Kinetic resolution of sec-alcohols using a new class of readily assembled (S)-proline-derived 4-(pyrrolidino)-pyridine analogues

Article abstract of DOI:10.1039/b419335k

We report the development of a new class of readily prepared chiral 4-(pyrrolidino)-pyridine catalysts capable of exploiting both van der Waals (π) and H-bonding interactions, thus allowing remote chiral information to stereo-chemically control the kinetic resolution of sec-alcohols. The Royal Society of Chemistry 2005.

Full text of DOI:10.1039/b419335k

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C O M M U N I C A T I O N
Kinetic resolution of sec-alcohols using a new class of readily
assembled (S)-proline-derived 4-(pyrrolidino)-pyridine analogues
´
Ciara´n O Da´laigh, Stephen J. Hynes, Declan J. Maher and Stephen J. Connon*
Department of Chemistry, University of Dublin, Trinity College, Dublin 2, Ireland.
E-mail: connons@tcd.ie; Fax: +353 1 6712826
Received 4th January 2005, Accepted 25th January 2005
First published as an Advance Article on the web 10th February 2005
We report the development of a new class of readily
prepared chiral 4-(pyrrolidino)-pyridine catalysts capable
of exploiting both van der Waals (p) and H-bonding inter-
actions, thus allowing remote chiral information to stereo-
chemically control the kinetic resolution of sec-alcohols.
a face-selective manner.12,13 We therefore reasoned that a 4-
pyrrolidino-analogue of 2 (i.e., 3 [Fig. 1]) held promise as a
tuneable and easily-constructed acyl-transfer catalyst template
capable of operating via an induced-fit mechanism. With a view
toward maximising both catalyst rigidity and potential for p–
p interaction, novel (S)-proline-derived structures 4 and 5 also
seemed worthy of investigation.
The synthesis of 3 was carried out as outlined in Scheme 1.
Treatment of 3-carboxy-4-chloropyridine (6)14 with thionyl chlo-
ride furnished the corresponding acid chloride hydrochloride,
which was then coupled with amine 715 to afford amide 8
in reasonable yield. Subsequent substitution of the 4-chloro-
substituent with excess pyrrolidine afforded catalyst 3. In a sim-
ilar fashion, 4† and 5 were prepared from 6 using commercially
available enantiopure (S)-a,a-diphenylprolinol (9) and its readily
accessible 2-naphthyl analogue 1016 (Scheme 1).
The development of small chiral organic molecules capable of
mimicking enzymatic action (in an asymmetric catalysis context)
is a challenge that is receiving considerable attention in contem-
porary organic chemistry.1 Significant advances have been made
recently in the design of chiral catalysts based on the tertiary
phosphine2 and amine3–5 structural motifs for enantioselective
acyl-transfer reactions and a range of other processes susceptible
to the influence of nucleophilic catalysis.3 The reactive and ro-
bust catalyst N,N-dimethylaminopyridine (DMAP),6 has been
demonstrated to be a particularly useful target for desymmetri-
sation by Vedejs,7 Fu,8 Spivey,9 and (inter alia10) Fuji.11
The most successful designs for pyridine-based catalytic
systems represent a practical compromise between the opposing
considerations of reactivity and selectivity; i.e. to maximise
selectivity it is desirable to install chiral information as close
to the site of acylation as possible, however reaction rates (and
therefore the kcat : kuncat ratio) in these systems are remarkably
sensitive to substitution adjacent to the nucleophilic ring-
heteroatom.3a An interesting approach to addressing this issue
is embodied by 1 (Fig. 1), which operates via an ‘induced-fit’
mechanism whereby, in the absence of an acylating agent, the
catalyst adopts an ‘open’ unhindered (and therefore reactive)
form, but which on acylation adopts a ‘closed’ conformation due
to an attractive p–p interaction between the pyridinium ring and
the naphthyl moiety, resulting in the stereoselective shielding of
one face of the acylated catalyst.11a
Scheme 1 Synthesis of catalysts 3,4 and 5.
Catalysts 3–5 were evaluated in the kinetic resolution of
mono-protected diols 13–15 in the presence of isobutryic anhy-
dride (Table 1). As expected, 3–5 promoted the smooth acylation
of 13–15 at low catalyst loadings. While the prototype catalyst
3 exhibited disappointing selectivity (entry 1),17 acylation pro-
moted by the (S)-prolinol-derived 4 and 5 was considerably
more enantioselective (entries 2–7), with synthetically useful
selectivity possible at low temperature (entry 3). It is noteworthy
that the exchange of the phenyl substituents of catalyst 4 for 2-
napthyl moieties (catalyst 5) resulted in a marginal improvement
in performance (entries 4 and 6), and that a decrease in
the substrate carbonyl Lewis-basicity led to an attenuation of
enantioselectivity (entries 5–7), indicating that catalyst-substrate
H-bonding may contribute to selectivity in these systems.19
To determine the influence of the hydroxyl group on catalyst
selectivity, reduced analogues of 4 and 5 (19 and 20, respectively),
were prepared using an identical strategy to that outlined in
Scheme 1.20 Catalysts 4, 5, 19 and 20 were then compared in the
kinetic resolution of alcohol 21 (Table 2).
Fig. 1 Chiral 4-(pyrrolidino)-pyridine analogues.
In this context, we were intrigued by a report demonstrating
that the 3-substituted pyridine 2 exhibited a similar p–p stacking
interaction on acylation/alkylation,12 allowing the subsequent
attack of a nucleophile at C-4 (2a, Fig. 1) to proceed in
T h i s j o u r n a l i s
T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 5
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 9 8 1 – 9 8 4
9 8 1
©

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Table 1 Evaluation of 3–5 in the kinetic resolution of sec-alcohols 13–15
Entry
Catalyst
ROH
T/◦C
C (%)a
Ee (%)b
Sc
Absolute configurationd
1
2
3
4
5
6
7
3
4
4
4
5
5
5
13
13
13
14
13
14
15
25
25
55
13
93
97
74
90
80
95
1.4
4.9
9.4
4.3
5.4
4.4
3.5
(1S, 2R)
(1S, 2R)
(1S, 2R)
(1S, 2R)f
(1S, 2R)
(1S, 2R)f
(1S, 2R)f
78
−78
69e
68
25
25
25
25
73.5
71
88
a Refers to conversion, which could be determined (with excellent agreement) either by 1H NMR spectroscopy or using chiral HPLC, where C = 100 ×
eealcohol/(eealcohol + eeester). b Ee of 13a–15a determined by chiral HPLC using a Chiralcel OD-H column (4.6 × 250 mm). c S = selectivity index (kfast/kslow
10d). e 1.5 eq. (iPrCO)2O, 8 h. f Tentative assignment assuming that the elution order is identical to that of the p-dimethylamino-benzoate.
,
see ref. 18). d Absolute configuration of the recovered alcohol (major enantiomer) as determined by comparison with literature retention times (ref.
Table 2 Determination of the H-bonding contribution to selectivity
Entry
Catalyst
C (%)a
Eealcohol (%)b
Eeester (%)b
Sc
Absolute configurationd
1
2
3
4
4
72
43e
36
43
93
51
22
30
29
63
36
38
6.3
8.7
2.8
3.0
(R)
(R)
(S)
(S)
5
19
20
1
a Refers to conversion, which could be determined (with excellent agreement) either by H NMR spectroscopy or using chiral HPLC, where C =
100 × eealcohol/(eealcohol + eeester). b Determined by chiral HPLC using a Chiralcel OD-H column (4.6 × 250 mm). c S = selectivity index (kfast/kslow, see
ref. 18). d Absolute configuration of the recovered alcohol (major enantiomer) as determined by comparison with literature retention times (ref. 9h).
e 0.8 eq. (iPrCO)2O, 8 h.
While the hydroxy-substituted catalysts 4 and 5 promoted
acylation with a useful level of selectivity (entries 1 and 2),
19 and 20 furnished recovered alcohol 21a with relatively poor
enantioselectivity and with the opposite sense of stereoinduction
to that observed using 4 and 5 (entries 3 and 4). These findings
strongly indicate that the hydroxyl moiety plays a critical role
in determining the preference of the acylated catalyst for one
antipode of the sec-alcohol racemate in these reactions.21
In an attempt to detect possible aryl-pyridinium ion p-
stacking interactions, the 1H NMR spectra of catalysts 4, 5, 19,
20 and control material 23 (prepared from 6 and pyrrolidine)
was compared to that of their corresponding products on
methylation with iodomethane (Table 3).12 These experiments
were instructive; while little evidence was found to support a
‘face–face’ p–p stacking interaction (Fig. 1),11,12 a strong upfield
shift associated with H-2 upon methylation of 4, 5, 19 and
20 (which is absent on methylation of 23) was observed, the
magnitude and localisation of which indicates that an interaction
between the substituted edge of the pyridinium cation (or H-2
itself) and one of the pendant aryl moieties takes place.22 This
effect is more dramatic in the case of naphthyl-substituted 5a and
20a, where even the pyridinium methyl protons are significantly
shielded relative to the corresponding 23a methyl group. It is also
noteworthy that d H-2 is observed at considerably higher field in
the cases of 4 and 5 than for 23, which we propose demonstrates
that the aforementioned interaction is also a feature of the
solution-state structure of the these materials.23
The results in Tables 1–3 indicate that the ability of 4 and 5 to
serve as active and enantioselective acyl-transfer catalysts is due
to a unique combination of both aryl-pyridinium ion p–p (or
p–H) and substrate–catalyst H-bonding interactions. Based on
this data, a rationale for the selectivity observed in the acylation
of 21 catalysed by 4 is shown in Fig. 2. H-2 is located in the
vicinity of the p-cloud of one of the phenyl substituents (the
proximity of which to the ring nitrogen forces the isopropyl
group to occupy the distal side of the N–N pyridine-axis), with
the second phenyl moiety orientated into the solvent. In this
conformation the hydroxyl group can control the Bu¨rgi–Dunitz
9 8 2
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 9 8 1 – 9 8 4

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Table 3 Selected 1H NMR chemical shifts for 4, 5, 19, 20 and 23 and
their methylated analogues
Engineering and Technology (IRCSET) and Trinity College
Dublin is also gratefully acknowledged.
Notes and references
† Characterisation data for 4: mp 144–146 ◦C, [a]D20 −98 (c 0.96, CHCl3);
dH (400 MHz, CDCl3) 0.95–1.18 (2H m), 1.80–2.20 (6H, m), 2.90–3.15
(3H, m), 3.40–3.55 (3H, m), 5.20 (1H, dd, J = 9.0, 8.5 Hz), 6.45 (1H,
d, J = 6.0 Hz), 7.25–7.38 (5H, m), 7.41–7.53 (4H, m), 7.60 (2H, d,
J = 6.0 Hz), 8.09 (1H, d, J = 6.0 Hz); dC (100 MHz, CDCl3) 23.3,
25.1, 30.2, 48.8, 51.6, 68.3, 81.5, 108.1, 116.2, 127.0, 127.1, 127.2, 127.3,
127.4, 127.6, 142.1, 144.6, 146.6, 147.6, 148.5, 170.4; HRMS calcd. for
C27H30N3O2 (M + 1) 428.2328, found 428.2338.
1 P. I. Dalko and L. Moisan, Angew. Chem., Int. Ed., 2004, 43, 5138.
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Catalyst
d H-2a,b,c
d H-5a,b,c
d H-6a,b,c
d CH3
4
4a
5
5a
19
19a
20
20a
23
23a
7.33
6.45
6.80 (0.45)
6.45
6.70 (0.25)
6.42
6.79 (0.37)
6.42
6.66 (0.24)
6.47
6.90 (0.43)
8.09
—
3.88
—
3.33
—
4.02
—
3.49
—
4.21
6.52 (−0.81)
8.04 (−0.05)
7.51
8.09
5.99 (−1.52)
7.73
7.88 (−0.21)
8.12
6.68 (−1.05)
8.10 (−0.02)
7.93
8.11
6.39 (−1.54)
8.19
8.17 (−0.02)
7.88 (−0.23)
8.16
8.21 (0.05)
a Values for d are quoted in ppm with CDCl3 as solvent. b Value in
parenthesis represents Dd: the change in chemical shift of the proton
indicated on methylation (in ppm); a negative value for Dd indicates an
upfield shift. c All pyridine ring proton resonances were unambiguously
assigned by NMR spectroscopy (1H–1H COSY, 1H–13C COSY, NOE
and 1-D TOCSY experiments).
trajectory of 21 by H-bonding and (assuming that the naphthyl
moiety avoids the acylated catalyst) the (R)-21 antipode reacts
relatively slowly due to catalyst-methyl group repulsion as the
substrate approaches (Fig. 2).
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Fig. 2 Possible pre-TS-assemblies for the acylation of 21 by (iPrCO)2O
catalysed by 4.
In summary, we have developed a new class of active, chiral
4-(pyrrolidino)-pyridine derivatives (4 and 5) for the kinetic
resolution of sec-alcohols such as 15 and 21 with selectivity
approaching synthetically useful levels. These proline-derived
promoters are readily prepared from simple starting materials
without the need for resolution steps.24 To our knowledge 4
and 5 represent the first chiral 4-N,N-dialkylaminopyridine
catalysts to (synergistically) employ both van der Waals (p)
interactions and hydrogen bonding to allow remote chirality
to exert stereochemical influence on an acylation reaction.
Experiments are underway to further explore both the mode-
of-action and potential utility of these catalysts (and modified
analogues) in a range of enantioselective acyl-transfer reactions.
The results of these studies will be reported in due course.
We would like to thank Dr John O’Brien for NMR spectra.
Financial support from the Irish Research Council for Science
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O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 9 8 1 – 9 8 4
9 8 3

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23 Preliminary crystal structure data indicates that the solid-state
conformation of 4 is dominated by an intramolecular hydrogen
bond between the hydroxy group and the amide carbonyl oxygen,
which could explain neither the observed selectivity nor the 1H NMR
chemical shift data outlined in Table 3.
17 It is noteworthy that two distinct rotameric forms of 3 (in a ca. 1
: 1 ratio) are identifiable by 1H NMR spectroscopy and that the
24 Both antipodes of a,a-diphenylprolinol are commercially available.
9 8 4
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 9 8 1 – 9 8 4