Highly Enantioselective Catalytic Kinetic Resolution of α-Branched Aldehydes through Formal Cycloaddition with Homophthalic Anhydrides

Article abstract of DOI:10.1002/chem.201902422

A new catalytic methodology was developed to promote an efficient one-pot kinetic resolution of racemic aldehydes with selectivity (s*) of up to 91 (99:1 d.r., >99 % ee) in a cycloaddition reaction with enolizable anhydrides to afford dihydroisocoumarin products (a core prevalent in natural products and molecules of medicinal interest) containing three contiguous stereocentres.

Full text of DOI:10.1002/chem.201902422

A Journal of
Accepted Article
Title: Highly Enantioselective Catalytic Kinetic Resolution of α-
Branched Aldehydes via Formal Cycloaddition with Homophthalic
Anhydrides
Authors: Stephen Connon, umar farid, and maria luisa aiello
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To be cited as: Chem. Eur. J. 10.1002/chem.201902422
Link to VoR: http://dx.doi.org/10.1002/chem.201902422
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10.1002/chem.201902422
Chemistry - A European Journal
DOI: 10.1002/anie.200((will be filled in by the editorial staff))
Organocatalysis
Highly Enantioselective Catalytic Kinetic Resolution of α-Branched
Aldehydes via Formal Cycloaddition with Homophthalic Anhydrides
Umar Farid, Maria Luisa Aiello and Stephen J. Connon*
Abstract: A new catalytic methodology was developed to promote
an efficient one-pot kinetic resolution of racemic aldehydes with
selectivity (s*) of up to 91 (99:1 dr, >99% ee) in a cycloaddition
reaction with enolizable anhydrides to afford dihydroisocoumarin
products (a core prevalent in natural products and molecules of
medicinal interest) containing three contiguous stereocentres.
The catalytic Kinetic Resolution (KR) of racemates remains an
indispensable method for obtaining enantioenriched compounds.[1]
While the substrate scope of this technology is generally broad, very
few non-enzymatic methods for the KR of racemic -substituted
aldehydes – arguably the most synthetically versatile of functional
groups - have emerged. Aldol type reactions involving KR of keto
aldehydes have been reported, however most of these reactions are
either non-catalytic or substrate-specific and result in poor
enantioselectivity.[2] Among other approaches, kinetic and parallel
kinetic resolution of α-amino aldehydes with chiral phosphonates,[3]
metal-based (parallel) KR of 훼 − and 훽 −substituted aldehydes,[4]
and the KR of α,α-disubstituted α-siloxy aldehydes[5] have been
reported. In 1991, Oguni et al. disclosed the moderately selective
KR of racemic aldehydes 1 via the enantioselective addition of
diethyl zinc in the presence of a 훽-amino alcohol ligand 2 (Fig.
1A).[6] Unreacted aldehyde 3 could be recovered in high ee only at
high conversions. Organocatalytic asymmetric fluorination of α-
chloroaldehydes 5 involving KR remains among the few examples
7
]
of the KR of α-branched aldehydes (Fig. 1B).[
Enantiodiscrimination was such that low conversions were required
to achieve high product ee – resulting in poor ee of the unreacted
aldehyde. In 2008, a highly selective protocol for the KR of racemic
specialized N-protected amino aldehydes 9 by oxidation with N-
iodosuccinimide in the presence of Cu(II)/(R,R)-Ph-BOX to afford
amino acid methyl esters 11 was reported (Fig. 1C).[8]
While the dynamic kinetic resolution of α-branched aldehydes[9]
involving their in situ racemization and subsequent enantioselective
conversion to less acidic non-aldehydic compounds has received
considerable attention; the simple KR of -branched aldehydes -
potentially important building blocks (e.g. 13a-b, Fig. 1D) -
remains elusive, due in part to the requirement for an
enantiodiscriminatory reaction at the aldehydic center while
simultaneously avoiding both mid- and post-reaction racemization.
Figure 1. Literature processes involving the KR of aldehydes and
relevant products of biological importance.
We (and others) have reported catalytic asymmetric cycloaddition
reactions between homophthalic anhydrides 17, behaving as
10
]
nucleophiles, with different electrophiles e.g, aldehydes,[
ketones,[11] alkylidene oxindoles,[12] imines[13] and nitrostyrenes.[14]
The processes involving aldehydes provide one-pot access to
dihydroisocoumarins such as 14 (Fig. 1D): core structural units in a
range of natural products possessing a diverse array of medicinally
relevant
biological
activities,
for
instance:
cytotoxic/antiproliferative,[15,16,17] antimicrobial,[18,19] antifungal,[20]
antiulcer,[21,22] antimalarial,[23] anti-inflammatory,[21,22] antioxidant[24]
and antiallergic[ 25 ] properties. A weakness associated with these
methodologies is that they provide no catalytic access to
dihydroisocoumarins incorporating a stereocentre adjacent to the
lactone core – a feature of a number of structurally important natural
products, such as the potent respiratory chain inhibitor Ajudazol A
(15)[ 26 ] and the recently discovered highly active herbicide
Bacilosarcin (16, Fig 1D). [27] Herein we report the results of a study
aimed at simultaneously addressing these twin synthetic challenges:
a catalytic cycloaddition between anhydride 17 and racemic -
branched aldehydes 18 which allows the one-pot formation of
stereochemically challenging a-branched 3,4-dihydroisocoumarins
[]
U. Farid, M. L. Aiello, Prof. S. J. Connon
Trinity Biomedical Sciences Institute, School of Chemistry
The University of Dublin, Trinity College, Dublin 2, Ireland
Fax: 0035316712826
E-mail: connons@tcd.ie
[] Financial support from Science Foundation Ireland (SFI –
12-IA-1645) is gratefully acknowledged. We thank Dr
Brendan Twamley for X-ray crystal diffraction analysis.
Supporting information for this article is available on the
WWW under http://www.angewandte.org or from the
1
This article is protected by copyright. All rights reserved.

10.1002/chem.201902422
Chemistry - A European Journal
19 with unprecedented levels of diastereo- and enantiocontrol, while
bringing about the first efficient catalytic KR of simple aldehydes
with good-outstanding levels of enantiodiscrimination (Fig. 1E).
Our study began with the reaction between 17 and racemic 2-
phenylpropionaldehyde ((rac)-18a) in the presence of a range of
cinchona alkaloid derived bifunctional catalysts (Table 1).
Table 1. Catalyst screening and optimization
entry
cat.
loading
(mol %)
solvent
(0.1 M)
temp
(oC)
t
17
dr[a]
ee (%)[b]
conv.[c]
ee (%)[b]
s*[d]
(d)
(equiv.)
21 (a : b : c : d)
21 (a : b : c :d)
18 (%)
22
1
2
i-Pr2NEt
C1
15
5
THF
MTBE
RT
RT
RT
RT
RT
-30
-30
-30
-30
-30
-60
-60
-30
-30
RT
RT
RT
RT
-60
-78
2
2
1.0
1.0
1.0
1.0
1.0
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
1.0
1.0
20 : 9 : 20 : 51
32 : 9 : 9 : 50
44 : 14 : tr[f] : 42
35 : 3 : 6 : 56
39 : 6 : 6 : 49
53 : 3 : tr : 44
31 : tr : tr : 69
21 : tr : 9 : 70
24 : tr : tr : 76
12 : tr : 15 : 73
13 : tr : 10 : 77
12 : tr : 9 : 79
39 : 4 : tr : 57
18 : 2 : tr : 80
22 : 6 : 5 : 67
38 : 4 : tr : 58
23 : 6 : 6 : 65
33 : 11 : 5 : 51
4 : tr : tr : 96
-
100 (47)[e]
100 (78) [e]
-
-
-
69 : - : - : 72
99 : 99 : - : 99
94 : 93 : - : 93
94 : - : - : 93
99 : 99 : - : 99
97 : - : - : 97
98 : - : - : 99
98 : - : - : 99
97 : - : - : 97
98 : - : - : 99
98 : - : - : 99
92 : 90 : - : 84
86 : - : - : 96
n.d.[h]
-
3
C2
5
MTBE
2
100 (74) [e]
100
100
50
-
-
4
C3
5
MTBE
2
-
-
5
C4
5
MTBE
2
-
-
6
C2
5
MTBE
9
0
-
7
C3
5
MTBE
13
9
50
42
49
51
50
53
49
6
3.6
4.6
5.0
4.8
5.4
4.6
1.2
7.2
3.4
1.8
3.2
2.0
12.6
91.3
8
C5
5
MTBE
50
9
C6
10
5
MTBE
9
50
10
11
12
13
14
15
16
17
18
19
20
C7
MTBE
5
50
C7
10
10
5
MTBE : THF[g]
MTBE : THF
MTBE
1
50
C8
4
50
C9
19
19
1
50
C10
C10
C11
C12
C13
C10
C10
5
MTBE
50
60
40
20
38
24
80
98
5
MTBE
50
5
MTBE
1
n.d. [h]
50
5
MTBE
1
n.d. [h]
n.d. [h]
50
5
MTBE
1
50
10
15
MTBE : THF
MTBE : THF
5
90 : - : - : 99
- : - : - : 99
54
8
3 : tr : tr : 97
52
[a]Determined by 1H NMR spectroscopy. [b]Determined by CSP-HPLC. [c]Conversion of 18 was determined by 1H NMR spectroscopy using p-iodoanisole
as an internal standard (note: conversion = 100 푋 eeS.M./( eeS.M. + eeProd.) could not be used because of multiple chiral centres). [d]Selectivity (s*) = ln[(1-C)(1-
eeS.M.)]/ln[(1-C)(1+eeS.M)].[10e,28] [e]Isolated yield of product 21. [f]Traces. [g]1:1 ratio. [h]not determined.
The use of Hünig’s base (devoid of a hydrogen bond donating unit)
as a catalyst in the reaction between anhydride 17 and 2-
phenylpropionaldehyde (18a, 1:1 ratio), led to the formation of all
possible dihydroisocoumarin diastereomers 21a-d (isolated after
esterification with trimethylsilyldiazomethane to facilitate CSP-
HPLC analysis) in racemic fashion (entry 1). When bifunctional
urea C1 and squaramide-based catalysts (i.e. C2) were employed,
the latter proved to be far superior: promoting the formation of 21
with improved (yet still impractical) diastereocontrol and
outstanding enantioselectivity (entries 2-3). However, both the t-
butyl-substituted squaramide C3 and its arylated-quinoline
derivative (i.e. C4 (highly efficacious in the previous studies[10]
)
promoted the catalysis with lower stereocontrol (entries 4-5). At this
point it was clear that even without the KR element of the process,
achieving the requisite control over the cycloaddition reaction is not
trivial.
2
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10.1002/chem.201902422
Chemistry - A European Journal
Initial results involving the KR of (rac)-18a (1.0 equiv.) with 17
(0.5 equiv.) with were far from encouraging: cycloaddition
proceeded smoothly at -30 °C catalyzed by squaramide C2 but
resulted in racemic alcohol 22 (isolated after reduction of unreacted
aldehyde with sodium borohydride to facilitate purification and
CSP-HPLC analysis, entry 6). Employing C3 led to improved
performance and the first direct catalytic asymmetric KR of α-
Table 2. Substrate scope: aldehyde component.
s*[b]
entry
alcohol
lactone
t
conv
(%)[a]
(d)
branched
aldehyde,
albeit
with
impractically
low
enantiodiscrimination (entry 7). Augmentation of the steric
requirement of the squaramide-substituent via the design of triethyl-
(i.e. C5, entry 8), adamantyl (i.e. C6, entry 9) and trityl (i.e. C7,
entry 10) variants allowed selectivity to reach s* = 5. At -60 °C the
reaction was no longer homogeneous and use of a mixture of methyl
tert-butyl ether (MTBE) and tetrahydrofuran (THF) was required
(entry 11). Evaluation of the even larger hexasubstituted trityl
catalyst (i.e. C8, entry 12) did not lead to an appreciable
improvement in terms of selectivity.
Faced with this ‘diminishing returns’ scenario stemming from
simply increasing the bulk of the squaramide group, yet cognisant
that this unit appears to be occupying space which influences the
stereochemical outcome of the process, we sought to introduce a
chiral N-substituent here seeking an advantageous (i.e. synergistic
with the alkaloid-derived catalyst chiral substituents) diastereomeric
interaction with the reacting partners in the transition state and bring
about ‘matched’ and ‘mismatched’ catalyst diastereomers.
We synthesized both (R)- (i.e. C9) and (S)-phenylglycine-
derived (i.e. C10) squaramide-substituted catalysts C-functionalized
as pyrrolidine amides. While C9 proved a particularly poor
‘mismatched’ catalyst, its epimer C10 delivered a reasonable (and
highest hitherto obtained) selectivity of 7.2, even at the higher
temperature of -30 °C (entries 13-14). Use of a (S)-phenylalanine-
derived catalyst containing either secondary- or bulky tertiary
amides did not improve catalyst performance relative to C10 (i.e.
C11-13 respectively, entries 15-18). Further optimization of the
conditions using C10 led to outstanding selectivity; allowing the
formation of the cycloadduct 21d (97:3 dr) in 99% ee and the
reduced alcohol 22 in 98% ee at close to 50% conv. at -78 °C (s* =
91.3, entries 19-20). It is interesting to note that no post-reaction
racemization was observed under these conditions even when the
reaction was left for more than 10 days.
Attention now turned to the question of substrate scope (Table
2). Diverse α-substituted aldehydes were well tolerated by the
catalyst: for instance, α-methyl, -ethyl and -allyl derivatives (entries
1-3) could be resolved with excellent selectivity (s* = 20-91);
allowing the isolation of reduced aldehydes 22-24 with 90-98% ee
along with novel cycloaddition products with outstanding diastereo-
and enantiocontrol (up to 32:1 dr and >99% ee). It was found that
the installation of methyl groups on the aldehyde’s aromatic
substituent resulted in excellent selectivity in the case of -ortho and
-meta substituents (s* = 50-51, entries 4-5) but it proved to be a
greater challenge when the phenyl unit was exchanged for a 1-
naphthyl moiety. However, synthetically useful selectivity was still
possible (s* = 12, entry 6). Variation at the para-position of the
aldehydes produced interesting results. Aldehydes with electron-
donating substituents reacted at slower rates and could be resolved
with s* = 13 (entries 7 and 8). The p-bromo analogue reacted more
rapidly, with excellent selectivity (s* = 27) and outstanding
stereocontrol over the product (up to 99:1 dr and >99% ee, entry 9).
A heteroaromatic substrate also could be resolved with good
selectivity (entry 10).
1
8
52
91
(45)[c]
22 98% ee
21d 35%, 24:1 dr, >99% ee
2
3
5
5
56
23
20
(31)[c]
23 94% ee
23d 39%, 32:1 dr, >99% ee
54.8
(45)[c]
24 90% ee
24d 38%, 10.5:1 dr, >99%
ee
4
5
9
4.5
9
54
50
51
12
(43)[c]
25 98% ee
26 >99.9% ee
27 77% ee
28 88% ee
29 91% ee
30 92% ee
31 82% ee
25d 27%, 9:1 dr, >99% ee
26d 29%, 24:1 dr, >99% ee
27d 24%, 10:1 dr, >99% ee
28d 39%, 48:1 dr, >99% ee
29d 26%, 49:1 dr, >99% ee
30d 27%, 99:1 dr, >99% ee
31d 24%, 32:1 dr, 96% ee
57
(43)[c]
6
53
(47)[c]
7
8
5
58
13
13
(42)[c]
10
59
(27)[c]
9
2
4
54
27
18
(46)[c]
10
52
(48)[c]
[a]Determined by 1H NMR spectroscopy using p-iodoanisole as an internal
standard. [b]s* = ln[(1-C)(1-eeS.M.)]/ln[(1-C)(1+eeS.M)],[10e] ee determined by CSP-
HPLC, dr by 1H NMR spectroscopy. [c]Isolated yield of the alcohol in parenthesis.
3
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10.1002/chem.201902422
Chemistry - A European Journal
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To demonstrate the potential utility of this methodology, we carried
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2009, 121, 1144; d) P. Kongsaeree, S. Prabpai, N. Sriubolmas, C.
Vongvein, S. Wiyakrutta, J. Nat. Prod. 2003, 66, 709; N. Nazir, S. Koul,
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Chen, J. Z. M. Fong, J. Xu, C. Mou, Y. Lu, S. Yang, B. A. Song, Y. R. Chi,
J. Am. Chem. Soc. 2016, 138, 7212.
Scheme 2. Ibuprofen precursor synthesis
In summary, it has been demonstrated that in the presence of a novel
amino acid-derived squaramide-based bifunctional catalyst, simple
α-aryl-substituted branched aldehydes can be kinetically resolved
with excellent efficiency (s* up to 91) for the first time; with a
concomitant (and synergistic from a stereocontrol standpoint)
cycloaddition reaction with enolizable anhydrides occurring with
unprecedented diastereo- and enantiocontrol. In addition to the
resolved aldehydes being potentially serviceable as precursors to
chiral pharmaceuticals, the lactone products represent a previously
not directly catalytically accessible class of dihydrocoumarins with a
stereocenter outside the ring system similar to the cores of several
important natural products. Studies to further explore this
phenomenon from are underway.
Keywords: Dynamic Kinetic resolution, cycloaddition reaction,
enolizable anhydrides, lactones.
[1]
For selected articles and reviews concerning kinetic resolution see: a) E.
Vedejs, M. Jure, Angew. Chem. Int. Ed. 2005, 44, 3974; b) H. Pellissier,
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4
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10.1002/chem.201902422
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5
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10.1002/chem.201902422
Chemistry - A European Journal
Entry for the Table of Contents
Layout 2:
Organocatalysis
U. Farid, M. L. Aiello and S. J. Connon*
Page – Page
Highly Enantioselective Catalytic Kinetic
Resolution of α-Branched Aldehydes via
Formal Cycloaddition with Homophthalic
Anhydrides **
A new bifunctional organocatalyst was developed to promote an efficient kinetic
resolution of α-branched aldehydes with a selectivity (s*) of up to 91 in a
cycloaddition reaction with enolizable anhydrides to afford highly functionalized
six-membered lactones containing three contiguous stereocenters in a one pot
reaction with excellent stereocontrol (up to 99:1 dr, >99% ee).
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6
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10.1002/chem.201902422
Chemistry - A European Journal
[27]M. Enomoto, S. Kuwahara, Angew. Chem. Int. Ed. 2009, 121, 1144.
[28] H. B. Kagan, J. C. Fiaud, Top. Stereochem. 1988, 18, 249.
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Chi, J. Am. Chem. Soc. 2016, 138 (23), 7212.
7
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