the use of acidic additives was of
To probe the effect of an organic acid additive we no real benefit to this catalytic system with respect to
selected entries from Table 2 which displayed poor these aldehyde/ketone combinations in Table 3.
conversion to the desired products when 1 mol% of 5
Finally, the excellent result with respect to yield
was used. Although these reaction products could be and stereochemical outcome obtained when employ-
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Direct Asymmetric Aldol Reactions in Water Catalysed by a Highly Active C2-Symmetrical Bisprolinamide
Although we have not conclusively elucidated the
reason for this effect, two possible explanations are
postulated, firstly, as the concentration of the alde-
hyde decreases with reaction progression, the effec-
tive catalyst loading (with respect to pentafluoroben-
zaldehyde) steadily increases. This observation is con-
sistent with our previous results whereby 2.5 mol% of
organocatalyst generally gave lower stereochemical
enrichment than 1 mol% in the same system.
Scheme 2. Ultra-low catalyst loading studies.
It is possible that an intramolecular cooperative
effect is occurring between each catalytic unit of orga-
nocatalyst 5 which is maximised at lower concentra-
ing pentafluorobenzaldehyde (entry 9, Table 2) and tion, or in this case lower catalyst loading. The cur-
cyclohexanone piqued our interest into how low the rent data suggest that when larger catalyst loadings of
catalyst loading could be reduced to while still afford- 5 are employed, the instance of intermolecular coop-
ing a usable amount of aldol product 11 in a viable eration increases thereby decreasing stereochemical
timeframe. Therefore, we reinvestigated this aldol re- purity of aldol products observed. This effect may
action (Scheme 2) using ultra-low catalyst loadings of become more pronounced considering that, in this
0.1 and 0.05 mol% in aqueous environment. Using or- study, the organocatalytic reactions were conducted
ganocatalyst 5 at an extremely low catalyst loading of as emulsions within an aqueous environment.
0.1 mol% gave 11 in quantitative yield and very high
The emulsion droplets of cyclohexanone are “nano-
optical purity in 72 h (>99/1, anti/syn, 90% ee), thus reactors“[11b] for the aldol reaction and as such the ef-
giving a catalyst turnover number of 1000. This fective concentration of the catalyst becomes much
number is exceptionally high for an organocatalysed more pronounced. As such it could be imagined that
reaction, the closest turnover numbers reported are (at low concentrations) each proline group acts inde-
given by Gruttadauria et al.[4b] and Lombardo et al.[3q] pendently and each of them generates a transition
Encouraged by the above result we reasoned that state stabilised by the hydrogen bonding effects at the
120 h would be
a
sufficient timeframe for
a
oil-water interface. Conversely, at higher concentra-
0.05 mol% catalyst loading of 5 to facilitate the aldol tions the ketone droplets contain a much higher con-
reaction to an acceptable degree. Therefore a series centration of the catalyst causing a much more
of five identical aldol reactions was initiated simulta- “crowded” reaction environment. As such the proline
neously, each employing 0.05 mol% of catalyst 5. groups would be in much closer proximity and thus
Each day a single reaction was quenched and the influence the transition state and stereochemical out-
crude product isolated (Table 4). The reaction prog- come.
ress and diastereomeric ratio were then determined
Alternatively, the high acidity of the hydroxy group
1
via analysis of key peaks in the H NMR spectrum.[12] of 11 may be influencing reaction outcome in a simi-
The reaction progression plateaus at approximately lar manner to the addition of TFA as previously in-
45% after 72 h with the remaining 48 h only giving an vestigated in this manuscript (Table 3). This acidic
additional 11% of aldol product 11. This plateau effect would become more pronounced as the reac-
effect is not surprising when considering that the ef- tion proceeds as the effective concentration of the
fective concentration of the aldehyde in solution de- proton source increases.
creases as the reaction proceeds. To the best of the
Given that the unequivocal elucidation of organo-
authorꢁs knowledge this example uses the lowest orga- catalytic cycles for simple proline-based systems is
nocatalyst loading reported in the literature. Interest- still under dispute it is beyond the scope of this article
ingly, a consistent decrease in diastereoselectivity is to provide a thorough study of the catalytic mecha-
observed as the reaction proceeds.
nism. Nevertheless these data are being used to pro-
vide an insight into reaction outcomes of several
structural variations on 5 in similar direct aldol reac-
tions with the goal to shed light on the catalytic mech-
anism.
Table 4. Aldol reaction progression with 0.05 mol% 5.
Entry Time [h] Conversion [%][a] dr [%][a] anti/syn TON
1
2
3
4
5
24
48
72
96
120
20
33
45
53
56
90/10
87/13
82/18
78/22
72/28
400
660
900
1040
1120
Conclusions
In conclusion, we have presented the synthesis of a
simple bis-prolinamide-derived organocatalyst 5 and
assessed its suitability to catalyse the direct aldol reac-
[a]
1
Determined via H NMR.
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Joshua P. Delaney and Luke C. Henderson
FULL PAPERS
phase was dried over MgSO4 which was filtered. The solvent
was removed under vacuum to give the crude product as a
viscous, pale yellow oil. The crude product was purified by
column chromatography using gradient elution (2:1 petrole-
um spirits:EtOAc!100% EtOAc) to give the benzyl pro-
tected species as a pale yellow oil; yield: 2.17 g (67%); Rf
=0.21 (2 petroleum spitis:1 EtOAc). 1H NMR (270 MHz,
CDCl3): d=7.72 (br s, 5H, aryl), 5.04–5.17 (m, 2H, CH2Ph),
4.42–4.30 (m, 2H, aH), 3.68–3.49(m, 2H, CH-CH2-CH),
2.20–1.97 (m, 2H, N-CH2-CH), 1.39–1.27 (m, 9H, tert-
butyl); [a]2D0:7: ꢀ61.18 (c 0.118, CHCl3). The spectra were
consistent with data previously reported.[10]
tion in water with a range of benzaldehydes. These re-
action are conducted at room temperature, using a
minimal amount of catalyst (1–2.5 mol%) in water
and do not require the use of additive or cocatalyst.
We have also demonstrated an organocatalysed aldol
reaction using catalyst 5 at an ultra-low loading of
0.05 mol% to give an optically enriched product
within a relatively short timeframe.
Experimental Section
General
trans-4-tert-Butyldiphenylsiloxy-N-Boc-l-proline
Benzyl Ester
1
All H and 13C NMR spectra were recorded on a Jeol JNM-
EX 270 MHz or Jeol JNM-EX 400 MHz as indicated. Sam-
ples were dissolved in deuterated chloroform (CDCl3) with
the residual solvent peak used as an internal reference
(CDCl3: dH =7.26 ppm). Proton spectra are reported as fol-
lows: chemical shift d (ppm), [integral, multiplicity (s=sin-
glet, br s=broad singlet, d=doublet, dd=doublet of dou-
blets, t=triplet, q=quartet, m=multiplet), coupling con-
stant J (Hz), assignment].
Thin layer chromatography (TLC) was performed using
aluminium-backed Merck TLC silica gel 60 F254 plates, and
samples were visualised using 254 nm ultraviolet (UV) light,
and potassium permanganate/potassium carbonate oxidising
dip (1:1:100 KMnO4:K2CO3:H2O w/w).
Column chromatography was performed using silica gel
60 (70–230 mesh). All solvents used were AR grade. Spe-
cialist reagents were obtained from Sigma–Aldrich Chemical
Company and used without further purification. Petroleum
spirits refers to the fraction boiling between 40–608C.
Chiral HPLC was performed with a 1200 series Agilent.
Separation of stereoisomers was carried out with a Diacel
Chiralpak AD-H chiral column (0.46 cmꢃ25 cm). Retention
times were reported at ambient temp (248C) with an injec-
tion volume of 10 mL at a flow rate of 1 mLminꢀ1. A mobile
phase of 10% 2-propanol/90% hexane was used.
HR-MS was found via a 6210 MSD TOF mass spectrome-
ter under the conditions: gas temperature (3508C), vapouris-
er (288C), capillary voltage (3.0 kV), cone voltage (40 V),
nitrogen flow rate (7.0 Lminꢀ1), nebuliser (15 psi). Samples
were dissolved in MeOH.
Benzyl-protected proline 2 (0.6726 g, 2.1 mmol) was dis-
solved in DMF (15 mL). Imidazole (0.57 g, 8.38 mmol),
DMAP (0.102 g, 0.838 mmol) and tert-butyldiphenylsilyl
chloride (0.928 mL, 2.31 mmol) were added to the solution
and the mixture was stirred for 24 h. The reaction was
quenched with cold H2O (100 mL) and acidified with 2M
HCl (50 mL). The final product was extracted into EtOAc
(3ꢃ30 mL), the combined organic phase was washed with
2M HCL (3ꢃ30 mL) and saturated NaHCO3 (3ꢃ30 mL).
The washed organic phase was dried over MgSO4 and the
solvent was removed under vacuum to give the silylated spe-
cies as a thick resin which was used without further purifica-
tion. An analytically pure sample was obtained for charac-
teriation purposes via flash chromatography (1:5 EtOAc, pe-
troleum spirits) to give 3 as a colourless oil; yield: 0.673 g
1
(57%); Rf =0.52. H NMR (270 MHz, CDCl3): d=7.61 (m,
4H, aryl), 7.37 (m, 10H, aryl), 5.11 (m, 2H, Bn), 4.423 (m,
2H, N-CH-CH2-CH), 3.48 (m, 2H, N-CH2), 2.26 (m, 1H,
CH-CH2-CH), 1.88 (m, 1H, CH-CH2-CH), 1.42 [d, J=
(CH3)3]; 13C NMR
23 Hz, 9H, Si-CACTHUNTRGENN(UG CH3)3], 1.05 [s, 9H, Si-CACHTUNGTRENNGUN
(100 MHz, CDCl3): d=127.86, 154.59, 135.57, 133.89, 129.87,
128.55, 128.43, 127.76, 80.03, 71.41, 70.65, 66.64, 58.27, 57.83,
54.70, 54.37, 39.51, 38.67, 28.37, 28.18, 26.77, 19.02; [a]D20:7
:
ꢀ37.28 (c 0.123, CHCl3); IR: nmax =1747 (s), 1427 (s), 1175
(s), 1105 cmꢀ1 (s); HR-MS: m/z=582.26402, calcd. for
[C33H41NO5SiNa]+ [M+]: 582.26462.
trans-4-tert-Butyldiphenylsiloxy-N-Boc-l-proline-
Specific rotations [a]D were obtained using a JASCO
DIPP digital polarimeter. Compounds were dissolved in
CHCl3 where indicated. Rotation was measured at l=
584 nm and reported with the units 10ꢀ1 8C cm2 gꢀ1. Melting
points were found on a Stuart Scientific melting point appa-
ratus SMP3, v. 5 and are uncorrected.
carboxylic Acid (3)
Crude silylated proline 2 was dissolved in MeOH (20 mL)
and Pd/C (0.89 g, 10% w/w) was added. The mixture was
stirred under H2 (balloon) for 18 h and the resulting solution
was vacuum filtered through celite and the filtrate evaporat-
ed under reduced pressure. The crude product was purified
by column chromatography (1: 9 EtOAc/petroleum spirits)
to give the deprotected acid 3 as a viscous, pale brown oil;
yield: 1.217 g (72% over two steps); Rf =0.22 (1/3; EtOAc/
trans-4-Hydroxy-N-Boc-l-proline Benzyl Ester (2)
Benzyl bromide (1.43 mL, 11.8 mmol) was added to a solu-
tion of 4-OH-Boc-proline 1 (2.483 g, 10.7 mmol) in THF and
cooled to 08C. Triethylamine (1.65 mL, 11.8 mmol) was
added and the resulting mixture was stirred for 18 h, gradu-
ally reaching room temperature. The solvent was subse-
quently removed under vacuum and the crude mixture was
redissolved in DCM. The solution was washed with 1M HCl
(2ꢃ30 mL), brine (2ꢃ30 mL), Na2CO3 (2ꢃ30 mL) and an
additional wash of brine (1ꢃ30 mL). The washed organic
1
petroleum spirits). H NMR (270 MHz, CDCl3): d=7.6 (m,
4H, aryl), 7.39 (m, 6H aryl), 4.52 (t, 1H, J=5.18 Hz, CH-
CO), 4.4 (m, 1H, CH2-CH-CH2), 3.52 (m, 1H, N-CH2), 3.44
(m, 1H, N-CH2), 2.25 (m, 1H, CH-CH2-CH), 2.06(br m, 1H,
CH-CH2-CH), 1.42 [d, 9H, J=12.6 Hz, Si-C
ACHTUGNTREN(UNNG CH3)3], 1.05 [s,
9H, Si-C
AHCTUNGTRENNUNG
135.6, 133.8, 130, 127.8, 82.1, 70.8, 55.0, 54.5, 39.5, 37.3, 28.3,
26.8, 19.0; [a]D20:3: ꢀ41.98 (c 0.126, CHCl3); IR: nmax =1748
202
asc.wiley-vch.de
ꢂ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2012, 354, 197 – 204

Direct Asymmetric Aldol Reactions in Water Catalysed by a Highly Active C2-Symmetrical Bisprolinamide
(s), 1472 (s), 1105 cmꢀ1 (s); HR-MS: m/z=492.21804, calcd.
for [C26H35NO5SiNa]+ [M+]: 492.21767.
1,6-Di(trans-N-Boc-4-tertbutlydiphenylsiloxy-l-prolinami-
de)hexane (4)
ed with CH2Cl2, the solvent was then removed under
vacuum to give the crude product as a yellow solid. Analysis
1
by H NMR spectroscopy was used to determine the desired
product, reaction conversion and the diastereomeric ratio.
The crude product was purified by silica gel column chroma-
tography and the pure product analysed by chiral HPLC
(Chiral Pak AD-H, hexane:2-propanol, 90:10, 1 mLminꢀ1)
to determine the enantiomeric excess.
Note that all chiral compounds were separated via chiral
HPLC and retention times were compared to their corre-
sponding racemates (chromatograms are provided in the
Supporting Information).[12]
TBDPSO-proline 3 (0.714 g, 2.34 mmol) was dissolved in
15 mL dichloromethane and cooled to 08C. HOBt (0.072 g,
0.533 mmol) was added to the mixture and stirred for 4 min
before the addition of EDCI (0.269, 1.41 mmol). To this
mixture 1,6-diaminohexane (0.139 g, 1.16 mmol) was added
and the resulting solution was stirred for 16 h, allowing it to
reach room temperature. The final mixture was diluted with
additional dichloromethane (50 mL) and washed with 2M
HCl (2ꢃ30 mL), Na2CO3 (2ꢃ30 mL) and brine (2ꢃ30 mL).
The solvent was removed under vacuum and the crude
product was purified by column chromatography (2:1 petro-
leum spirits:EtOAc) to afford the N-Boc-diprolinamide as a
white amorphous solid; yield: 0.484 g (80%); mp 67–688C;
Rf =0.14. 1H NMR (270 MHz, CDCl3): d=7.59–7.25 (m,
20H, aryl), 4.39 (m, 4H, chiral H), 3.69–3.42 (m, 4H, CH-
CH2-CH), 3.17 (br s, 4H, CH2-HN), 2.39–1.97 (br m, 4H, N-
CH2), 1.43 (s, 18H, Boc), 1.40 (br, 4H, alkyl), 1.24 (br, 4H,
Representative Syntheses for Aldol Product
Racemates (Benzaldehyde)
Procedure A: A stirred solution of water (15 mL) was
charged with 10M NaOH (1 mL). Ketone (0.28 mL,
2.7 mmol, 5 equival) was added and the solution was stirred
for 1 min. To the mixture was added arylaldehyde (0.6 mL,
0.54 mmol, 1 equiv.) and the solution was stirred for 3 h. The
mixture was extracted into CHCl3 (3ꢃ20 mL) and the com-
bined 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 mix-
ture was added ketone (0.223 mL, 2.65 mmol, 5 equiv.) and
aldehyde (80 mg, 0.53 mmol, 1 equiv.). Benzoic acid (20 mg,
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
2M HCl (2ꢃ20 mL). The organic phase was dried with
MgSO4. The racemic mixture was analysed by chiral HPLC
without purification.
alkyl), 1.02 [s, 18H, Si-CACHTNUGRTNEUNG
(CH3)3]; 13C NMR (100 MHz,
CDCl3): d=172.58, 156.26, 135.72, 135.66, 129.94, 127.86,
80.52, 71.62, 71.12, 58.9, 55.18, 40.24, 39.21, 27.23, 28.42,
26.89, 26.31, 19.15; [a]2D0:7: ꢀ498 (c 0.051, CHCl3); IR: nmax
[C52H82N4O8Si2Na]+ [M+]: 1041.55634.
=
1662 (s), 1472 cmꢀ1 (s); HR-MS: m/z=1041.55572, calcd. for
1,6-Di(trans-4-tertbutlydiphenylsiloxy-l-prolinamide)-
hexane (5)
Boc-protected dimer 4 (0.318 g, 0.312 mmol) was stirred in a
solution of 10% trifluoroacetic acid (0.5 mL) in dichlorome-
thane (4.5 mL) for 4 h under an N2 atmosphere. The result-
ing solution was dissolved in additional dichloromethane
(20 mL) and basified with saturated NaHCO3 (30 mL). The
deprotected compound was extracted into dichloromethane
(3ꢃ30 mL) and the combined organic phase was washed
with NaHCO3 (3ꢃ30 mL). The solvent was removed under
vacuum to give 5 as a pale brown solid; yield: 0.252 g
(99%); Rf =0.25 (100%, EtOAc); mp 60–618C. 1H NMR
(270 MHz, CDCl3): d=7.608 (br m, 8H, aryl), 7.38 (br m,
12H, aryl), 4.35 (br, 2H, CH1-O), 3.99 (t, J=8.4 Hz, CH1-
N), 3.14 (sept, 4H, CH2-N), 2.89 (d, J=12.1 Hz, 2H, N-CH2-
CH), 2.56 (dd, J=4.45, 7.7 Hz, 2H, N-CH2-CH), 2.24 (m,
2H, CH-CH2-CH), 1.7 (m, 2H, CH-CH2-CH), 1,41 (m, 4H,
alkyl), 1.27 (m, 4H, alkyl), 1.03 (br s, 18H, tert-butyl);
13C NMR (100 MHz, CDCl3): d=174.6, 135.7, 134.1, 129.9,
Acknowledgements
The authors would like to thank Dr. Jacqui Adcock for gen-
erous assistance with HPLC and Dr. Fred Pfeffer for manu-
script perparation. Also we gratefully acknowledge the
Deakin University CRGS and the Strategic Research Center
for Biotechnology, Chemistry and Systems Biology for fund-
ing.
127.8, 75.1, 56.9, 55.7, 40.1, 38.7, 29.6, 27, 26.53, 19.2; [a]D20:7
:
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ꢀ137.58 (c 0.024, CHCl3); IR: nmax =1654 (s), 1205 (s),
699 cmꢀ1 (s); HR-MS: m/z=819.46880, calcd. for
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Adv. Synth. Catal. 2012, 354, 197 – 204