Synthesis of α-alkylated γ-butyrolactones with concomitant anhydride kinetic resolution using a sulfamide-based catalyst

Article abstract of DOI:10.1039/c8ob02248h

The Kinetic Resolution (KR) of α-alkylated enolisable disubstituted anhydrides has been shown to be possible for the first time. In the presence of an ad hoc designed novel class of bifunctional sulfamide organocatalyst, a regio-, diastereo- and enantioselective cycloaddition reaction between the enolisable anhydride and benzaldehydes provides densely functionalised γ-butyrolactones in one pot (up to 19:1 dr, 94% ee) with control over three contiguous stereocentres. The concomitant resolution of the starting material anhydride, provides access to a range of chiral succinate derivatives with selectivity factors up to S? = 10.5.

Full text of DOI:10.1039/c8ob02248h

Organic &
Biomolecular Chemistry
View Article Online
View Journal | View Issue
COMMUNICATION
Synthesis of α-alkylated γ-butyrolactones with
concomitant anhydride kinetic resolution using a
sulfamide-based catalyst†
Cite this: Org. Biomol. Chem., 2018,
16, 7574
Received 11th September 2018,
Accepted 3rd October 2018
Romain Claveau,
Brendan Twamley‡ and Stephen J. Connon
*
DOI: 10.1039/c8ob02248h
rsc.li/obc
The Kinetic Resolution (KR) of α-alkylated enolisable disubstituted
In 2012, we reported the catalytic dynamic kinetic resolu-
anhydrides has been shown to be possible for the first time. In the tion (DKR) reaction between racemic α-aryl succinic anhy-
presence of an ad hoc designed novel class of bifunctional sulfa- drides (rather unusually behaving as nucleophiles in the first
mide organocatalyst, a regio-, diastereo- and enantioselective reaction step) with aldehydes as electrophiles.8–10 When
cycloaddition reaction between the enolisable anhydride and ben- mediated by a cinchona alkaloid-based organocatalyst, under
zaldehydes provides densely functionalised γ-butyrolactones in mild conditions, these enolisable anhydrides underwent reac-
one pot (up to 19 : 1 dr, 94% ee) with control over three contiguous tion with a range of aromatic and aliphatic aldehydes to
stereocentres. The concomitant resolution of the starting material furnish γ-butyrolactone derivatives in excellent yields, dia-
anhydride, provides access to a range of chiral succinate deriva- stereo- and enantioselectivities.
tives with selectivity factors up to S* = 10.5.
Recently we expanded the scope to include the DKR of
bis-aryl succinic anhydrides of general type (rac)-9 (Fig. 2A)
involving reaction with aldehydes 10 mediated by catalyst 12 to
afford lactones of general type 11 via enolate 13 9h with good to
excellent levels of enantio- and diastereocontrol.11 Rapid (rela-
tive to addition) enolate transfer between carbonyl units
(thereby racemising the starting material via its achiral meso
form) allows for efficient DKR. Processes involving α-alkylated-
succinic anhydrides are much less studied.
Parallel kinetic resolution (where both enantiomers of the
starting material react but form non-enantiomeric products) of
chiral α-alkyl succinic anhydrides has been reported. Seebach
and co-workers12 showed that in the presence of a stoichio-
metric Ti-complex, that the net transfer of isopropanol to
anhydride 14 could occur in a face-selective manner to
γ-Butyrolactones substituted at each saturated carbon consti-
tute a highly important structural motif in organic chemistry
which serve as scaffolds in a wide range of complex natural
products such as 1–3 (Fig. 1A).1 Derivatives bearing
a
β-substituted carboxylic acid moiety to the carbonyl group are
known as paraconic acids (4)2 – an important butyrolactone
natural product subclass (e.g. 5–7) possessing diverse biologi-
cal activities2,3 (Fig. 1B).
The development of one-pot catalytic asymmetric methods
for the preparation of these important structural cores
remains a challenge which attracts considerable attention.4,5
In particular, such a methodology for the construction of the
often-encountered α-methyl substituted analogues is not
known. These methylated butyrolactones are precursors (via
an α-selenation/oxidation/β-elimination sequence6) to the
widely bioactive α-methylene-γ-butyrolactones (e.g. 8, Fig. 1B)
which have been estimated to be present in over 14 000 natural
products.7
School of Chemistry Trinity Biomedical Sciences Institute, Trinity College Dublin
152-160, Pearse Street, Dublin 2, Ireland. E-mail: connons@tcd.ie;
Tel: +35318961306
†Electronic supplementary information (ESI) available: Procedures for the synth-
eses of starting materials, catalysts and additional data: NMR spectra of the pro-
ducts, HPLC chromatograms, etc. CCDC 1866833 and 1866834. For ESI and crys-
tallographic data in CIF or other electronic format see DOI: 10.1039/c8ob02248h
‡X-Ray crystallography facility: twamleyb@tcd.ie
Fig. 1 Natural products incorporating the trisubstituted butyrolactone
motif.
7574 | Org. Biomol. Chem., 2018, 16, 7574–7578
This journal is © The Royal Society of Chemistry 2018

View Article Online
Organic & Biomolecular Chemistry
Communication
Table 1 Catalyst screening
Conv.a
Entry Cat. t (h) (%)
dra 26
(a : b : c : d)
eeb (%)
26a
eeb (%) 25 S*
1
2
3
4
5
6
7
8
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
20
48
72 70d
96 37
120 33
96 32
96 37
96 30
168 44
216 52d
168 44
168 42
168 40
168 43
96 46
168 35
144 43
168 45
168 46
168 46
144 43
120 45
96 46
n.d.c
n.d.c
10
n.d.c 72 : <1 : <1 : 28
3
n.d.c 58 : <1 : <1 : 42 15
1.7
n.d.c 63 : <1 : <1 : 37 17
1.3 80 : <1 : <1 : 20 12
n.d.c 94 : <1 : <1 : 6 41
59 : <1 : <1 : 41 14
n.d.c
6
n.d.c
35
26
40
43
3.6
2.0
4.5
5.9
4.0
2.7
3.6
79 : <1 : <1 : 21 30
90 : <1 : <1 : 10 36
64 : <1 : <1 : 36
9
6
10
11
12
13
14
15
16
17
18
19
20
21
22
23
65 : <1 : <1 : 35 10
76 : <1 : <1 : 24 30
82 : <1 : <1 : 18 21
69 : <1 : <1 : 31 29
33
27
37
n.d.c
n.d.c
50
n.d.c 67 : <1 : <1 : 33 33
n.d.c 81 : <1 : <1 : 19 57
6.7
3.9
1.1
2.6
5.8
5.4
95 : <1 : <1 : 5 59
94 : <1 : <1 : 6 56
82 : <1 : <1 : 18
97 : <1 : <1 : 3 48
96 : <1 : <1 : 4 47
94 : <1 : <1 : 6 47
39
3
26
47
47
64
52
5
168 48
144 48
10.5 95 : <1 : <1 : 5 63
5.9 94 : <1 : <1 : 6 55
Fig. 2 Previous DKR/PKR of anhydrides and the current KR approach.
a Determined by 1H NMR spectroscopy. b Determined by CSP-HPLC,
refers to the major diastereomer. c Not determined. d 24 (0.7 eq.).
produce hemiesters 15–16.13 In 2001, Deng and Chen14 devel-
oped an efficient, modified cinchona alkaloid-catalysed simul-
taneous enantioselective and regioselective alcoholysis of the
two enantiomers of the racemic anhydride 17 – leading to the
formation of enantioenriched hemiesters 18a–b.
To the best of our knowledge, the simple kinetic resolution
of an α-substituted anhydride which provides access to
enantioenriched unreacted anhydride starting material is
unknown.
Herein we report the development of the first KR of asym-
metrically substituted racemic anhydrides, which also rep-
resents an exceedingly rare example of the challenging cata-
lytic kinetic resolution of a racemic enolate.15 In the presence
of a novel sulfamide catalyst 20, anhydrides such as 19 could
be resolved via reaction with substoichiometric aldehydes to
yield densely functionalised γ-butyrolactone products 22 with
up to 19 : 1 dr and 94% ee. The slower reacting anhydride
enantiomer can be derivatised in situ for HPLC analysis to
yield enantioenriched 2,3-asymmetrically disubstituted succi-
nate derivatives 21 – a highly important class of 1,4-dioxyge-
nated synthetic building block in natural product – and medic-
inal chemistry.16
Our study began with a catalyst screen (Table 1). The
2-methyl-3-phenyl succinic anhydride (rac)-23 was reacted with
4-nitro benzaldehyde (0.5 eq., 24) in the presence of catalyst
(5 mol%) in MTBE at ambient temperature (Fig. 3). The reac-
tions were quenched with MeOH (150 eq.) and both the ring
opened hemiesters (derived from unreacted 23) and the
lactone carboxylic acid stemming from the reaction were esteri-
Fig. 3 Catalysts designed for use in anhydride KR.
This journal is © The Royal Society of Chemistry 2018
Org. Biomol. Chem., 2018, 16, 7574–7578 | 7575

View Article Online
Communication
Organic & Biomolecular Chemistry
fied (to give 25 and 26 respectively) in situ through the addition tion with selectivity generally regarded as synthetically useful
of trimethylsilyldiazomethane. The results of these experi- (i.e. S* > 10, entry 22). This allows the isolation of both the
ments are outlined in Table 1. While 25 was always formed stereochemically dense lactone 26a (with excellent diastereo-
with near perfect diastereocontrol, this product does possesses control) and the unreacted enantioenriched anhydride deriva-
more than one stereogenic centre, so the determination of the tive (i.e. the asymmetrically disubstituted succinate ester 25)
conversion-independent selectivity factor (S = kfast/kslow) is not with >60% ee at ca. 50% conversion. The incorporation of a C-
straightforward. Therefore, in these studies we utilised an 2 phenyl unit into catalyst 20 was not advantageous (entry 23).
approximate, simplified parameter S*,15 based on conversion We also utilised benzaldehyde and hydrocinnamaldehyde as
determined by 1H NMR spectroscopy and the ee data associ- reacting partners, with inferior results (see ESI†).
ated with the major product diastereomer only, which served
Attention next turned to the question of substrate scope. A
solely as a guide for catalyst design. Use of the prototype urea range of 2,3-disubstituted succinic anhydrides in which either
and thiourea-substituted cinchona alkaloid catalysts17 (both the alkyl- or the aryl unit was varied could be resolved via reac-
with and without the C-2 aryl modification) 27–30 provided tion with 27 in the presence of catalyst 20 to form (after deriva-
poor levels of diastereocontrol and enantiodiscrimination tisation) succinate esters 49–56 and γ-butyrolactones 57–64
(entries 1–4).
with moderate-good selectivity factors (S*, Table 2). In general,
Squaramide-based bifunctional systems18 were next investi- substitution of the anhydride’s aromatic ring with an electron-
gated: the simple N-aryl catalyst 31 exhibited a similar level of withdrawing group led to faster but less selective resolution
performance to (thio)ureas 27–30 (entry 5), however an analogue (i.e. products 49–52 and 57–60). Extension of the aromatic sub-
where a phenyl unit had been installed at the catalyst’s stituent also attenuated enantioselectivity (i.e. 53 and 61). It
quinoline ring (i.e. 32) promoted the highly diastereoselective seems likely that interactions with the catalyst in the preferred
formation of the major lactone 26a with 41% ee at 30% conver-
sion (entry 6). Squaramides characterised by the exchange of
the N-aryl moiety for an N-alkyl group (despite considerable
Table 2 Evaluation of substrate scope
structure diversity) promoted less selective catalysis (entries
7–14).
We next evaluated the monoprotic yet more acidic sulfona-
mide-based alkaloid catalyst family – which have previously
been shown19 to effectively catalyse the enantioselective
addition of nucleophiles to meso-anhydrides. This catalyst class
proved superior: the hindered, mesityl-substituted material 41
allowed the preparation of 26a (with good diastereocontrol)
with considerably higher ee (and at higher conversion – which
does not favour the formation of the product with high ee) than
the hitherto best catalyst evaluated (compare entries 6 and 15).
Augmentation of the steric demand of the sulfonamide aryl sub-
stituent (i.e. catalyst 42) provided excellent diastereocontrol and
a marginal improvement in product ee at similar conversion
(i.e. 43, entry 16), however the addition of the catalyst C-2
phenyl unit is not beneficial (entry 17). Increasing the steric
bulk around the sulfonamide hydrogen-bond donor through
the synthesis and evaluation of the diphenyl catalyst 44 proved
a retrograde step (entry 18).
Given that we obtained encouraging results with both hin-
dered squaramides and sulfonamides, we hypothesised that a
sulfamide catalyst capable of both participating in bifurcated
hydrogen bonding (similar to squaramides) but with acidity
more akin to the successful sulfonamide class could serve as a
superior promoter of the process. Several groups20 have uti-
lised sulfamides as organocatalysts, however their incorpor-
ation into a cinchona alkaloid backbone is, to the best of
our knowledge, unknown. While 45 promoted resolutions
twice as enantioselectively as its squaramide variant 31 (S* =
1.3 vs. 2.6, entries 5 and 19), when the steric bulk of the sulfa-
a Isolated yield. b dr determined by 1H NMR spectroscopic analysis. ee
mide substituent is systematically increased (entries 20–22),
enantioselectivity improves dramatically, leading to the ada-
mantly-substituted catalyst 20, which can mediate the resolu-
determined using CSP-HPLC. S* = ln[(1 − C)(1 − eeSM)]/ln[(1 − C)(1 +
eeSM)]. c Data reproduced from Table 1. d Enantiomeric excess after
recrystallisation from CHCl3 indicated in parentheses.
7576 | Org. Biomol. Chem., 2018, 16, 7574–7578
This journal is © The Royal Society of Chemistry 2018

View Article Online
Organic & Biomolecular Chemistry
Communication
Notes and references
1 (a) H. M. R. Hoffmann and J. Rabe, Angew. Chem., Int. Ed.
Engl., 1985, 24, 94; (b) S. S. C. Koch and A. R. Chamberlin,
Studies in Natural Products Chemistry, ed. Atta-ur-Rahman,
Elsevier Science, 1995, vol. 16, p. 687.
2 R. Bandichhor, B. Nosse and O. Reiser, Top. Curr. Chem.,
2005, 243, 43.
3 (a) M. S. Maier, D. I. G. Marimon, C. A. Stortz and
M. T. Adler, J. Nat. Prod., 1999, 62, 1565; (b) B. K. Park,
M. Nakagawa, M. A. Hirota and M. Nakayama, J. Antibiot.,
1988, 41, 751.
Fig. 4 Stereochemical rationale.
4 B. Mao, M. Fañanás-Mastral and B. L. Feringa, Chem. Rev.,
2017, 117, 10502.
transition state are hampered (relative to the other aromatic
substrates) in this instance. With regards to the alkyl substitu-
ents: ethyl- and propyl-substituted analogues (i.e. leading to
products 54–55 and 62–63) could be resolved with S* of 7.6
and 7.7 respectively, while the bulkier isopropyl-variants 56
and 64 were formed in a less selective process which still had
an associated S* of 5.3.
A single recrystallisation of the major lactone diastereomer
produced by the reaction afforded an enantiomerically pure
sample of 57 (>99% ee) which was suitable for single crystal
X-ray diffraction pattern analysis (see ESI†). The absolute con-
figuration of 57 (Fig. 3) was subsequently assigned as (S,S,S).21
5 Selected other reviews: (a) I. Collins, J. Chem. Soc., Perkin
Trans. 1, 1998, 1869; (b) N. B. Carter, A. E. Nadany and
J. B. Sweeney, J. Chem. Soc., Perkin Trans. 1, 2002, 2324;
(c) M. Seitz and O. Reiser, Curr. Opin. Chem. Biol., 2005, 9,
285; (d) R. R. A. Kitson, A. Millemaggi and R. J. K. Taylor,
Angew. Chem., Int. Ed., 2009, 48, 9426; (e) S. Gil, M. Parra,
P. Rodriguez and J. Segura, Mini-Rev. Org. Chem., 2009, 6,
345.
6 For examples of such transformations see: (a) A. F. Barrero,
A. Rosales, J. M. Cuerva and J. E. Oltra, Org. Lett., 2003, 5,
1935; (b) F. F. P. Arantes, L. C. A. Barbosa, E. S. Alvarenga,
A. J. Demuner, D. P. Bezerra, J. R. O. Ferreira, L. V. Costa-
Lotufo, C. Pessoa and M. O. Moraes, Eur. J. Med. Chem.,
2009, 44, 3739.
A
stereochemical rationale consistent with the calculated
mechanism9h for these types of reactions is presented in Fig. 4.
In summary, we have developed the first kinetic resolution
(in the traditional sense) of racemic chiral anhydrides. The
reaction provides access to resolved enantioenriched anhy-
drides for the first time, which can be ring-opened and esteri-
fied in situ to form synthetically valuable 2,3-disubstituted suc-
cinate esters. The resolution processes were accompanied with
the simultaneous formation of stereochemically dense
α-alkylated γ-butyrolactones via control over 3 contiguous
stereocentres (one quaternary) with modest to excellent
enantioselectivity (up to 94% ee, S* = 10.5) and excellent dia-
stereocontrol. These reactions were mediated by a new class of
chiral sulfamide bifunctional catalysts based on a cinchona
alkaloid scaffold, the bulkiest of which bears an adamantyl
unit and easily outperforms more traditional bifunctional cata-
lyst structures in this process. Studies to further improve the
performance and scope of this new KR process as well as the
evaluation of the potential of the novel alkaloid-based sulfa-
mide organocatalysts are underway.
7 R. R. A. Kitson, A. Millemaggi and R. J. K. Taylor, Angew.
Chem., Int. Ed., 2009, 48, 9426.
8 F. Manoni, C. Cornaggia, J. Murray, S. Tallon and
S. J. Connon, Chem. Commun., 2012, 48, 6502.
9 For related reactions see: (a) C. Cornaggia, F. Manoni,
E. Torrente, S. Tallon and S. J. Connon, Org. Lett., 2012, 14,
1850; (b) F. Manoni and S. J. Connon, Angew. Chem., Int.
Ed., 2014, 53, 2628; (c) C. Cornaggia, S. Gundala,
F. Manoni, N. Gopalasetty and S. J. Connon, Org. Biomol.
Chem., 2016, 14, 3040; (d) S. A. Cronin, A. Gutiérrez Collar,
S. Gundala, C. Cornaggia, E. Torrente, F. Manoni, A. Botte,
B. Twamley and S. J. Connon, Org. Biomol. Chem., 2016, 14,
6955; (e) F. Manoni, U. Farid, C. Trujillo and S. J. Connon,
Org. Biomol. Chem., 2017, 15, 1463; (f) C. L. Jarvis,
J. S. Hirschi, M. J. Vetticatt and D. Seidel, Angew. Chem.,
Int. Ed., 2017, 56, 2670; (g) U. Nath and S. C. Pan, J. Org.
Chem., 2017, 82, 3262; (h) C. Trujillo, I. Rozas, A. Botte and
S. J. Connon, Chem. Commun., 2017, 53, 8874.
10 For a review of this type of reaction (racemic) see:
M. González-López and J. T. Shaw, Chem. Rev., 2009, 109,
164.
11 R. Claveau, B. Twamley and S. J. Connon, Chem. Commun.,
2018, 54, 3231.
Conflicts of interest
There are no conflicts to declare.
12 G. Jaeschke, K. Gottwald, K. Matsuda, R. Formisano,
D. A. Chaplin and D. Seebach, Tetrahedron, 1977, 53, 7539.
13 For related stoichiometric parallel kinetic resolutions see:
(a) I. Schiffers, C. L. Dinter, L. Defrère, A. Gerlach,
G. Raabe and C. Bolm, Synthesis, 2001, 1719; (b) Y. Uozumi,
Acknowledgements
This publication has emanated from research supported by
the Science Foundation Ireland (SFI – 12-IA-1645).
This journal is © The Royal Society of Chemistry 2018
Org. Biomol. Chem., 2018, 16, 7574–7578 | 7577

View Article Online
Communication
Organic & Biomolecular Chemistry
K. Yasoshima, T. Miyachi and S.-i. Nagai, Tetrahedron Lett.,
2001, 42, 411.
14 Y. Chen and L. Deng, J. Am. Chem. Soc., 2001, 123, 11302.
15 For examples see the following (and referenced cited therein):
E. Sorrentino and S. J. Connon, Org. Lett., 2016, 18, 5204.
2008, 1208; (b) S. H. Oh, H. S. Rho, J. W. Lee, J. E. Lee,
S. H. Youk, J. Chin and C. E. Song, Angew. Chem., Int. Ed.,
2008, 47, 7872; (c) A. Peschiulli, B. Procuranti,
C. J. O’Connor and S. J. Connon, Nat. Chem., 2010,
2, 380.
16 For examples see the following (and referenced cited 20 (a) X.-J. Zhang, S.-P. Liu, X.-M. Li, M. Yan and
therein): M. P. DeMartino, K. Chen and P. S. Baran, J. Am.
Chem. Soc., 2008, 130, 11546.
A. S. C. Chan, Chem. Commun., 2009, 7, 833; (b) J.-R. Chen,
L. Fu, Y.-Q. Zou, N.-J. Chang, J. Rong and W.-J. Xiao, Org.
Biomol. Chem., 2011, 9, 5280; (c) S. Tortoioli, S. Bacchi,
C. Tortoreto, J. B. Strachana and A. Perboni, Tetrahedron
Lett., 2012, 53, 1878; (d) T. C. Nugent, A. Sadiq, A. Bibi,
T. Heine, L. L. Zeonjuk, N. Vankova and B. S. Bassil, Chem.
– Eur. J., 2012, 18, 4088.
17 (a) B.-J. Li, L. Jiang, M. Liu, Y.-C. Chen, L.-S. Ding and
Y. Wu, Synlett, 2005, 603; (b) B. Vakulya, S. Varga,
A. Csámpai and T. Soós, Org. Lett., 2005, 7, 1967;
(c) S. H. McCooey and S. J. Connon, Angew. Chem., Int. Ed.,
2005, 44, 6367; (d) J. Ye, D. J. Dixon and P. S. Hynes, Chem.
Commun., 2005, 4481.
18 For the seminal example see: J. P. Malerich, K. Hagihara
and V. H. Rawal, J. Am. Chem. Soc., 2008, 130, 14416.
19 For representative examples see: (a) H. S. Rho, S. H. Oh,
J. W. Lee, J. Y. Lee, J. Chin and C. E. Song, Chem. Commun.,
21 The stereochemical assignment of diester 25 was made fol-
lowing a combination of 1H NMR spectroscopic analysis
and by analogy with the absolute stereochemistry of the
cognate lactone product (known from XRD analysis) – see
the ESI.†
7578 | Org. Biomol. Chem., 2018, 16, 7574–7578
This journal is © The Royal Society of Chemistry 2018