Dynamic kinetic resolution of bis-aryl succinic anhydrides: Enantioselective synthesis of densely functionalised γ-butyrolactones

Article abstract of DOI:10.1039/c8cc00609a

The efficient Dynamic Kinetic Resolution (DKR) of disubstituted anhydrides has been shown to be possible for the first time. Using an ad hoc designed organocatalyst and an enantio- and diastereoselective cycloaddition process with aldehydes, stereochemically complex γ-butyrolactone derivatives can be obtained-with control over three contiguous stereocentres, one of which is all carbon quaternary.

Full text of DOI:10.1039/c8cc00609a

ChemComm
View Article Online
View Journal
COMMUNICATION
Dynamic kinetic resolution of bis-aryl succinic
anhydrides: enantioselective synthesis of densely
functionalised c-butyrolactones†
Cite this:DOI: 10.1039/c8cc00609a
Received 24th January 2018,
Accepted 2nd March 2018
Romain Claveau, Brendan Twamley‡ and Stephen J. Connon
*
DOI: 10.1039/c8cc00609a
rsc.li/chemcomm
The efficient Dynamic Kinetic Resolution (DKR) of disubstituted
anhydrides has been shown to be possible for the first time. Using an
ad hoc designed organocatalyst and an enantio- and diastereoselective
cycloaddition process with aldehydes, stereochemically complex
c-butyrolactone derivatives can be obtained – with control over three
contiguous stereocentres, one of which is all carbon quaternary.
Stereochemically dense g-butyrolactones form the core of a
considerable proportion (which has been estimated at ca. 10%)
of natural products which possess remarkably diverse biological
activities1 – of which the paraconic acids2 would be typical (Fig. 1A).
The development of one-pot catalytic methods for the rapid,
enantioselective construction of these privileged structural units
continues to challenge synthetic chemists and the topic has very
recently been reviewed.3,4 A recently developed, attractive and
simplifying approach involves the face-selective coupling of achiral
partners with readily prepared racemic chiral materials with
concomitant Dynamic Kinetic Resolution,5 such the recent con-
struction of lactones 3 from the racemic a-ketoesters 1 and enals
2 using homoenolate chemistry.6
Fig. 1 g-Butyrolactones and the dearth of anhydride resolution processes.
the starting material leading to the formation of optically active
Anhydrides have been used as acylation agents for over 100 mono esters 5 and 6 (Fig. 1B). Recently, we have shown that aryl
years7 and are often used as the electrophilic component of an succinic anhydrides of general type (rac)-7 undergo efficient DKR
Kinetic Resolution (KR) reaction8 involving a racemic nucleo- during a formal cycloaddition reaction with aldehydes to form
phile. However, despite their enormous synthetic utility, their substituted butyrolactones only if the aryl units were equipped
use as the subject of resolution processes (i.e. the resolution of with electron withdrawing substituents.10–12 To the best of our
chiral anhydrides) is entirely undeveloped. In 2001, Deng et al. knowledge represents the sum total of what is known concerning
reported the first catalytic Parallel Kinetic Resolution (PKR) of the catalytic resolution of anhydrides.
monosubstituted succinic anhydrides (4) promoted by a chiral
More stereochemically complex substituted anhydrides are less
amine catalyst.9 The process involved the simultaneous enantio- studied still: the desymmetrisation of meso-disubstituted anhydrides
selective and regioselective alcoholysis of the two enantiomers of (i.e. the conversion of (meso)-10 to 11) is a well-established
process,13–15 however, (D)KR processes involving racemic trans-
anhydrides are completely unknown, despite the potential
efficiencies with regard to controlling the configuration at
multiple stereocentres during a single coupling operation.
Herein we report the highly selective DKR of diaryl succinic
anhydrides of general type (rac)-12 (via the in situ formed
enolates12g (rac)-12a) as nucleophilic coupling partners in a catalytic
asymmetric cycloaddition with a range of aromatic and aliphatic
School of Chemistry Trinity Biomedical Sciences Institute, Trinity College Dublin,
152-160 Pearse Street, Dublin 2, Ireland. E-mail: connons@tcd.ie;
Tel: +353 18961306
† Electronic supplementary information (ESI) available: Procedures for the syntheses of
starting materials, catalysts and additional data: NMR spectra of the products, HPLC
chromatograms, etc. CCDC 1578091 and 1578092. For ESI and crystallographic data in
CIF or other electronic format see DOI: 10.1039/c8cc00609a
‡ X-Ray Crystallography Facility. E-mail: twamleyb@tcd.ie
This journal is ©The Royal Society of Chemistry 2018
Chem. Commun.

View Article Online
Communication
ChemComm
formation12g led to the formation of the diastereomeric products
17a–d (obtained after esterification with trimethylsilyldiazo-
methane in order to facilitate CSP-HPLC analysis) with a pre-
ference for 17a (entry 2). The use of either urea catalyst 18 or its
C-2 arylated analogue 19 allowed for the formation of the same
lactones with moderate diastereo- and enantiocontrol (entries 3
and 4). The exchange of the urea functionality for the thiourea16
(i.e. 20–21) led to comparable results (entries 5 and 6). Improve-
ments were observed upon evaluation of their squaramide
analogues (i.e. 22–23).17 These catalysts promoted reactions with
excellent diastereoselectivity – the major lactone 17a was formed
as almost the sole product (entries 7 and 8). While these
encouraging results indicated that two-stereocentre DKR of
enolisable anhydrides was possible – the enantioselectivity of
the process remained far from useful.
Table 1 Catalyst screening
Given the disappointing levels of enantiocontrol obtained, it
seemed clear that a change in the catalyst structure of more
consequence was necessary. The recently developed tert-butyl-
substituted squaramide catalysts 24 and 25 (previously successful
in a catalytic Tamura cycloaddition reaction involving enolisable
glutaconic anhydride with alkyldiene oxindoles)6 proved to be rather
inefficient (entries 9 and 10). Interestingly, as was the case with
catalysts 19, 21 and 23, the introduction of a C-2 phenyl substituent
on the catalyst’s quinoline led to improved performance.
Augmentation of the N-alkyl substituent’s steric requirement
from a tert-butyl to a trityl moiety (i.e. catalysts 26 and 27) resulted
in an unexpected outcome. The observed diastereoselectivity
was marginally diminished but reversed in favor of 17d, along
with dramatic improvement in enantioselectivity up to 95% ee
(entries 11 and 12). Further attempts to influence the stereocontrol
of the process through modification of the trityl group’s steric and
electronic characteristics were unproductive (i.e. 28–29, entries 13
and 14). After a short optimisation study, (see ESI†) attention now
turned to the question of the substrate scope with respect to the
aldehyde component (Table 2). The methodology proved to be
rather robust: the anhydride (rac)-15 was reacted in a 1 : 1 ratio with
electron-deficient (i.e. lactones 31–36), electron-neutral (i.e. lactones
37–38), electron-rich (i.e. lactone 39) and heterocyclic (i.e. lactone
40) aromatic aldehydes in the presence of catalyst 26 (5 mol%) at
ambient temperature.
Catalyst T (h) Conv.a (%) drb 17 (a : b : c : d) eeb (%) 17 (a : d)
Entry
1
2
3
4
5
6
7
8
—
24
0
—
— : —
0 : 0
10 : 81
i-Pr2NEtc 24
87
83
83
78
87
86
84
84
86
81
68
98
98
81 : 14 : 4 : 1
18
19
20
21
22
23
24
25
26
27
28
29
48
48
48
48
48
48
48
48
73 : o1 : o1 : 27
63 : o1 : o1 : 37
68 : o1 : o1 : 32
67 : o1 : o1 : 33
97 : o1 : o1 : 3
94 : o1 : o1 : 6
70 : o1 : o1 : 30
84 : o1 : o1 : 16
35 : o1 : o1 : 65
37 : o1 : o1 : 63
50 : o1 : o1 : 50
37 : o1 : o1 : 63
40 : 79
24 : n.d.d
38 : n.d.d
31 : n.d.d
42 : n.d.d
8 : 89
9
10
11
12
13
14
41 : n.d.d
30 : 95
144
120
48
26 : 85
33 : 90
34 : 83
Substrates reacted smoothly, with the exception of the less
electrophilic aldehydes which furnished lactones 39 and 40.
While diastereocontrol was variable, enantioselectiviy was generally
high-excellent (85–99% ee). Aliphatic aldehydes are also compatible:
hydrocinnamaldehyde was demonstrated to serve as an excellent
96
a
b
Determined by 1H NMR spectroscopy. Determined by CSP-HPLC.
c
d
20 mol%. Not determined.
aldehydes 13 to form tetrasubstituted g-butyrolactone/paraconic acid substrate, providing the corresponding lactone 41 in high yield,
derivatives with three stereocentres (one all carbon quaternary). The excellent dr and 499% ee. The lactone derived from the bulkier
reaction is mediated by a novel bulky bifunctional catalyst and the cyclohexane carbaldehyde (i.e. 42) was also formed in near optical
scope is no longer restricted to anhydrides bearing electron deficient purity and good yield albeit with diminished diastereoselectivity
aromatic substituents.
(Table 2).
The stereochemical configuration of lactones 31–42 was
The results of our preliminary experiments into the cycloaddi-
tion of diphenyl succinic anhydride (15) to para-nitrobenzaldehyde assigned using a combination of H NMR Nuclear Overhauser
(16) in MTBE12a–d catalysed by a series of Cinchona alkaloid based Effect (NOE) experiments and crystal X-ray diffraction pattern
1
organocatalysts are presented in Table 1.
analysis (Fig. 2).
In the absence of catalyst or base, no reaction occurs (Table 1,
We had previously shown that the ease of enolate formation
entry 1). The use of Hu¨nig’s base as a catalyst to facilitate enolate is key to the success of this class of process.10,12g Bearing in
Chem. Commun.
This journal is ©The Royal Society of Chemistry 2018

View Article Online
ChemComm
Communication
Table 2 Substrate scope: the electrophilic component
Table 3 Substrate scope: the anhydride component
a
dr determined by 1H NMR spectroscopy analysis of the unpurified
reaction mixture using 4-iodoanisole as an internal standard. Here
P
dr = (major diastereomer):( other diastereomers). Isolated yield of the
b
major diastereomer in parentheses. Data reproduced from Table 2.
c
d
As a mixture of diastereomers. Reaction at À30 1C.
a
dr determined by 1H NMR spectroscopic analysis of the unpurified
reaction mixture using 4-iodoanisole as an internal standard. Here
P
46–48 could be obtained with dramatically enhanced diaster-
dr = (major diastereomer):( other diastereomers). Isolated yield of the
major diastereomer and/or ee of the minor diastereomer in parentheses eocontrol, (up to 34 : 1 dr, 98% ee).18 The dibromo anhydride
b
where available. 10 mol% catalyst used.
derivative 43 was also reacted with representative electron
neutral, electron rich and electron deficient aromatic aldehydes
to give the highly functionalised lactones 49–51 (Table 3).
Again, significant improvements in both the efficiency and
diastereoselectivity of the process were observed. The metho-
dology also tolerates functionality in the aldehyde electrophile –
the protected amino-aldehyde-derived lactone 52 could be
prepared with excellent levels of diastereo- and enantiocontrol
in a one pot process. Since the hydro-debromination of aryl
units is trivial,19 the use of (rac)-43 allows the circumvention of
the drawbacks in terms of reaction rate and diastereocontrol
associated with (rac)-15.
Highly substituted piperidines and their precursor piperidones
are very common motifs in both natural products/drug molecules
and methods to access them via asymmetric synthesis have been
intensively investigated.20 To demonstrate the potential utility and
malleability of the methodology outlined above, the lactone 52
(19 : 1 dr, 90% ee) was deprotected with TFA to afford 53 in near
quantitative yield. Amine 53 then underwent a room temperature
intramolecular amidation to yield the piperidonyl g-lactone 54a in
high yield and 86% ee (Scheme 1). Notably, the product resulting
from the attack at the methyl ester was dominant: none of the
regioisomeric product 54b was detected.
mind that for efficient DKR to occur, enolisation at both a-carbon
atoms of the anhydride must be significantly faster than the rate of
reaction of the enolate derived from the slow reacting anhydride
enantiomer, we supposed that the installation of electron with-
drawing groups on the anhydride’s aryl substituents could impact
both activity and selectivity by (i) increasing both the rate of enolate
formation and the rate of racemisation relative to cycloaddition and
(ii) stabilising the enolate; thereby affording greater scope for
catalyst-mediated enantiodiscrimination. To test this hypothesis,
we prepared the modified anhydrides 43–45 equipped with bromo-,
trifluromethyl- and nitro functionality respectively and evaluated
them in the cycloaddition process with various aldehydes (Table 3).
Beginning with the reaction involving hydrocinnamaldehyde,
under conditions identical to those used in Table 2 we observed
some background reaction with each of the new anhydride sub-
strates, indicating significantly faster reaction rates. Gratifyingly,
upon cooling (i.e. to À15 1C), good to excellent product yields of
In summary, we have developed the first DKR reaction
involving a trans-substituted anhydride. Using an ad hoc developed
squaramide based organocatalyst, a range of electron-rich/
electron-deficient/heterocyclic aromatic and aliphatic aldehydes
Fig. 2 Absolute configuration assignment of lactones 37 and 41.
This journal is ©The Royal Society of Chemistry 2018
Chem. Commun.

View Article Online
Communication
ChemComm
7 A. Verley and F. Bølsing, Ber. Dtsch. Chem. Ges., 1901, 34, 3354.
8 Selected reviews: (a) J. M. Keith, J. F. Larrow and E. N. Jacobsen, Adv.
Synth. Catal., 2001, 343, 1615; (b) E. Vedejs and M. Jure, Angew.
Chem., Int. Ed., 2005, 44, 3974; (c) A. C. Spivey and P. McDaid, in
Enantioselective Organocatalysis, ed. P. I. Dalko, Wiley-VCH Verlag
GmbH & Co. KGaA, Weinheim, 2007, p. 287; (d) A. C. Spivey and
S. Arseniyadis, in Asymmetric Organocatalysis, ed. B. List, Springer,
Heidelberg, 2009, p. 233; (e) C. E. Mu¨ller and P. R. Schreiner, Angew.
Chem., Int. Ed., 2011, 50, 6012.
9 Y. Chen and L. Deng, J. Am. Chem. Soc., 2001, 123(45), 11302.
10 M. F. Manoni, C. Cornaggia, J. Murray, S. Tallon and S. J. Connon,
Chem. Commun., 2012, 48, 6502.
´
11 For a review of this type of cycloaddition (racemic) see: M. Gonzalez-
´
Lopez and J. T. Shaw, Chem. Rev., 2009, 109, 164.
12 For related catalytic asymmetric processes involving cycloadditions with
enolisable anhydrides 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.
Scheme 1 Sequential deprotection–lactamisation of
product.
a cycloaddition
can participate in a unique, one-pot formal cycloaddition with
disubstituted enolisable anhydrides to afford highly functiona-
lised butyrolactone (paraconic acid) synthetic building blocks
with good-excellent control over three product stereocentres, one
of which is all-carbon quaternary in nature. The ready manip-
ulation of one of the products to form a stereochemically dense
fused lactone–lactam system was also demonstrated. Modifica-
tion of the anhydride to increase its enolisability led to faster,
more efficient and selective lactone formation. Studies to further
explore the scope of this methodology are underway in our
laboratory.
´
Chem., 2016, 14, 3040; (d) S. A. Cronin, A. Gutierrez 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) C. Trujillo, I. Rozas, A. Botte and S. J. Connon,
Chem. Commun., 2017, 53, 8874.
13 For selected reviews detailing anhydride desymmetrisation by
alcoholysis see: (a) Y. Cheng, P. McDaid and L. Deng, Chem. Rev.,
2003, 103, 2965; (b) S.-K. Tian, Y. Chen, J. Hang, L. Tang, P. McDaid
and L. Deng, Acc. Chem. Res., 2004, 37, 621; (c) Z. Rodriguez-Docampo
and S. J. Connon, ChemCatChem, 2012, 4, 151.
14 Selected examples of anhydride desymmetrisation by thiolysis:
(a) T. Honjo, S. Sano, M. Shiro and Y. Nagao, Angew. Chem., Int. Ed.,
´
2005, 44, 5838; (b) A. Peschiulli, C. Quigley, S. Tallon, Y. K. Gunko and
This publication has emanated from research supported by
the Science Foundation Ireland (SFI – 12-IA-1645).
S. J. Connon, J. Org. Chem., 2008, 73, 6409; (c) A. Peschiulli, B. Procuranti,
C. J. O’Connor and S. J. Connon, Nat. Chem., 2010, 2, 380.
15 Selected examples of anhydride alkylative desymmetrisation: (a) E. A.
Bercot and T. Rovis, J. Am. Chem. Soc., 2002, 124, 174; (b) E. A. Bercot and
T. Rovis, J. Am. Chem. Soc., 2005, 127, 247; (c) E. E. Stache, T. Rovis and
A. G. Doyle, Angew. Chem., Int. Ed., 2017, 56, 3679.
Conflicts of interest
There are no conflicts to declare.
16 (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. Csampai and T. Soos, 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.
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.
17 These are derivatives of catalysts first introduced by Rawal et al.:
J. P. Malerich, K. Hagihara and V. H. Rawal, J. Am. Chem. Soc., 2008,
130, 14416.
18 As a control experiment, different ratios (trans)-43 : (meso)-43 were
evaluated and yielded identical product mixtures proving that it
reacts via an analogue to enolate (rac)-12a (Fig. 1C).
19 For recent examples of the use of a bromo-substituent as a removable
tool to influence substrate control see: (a) C. A. Rose, S. Gundala,
K. Zeitler and S. J. Connon, Synthesis, 2011, 190; (b) S. P. Curran and
S. J. Connon, Angew. Chem., Int. Ed., 2012, 51, 10866.
20 Selected reviews: (a) D. L. Comins and S. P. Joseph, in Advances in
Nitrogen Heterocycles, ed. C. J. Moody, JAI, Greenwich, CT, 1996, vol. 2,
pp. 251–294; (b) P. D. Bailey, P. A. Millwood and P. D. Smith, Chem.
Commun., 1998, 633; (c) H.-P. Husson and J. Royer, Chem. Soc. Rev.,
1999, 28, 383; (d) S. Laschat and T. Dickner, Synthesis, 2000, 1781;
(e) P. M. Weintraub, J. S. Sabol, J. M. Kane and D. R. Borcherding,
Tetrahedron, 2003, 59, 2953; ( f ) N. Toyooka and H. Nemoto, in Studies
in Natural Products Chemistry, ed. Atta-ur-Rahman, Elsevier, Amsterdam
(The Netherlands), 2003, vol. 29, pp. 419–448; (g) M. G. P. Buffat,
Tetrahedron, 2004, 60, 1701; (h) M. S. M. Pearson, M. MathL-Allainmat,
V. Fargeas and J. Lebreton, Eur. J. Org. Chem., 2005, 2159; (i) J. Cossy,
Chem. Rec., 2005, 5, 70.
˜
´
3 B. Mao, M. Fananas-Mastral and B. L. Feringa, Chem. Rev., 2017,
117, 10502.
4 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.
5 Selected reviews on DKR: (a) R. Noyori, M. Tokunaga and
M. Kitamura, Bull. Chem. Soc. Jpn., 1995, 68, 36; (b) S. Caddick and
K. Jenkins, Chem. Soc. Rev., 1996, 25, 447; (c) F. F. Huerta, A. B. E.
¨
Minidis and J.-E. Backvall, Chem. Soc. Rev., 2001, 30, 321; (d) J. Steinreiber,
K. Faber and H. Griengl, Chem. – Eur. J., 2008, 14, 8060; (e) H. Pellissier,
Tetrahedron, 2008, 64, 1563; ( f ) H. Pellissier, Adv. Synth. Catal., 2011,
353, 659.
6 C. G. Goodman, M. M. Walker and J. S. Johnson, J. Am. Chem. Soc.,
2015, 137, 122.
Chem. Commun.
This journal is ©The Royal Society of Chemistry 2018