The first example of enamine-Lewis acid cooperative bifunctional catalysis: Application to the asymmetric Aldol reaction

Article abstract of DOI:10.1039/b806779a

(-)-Sparteine directed lithiation of N-Boc-pyrrolidine, alkylation with chloromethylboronate pinacol ester and acid-based deprotection provides homoboroproline HX salt in 94% ee, which is then an efficient enamine-type pyrrolidine catalyst in an asymmetric aldol reaction when neutralised and especially when esterified in situ with a tartrate ester, for example, providing 90% ee of the aldol adduct derived from acetone and p-nitrobenzaldehyde. The Royal Society of Chemistry.

Full text of DOI:10.1039/b806779a

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The first example of enamine–Lewis acid cooperative bifunctional
catalysis: application to the asymmetric Aldol reactionw
Kenny Arnold,a Andrei S. Batsanov,a Bryan Davies,b Christophe Grosjean,a
Thorben Schu
¨
tz,a Andrew Whiting*a and Kerstin Zawatzkya
Received (in Cambridge, UK) 21st April 2008, Accepted 14th May 2008
First published as an Advance Article on the web 24th June 2008
DOI: 10.1039/b806779a
(ꢀ)-Sparteine directed lithiation of N-Boc-pyrrolidine, alkylation
with chloromethylboronate pinacol ester and acid-based deprotec-
tion provides homoboroproline HX salt in 94% ee, which is then an
efficient enamine-type pyrrolidine catalyst in an asymmetric aldol
reaction when neutralised and especially when esterified in situ
with a tartrate ester, for example, providing 90% ee of the aldol
adduct derived from acetone and p-nitrobenzaldehyde.
synthesis of the homoboroproline analogue 2 was initiated via
homologation of 39 (eqn (1)).
ð1Þ
Reaction of 3 with ClCH2Li10 gave homologated product 4
in low yield,11 however, with the expected retention of the (S)-
configuration. Optimisation could not be achieved, hence, a
(ꢀ)-sparteine-directed lithiation12,13 of 5 using chloromethyl-
boronate pinacol ester14 was attempted (Scheme 1). Initial
reaction of 5 with (ꢀ)-sparteine-s-BuLi followed by the addi-
tion of chloromethylboronate ester provided 4 in low yield
(12%). To assist the collapse of the intermediate ‘‘ate’’-com-
plex, anhydrous zinc(II) chloride10a was added, resulting in an
improved 69% yield (94% ee) of 4. To develop a chiral GC
resolution method,z racemic 4 was also prepared using
TMEDA–s-BuLi (Scheme 1). Deprotection of 4 was achieved
by removal the pinacol ester with diethanolamine (Scheme 1),
followed by acid hydrolysis to give 6 (56%).15
Bifunctional aminoboronic acids1 are showing promise as green,
non-transition-based catalysts in direct amide formation2 and
aldol reactions.3 A key element in their catalytic reactivity is the
cooperative relationship between the Lewis acidic boronic acid
and basic or nucleophilic nature of the amino group, without
intramolecular deactivation through B–N chelation.1,2 A further
development for potential asymmetric catalytic applications of
these systems could be a cooperative catalytic interaction between
an enamine and a boronate, assuming that the boronate could be
prevented from enamine activation and hydrolysis, and that the
enamine would not coordinate the Lewis acid. Since the report4 of
a proline-catalysed asymmetric aldol reaction,5 and other related
systems,6 a pyrrolidine-substituted boronic acid seemed to be
worthy of initial investigations. It is widely accepted that proline
and related compounds act similarly to aldolases, i.e. through
enamine/iminium ion catalysis and the carboxylic acid acts as
Brønsted co-catalyst.7 The substitution of the carboxylic acid in
proline by functions with lower pKa’s is known to give new
organocatalysts with improved solubility without loss of asym-
metric induction,8 however, there is no example featuring a Lewis
acid as the complimentary functionality to the amine, and hence,
enamine. In this communication, we report preliminary investiga-
tions into the synthesis and application of pyrrolidine-boronic
acid-based bifunctional asymmetric catalysts.
Boronic acid 6 was isolated as a crystalline solid and recrys-
tallisation from THF gave crystals suitable for X-ray analysis and
structural confirmation (see ESI,w Fig. S1). N-Boc-deprotection
of 6 was accomplished with TFA to give homoboroproline TFA
salt of (S)-2. Alternatively, simultaneous deprotection of both N-
Boc and pinacol ester groups was achieved using aq. HCl.
Attempts at purification of (S)-2ꢁHCl using Dowex 50WX8-200
resin16 proved unsuccessful, however, azeotroping with toluene
gave 2ꢁHCl, the identity of which was confirmed by re-esterifica-
tion with pinacol to give 7 (eqn (2)).
Following our recent asymmetric synthesis of boroproline 1
as its TFA salt using a sparteine-directed metallation,9 the
a Department of Chemistry, Durham University, Science Laboratories,
South Road, Durham, UK DH1 3LE. E-mail:
andy.whiting@durham.ac.uk; Fax: (+44) 191 384 4737;
Tel: (+44) 191 334 2081
Scheme 1 Synthesis of (S)-homoboroproline 2 as TFA and HCl salts.
b GlaxoSmithKline Pharmaceuticals, Stevenage, Hertfordshire
UK SG1 2NY
w Electronic supplementary information (ESI) available: Experimental
procedures, characterisations of new compounds, analytical methods,
1H, 13C and 11B NMR spectra. CCDC 666984 and 666985. For ESI
and crystallographic data in CIF or other electronic format see
DOI: 10.1039/b806779a
ð2Þ
ꢂc
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Table 1 Aminoboronic acid-catalysed aldol reaction of p-nitrobenz-
aldehyde and acetone
of both 1 and 2 are inactive as aldol catalysts, as is Et3N. The use
of a stronger base (KOtBu) highlights the potential for back-
ground base-mediated reactions (Table 1, entry 2); the low asym-
metric induction recorded in Table 1, entry 3 represents the
competition between the general base-catalysed aldol and enamine
catalysis. In contrast, Et3N prevents the background reaction
(Table 1, entry 4) and under these conditions, the aminoboronic
acids 1 and 2 showed catalytic activity (Table 1, entries 5 and 7).
Boroproline 1 was a poor catalyst (Table 1, entry 7, no asymmetric
induction) whereas homoboroproline 2 showed good catalytic
activity (Table 1, entry 5, 90% conversion and 38% ee)
Yield 9
(%)
eea
(%)
Yield 10
(%)
Entry
Conditions
t/h
1
2
3
4
5
6
7
a
(S)-2ꢁHCl
24
24
24
24
24
24
24
0
—
0
8
—
38
—
0
0
KOtBu
43
62
0
90
0
11
11
0
10
0
(S)-2ꢁHCl + KOtBu
Et3N
(S)-2ꢁHCl + Et3N
(S)-1ꢁTFA
In order to try and probe the mode of action of 2 further, it
was necessary to determine if changing either the base, coun-
terion, boronate Lewis acidity or sterics might have any effect
on either the rate of the aldol reaction or ee The HBr and HI
salts of 2 (prepared as the HCl salt, see ESIw) were compared
using both Et3N and Hunig’s base. Also, 2 was examined in
the presence of diols which were expected to both increase
boron Lewis acidity and stereochemistry around the boronate
group through in situ esterification of the boronic acid. Steric
effects were probed by examination of pinacol ester 7. The
results are summarised in Table 2.
(S)-1ꢁTFA + Et3N
14
0
Determined by chiral HPLC and major enantiomer was (S).y
Recrystallisation from acetone provided crystals of 7 suitable
for X-ray analysis (See ESI,w Fig. S2). Confirmation of the
absolute stereochemistry of 2 was achieved by oxidation of 4
(H2O2–NaOH) to give prolinol 8 (eqn (3)). Comparison of its
optical rotation with the literature17 confirmed the (R)-absolute
stereochemistry of 8.
Entries 1, 5 and 7 (Table 2) demonstrate that there is no effect
from either the ammonium salt or the counterion. Trifluoroace-
tate, bromide and iodide anions compare similarly to chloride
(Table 2, entry 3), hence, anion association or exchange is
negligible. Ammonium counterions also have no influence (see
Table 2, entries 2, 4, 6 and 8) (Note: Hunig’s base has a very minor
influence on the aldol reaction, entry 9. Table 2). Most impor-
tantly, it is possible to confirm that the enamine-based reactions
are assisted by the intramolecular boronic moiety in homobor-
oproline 2, and the relative placement of the boronic acid to the
secondary amine is key to reactivity. This is shown by the
observation that boroproline 1 is a poor catalyst (entry 7, Table 1)
ð3Þ
With both (S)-1 and (S)-2 in hand as salts, their preliminary
catalytic activity could be determined on an aldol reaction (eqn
(3)) with the results shown in Table 1. Because it was not possible
to isolate neutral boroproline 1 or its homologue 2, formation of
both was achieved in situ by neutralisation with base (Table 1).
None of the salts 1 or 2 were soluble in acetone, however, upon
addition of Et3N, solvation occurred along with the aldol reaction
between acetone and p-nitrobenzaldehyde. Importantly, the salts
Table 2 Aminoboronic acid-catalysed aldol reaction of p-nitrobenzaldehyde and acetone
Base/
additive
t/
h
Conversion
(%)
Yield 9
(%)
eea
(%)
Yield 10
(%)
Entry
Conditions
1
2
3
4
5
6
7
8
9
(S)-2ꢁTFA
(S)-2ꢁTFA
(S)-2ꢁHCl
(S)-2ꢁHCl
(S)-2ꢁHBr
(S)-2ꢁHBr
(S)-2ꢁHI
(S)-2ꢁHI
—
Et3N
iPr2NEt
Et3N
iPr2NEt
Et3N
6
6
6
6
24
24
40
24
24
499
92
499
95
97
97
86
63
6
92
71
90
92
93
92
81
61
6
40
43
38
40
43
43
38
37
N/
A
7
21
10
3
4
5
5
2
o1
iPr2NEt
Et3Nb
iPr2NEtb
iPr2NEt
10
11
12
Pyrrolidine
6
6
6
499
N/A
49
499
N/A
49
N/
A
N/
A
N/
A
o1
PhB(OH)2
N/A
o1
Pyrrolidine + PhB(OH)2
—
13
14
15
16
17
18
19
a
(S)-2ꢁHCl, (R,R)-diisopropyl tartrate
(S)-2ꢁHCl, (S,S)-diisopropyl tartrate
(S)-2ꢁHCl, (R,R)-Diethyl tartrate
(S)-2ꢁHCl, catechol
Et3N, 4 A M.S.
Et3N, 4 A M.S.
Et3N, 4 A M.S.
Et3N, 4 A M.S.
Et3N
20
20
20
20
20
6
65
76
87
14
98
82
o2
58
63
78
11
94
46
o2
90
90
90
70
82
30
—
7
13
9
3
4
36
o1
(S)-2ꢁHCl, (R,R)-diisopropyl tartrate
(S)-7ꢁHCl
Et3N
Et3N
(S)-1.TFA, (R,R)-diisopropyl tartrate
20
b
Determined by chiral HPLC, major enantiomer (S) in all cases.y Two equivalents.
ꢂc
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y Chiral HPLC conditions: Chiracel OJ-H, hexane–IPA (90 : 10), 1 mL
minꢀ1, l = 254 nm; tR [(R)-9] = 36.3 min, tR [(S)-9] = 41.9 min.
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Scheme 2 Proposed mechanism of action of catalyst 2 and its diol
ester derivatives.
and that pyrrolidine reactivity (entry 10, Table 2) is reduced by the
presence of a boronic acid (entry 12, Table 2) (which is also
unreactive, (entry 11, Table 2). In order to answer the question as
to whether the boronate function has a major impact upon the
stereochemistry-controlling step, match/mismatch stereochemical
effects18 were investigated by in situ boronate esterification (entries
13–17, Table 2). When catalyst 2 was esterified (assisted by
molecular sieves) with either enantiomer of diisopropyl tartrate,
essentially identical results were obtained (entries 13 and 14,
Table 2), and the ee was amplified to 90 from 38%. The lack of
matching or mismatching effects demonstrates that the absolute
stereoselection of homoboroproline 2 is controlled by the sub-
stituted-pyrrolidine and not the boronate. Indeed, steric effects
around the tartrate have no influence (entry 15, Table 2) since
diethyl tartrate provides an identical ee to the diisopropyl tartrate
(entry 13, Table 2). This less hindered diethyl ester is more reactive
(87% conversion in 20 h, vs. 65% for the more hindered ester)
which reinforces the finding that the major effect is neither
stereochemical nor steric, but entirely electronic. Hence, the overall
effect of the boronate group is to assist aldehyde activation and
aldol transition state is predicted to be tightened by a more Lewis
acidic boron (i.e. via Scheme 2). This is confirmed by in situ
formation of the catechol ester (entry 16, Table 2); the ee is
roughly double that of the free boronic acid (70%). This is a slow
reaction which may result from competitive ‘‘ate’’-complex for-
mation with hydroxide or catechol anion. The balance between
increasing boronate Lewis acidity through tartrate ester formation
vs.the need for water to be present for catalyst turnover is
exemplified in entries 13 and 17 (Table 2). Better catalyst turnover
(98% conversion, 20 h) is assisted by not drying the reaction (no
molecular sieves, entry 17); a slower reaction results from drying.
Steric effects at boron were confirmed by use of pinacol ester 7
since no improvement in ee was observed (Table 2, entry 18 vs.
entry 3). Indeed, (S)-7 merely causes increased dehydration to
derive the chalcone (36%). Finally, there is reinforcement of the
importance of a transition state such as 117 (Scheme 2) in these
reactions involving 2, since esterification of 1 with a tartrate fails to
switch on catalyst reactivity (entry 19, Table 2) and results in
almost complete catalyst deactivation.
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Proline and its derivatives are general catalysts for a wide range
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herein which are readily accessible catalysts based on homoboro-
proline are tunable in situ and they provide the enantiomeric aldol
products to those derived from L-proline, and in high ee (90% for
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Notes and references
z GC conditions: CP-Chiralsil-Dex-CB column (35 m ꢃ 0.25 mm ꢃ
0.25 mm), 128 1C, FID, tR (S) = 124 min; tR (R) = 127 min.
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ꢂc
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Chem. Commun., 2008, 3879–3881 | 3881