Catalytic Asymmetric γ-Lactam Synthesis from Enolisable Anhydrides and Imines

Article abstract of DOI:10.1002/chem.201901028

An anion-binding approach to the problem of preparing enantioenriched γ-lactams from enolisable anhydrides and imines is reported. A simple bisurea catalyst promotes the cycloaddition between α-aryl succinic anhydrides and either PMP- or benzhydryl-protec

Full text of DOI:10.1002/chem.201901028

DOI: 10.1002/chem.201901028
Communication
&
Synthetic Methods |Hot Paper|
Catalytic Asymmetric g-Lactam Synthesis from Enolisable
Anhydrides and Imines
Aarꢀn Gutiꢁrrez Collar, Cristina Trujillo, Bruce Lockett-Walters, Brendan Twamley, and
Stephen J. Connon*[a]
Abstract: An anion-binding approach to the problem of
preparing enantioenriched g-lactams from enolisable an-
hydrides and imines is reported. A simple bisurea catalyst
promotes the cycloaddition between a-aryl succinic anhy-
drides and either PMP- or benzhydryl-protected aldimines
to provide g-lactams with two contiguous stereocentres
(one quaternary) with complete diastereocontrol and high
to excellent enantioselectivity for the first time. A DFT
study has provided insight into the catalyst mode of
action and the origins of the observed stereocontrol.
g-Lactams are a structural unit prevalent in a large number of
natural products/medicinally relevant molecules, and as such,
methods for their synthesis are highly prized.[1] Often these lac-
tams are stereochemically dense and arylated. Examples (Fig-
ure 1A) are the hepatoprotective, anti-viral hepatitis and anti-
Alzheimer’s disease natural product (À)-clausenamide (1)[2,3]
and the transcription factor inhibitor (rac)-2; which was effi-
ciently prepared as a racemate by Shaw and co-workers[4] by
using a Castagnoli–Cushman-type cycloaddition[5] between an
imine and an enolisable anhydride, as no catalytic enantiose-
lective version of this reaction was available.[6]
The construction of these motifs is not trivial. Sheidt[7] has
reported that hydrazide 3 could be reacted with enals such as
cinnamaldehdye (4) in the presence of a binary catalyst system
comprising the chiral N-heterocyclic carbene precursor 5 and a
magnesium salt to furnish the syn-heterocycle 6 in 78% yield
and excellent ee and d.r. (Figure 1B; ee=enantiomeric excess;
Figure 1. g-Lactam molecules of medicinal interest and selected catalytic
asymmetric g-lactam syntheses. TDB=1,5,7-triazabicyclo[4.4.0]dec-5-ene;
DBU=1,8-diazabicyclo[5.4.0]undec-7-ene; MTBE=methyl tert-butyl ether;
TMSCHN2 =trimethylsilyldiazomethane.
d.r.=diastereomeric ratio). NÀN bond reduction could subse-
quently be carried out to yield the g-lactam analogue. Very re-
cently, Bolm and co-workers[8] have disclosed an efficient enan-
tioselective methodology for the synthesis of analogous bis-C-
arylated trans-g-lactams such as 10 with excellent stereocon-
trol through the formal [3+2] cycloaddition of o-hydroxy aro-
matic imines such as 7 and enal 8 employing a chiral N-hetero-
cyclic carbene precatalyst 9 and base (Figure 1C).[9]
Seidel, Vetticatt, and co-workers[10] have very recently dis-
closed an elegant anion-binding approach to asymmetric cy-
cloadditions between imines and homophthalic anhydride to
produce 3,4-dihydroisoquinolones (see the preceding Commu-
nication in this issue, DOI: 10.1002/chem.201900119). The reac-
tion is highly efficient; however only homophthalic anhydride
was used as the enolate precursor, meaning that all products
contained the specific fused bicyclic dihydroisoquinolone core.
Previously, we had developed a mechanistically distinct (less
enantioselective) organocatalytic cycloaddition between homo-
[a] A. G. Collar, Dr. C. Trujillo, B. Lockett-Walters, Dr. B. Twamley,
Prof. S. J. Connon
School of Chemistry Trinity Biomedical Sciences Institute
Trinity College Dublin
152-160 Pearse Street, Dublin 2 (Ireland)
E-mail: connons@tcd.ie
Supporting information and the ORCID identification number(s) for the
author(s) of this article can be found under:
https://doi.org/10.1002/chem.201901028.
Chem. Eur. J. 2019, 25, 1 – 6
1
ꢂ 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
&
These are not the final page numbers! ÞÞ

Communication
phthalic anhydride and N-mesyl imines.[11] Again, only the use
of homophthalic anhydride was possible. Homophthalic anhy-
dride (pKa =8.2)[12] is a substrate particularly well-disposed to-
wards enolate formation, however most anhydrides do not
possess the requisite acidity for deprotonation by an amine or
imine to occur significantly at room temperature. Consequent-
ly, the substrate scope with respect to the anhydride compo-
nent is now the key challenge associated with these potential-
ly very powerful cycloadditions.
Table 1. Catalyst screening.
Following our application of Seidel’s anion-binding[13] ap-
proach to the Tamura cycloaddition (see the preceding Com-
munication in this issue) we herein report the expansion of the
scope of the process involving the cycloaddition of simple
imines 11 by utilising a-substituted succinic anhydrides 12[14,15]
in the presence of the simple catalyst 13 to yield enantioen-
riched trisubstituted g-lactams 14 with excellent enantio- and
diastereocontrol (Figure 1D) through anion binding catalysis
(13a).
We began by investigating the influence of various hydro-
gen bond-donating catalysts on the cycloaddition between the
p-methoxyphenyl
(PMP)-protected
benzaldehyde-derived
imine 15 and the p-nitrophenyl-substituted succinic anhydride
16 in MTBE at ambient temperature. To facilitate CSP-HPLC
analysis the carboxylic acid unit was esterified after reaction
with methanol/trimethylsilyldiazomethane to yield the g-
lactam 17 (Table 1).
Entry
Catalyst
T
[8C]
t
[h]
Conversion
[%][a]
d.r.[b]
(syn/anti)
ee
[%][c]
1
2
3
4
5
6
7
8[d]
18
19
20
21
13
18
13
13
RT
20
20
20
20
20
24
24
47
>99
>99
>99
>99
>99
>99
>99
>99
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
80
78
69
88
91
83
90
82
RT
RT
RT
RT
0
Catalyst 18 (entry 1), which promoted highly enantioselec-
tive cycloadditions in Seidel’s study involving homophthalic
anhydride, promoted the formation of 17 as a single diastereo-
mer with 80%ee. Its tert-butyl substituted analogue 19 (de-
signed as part of the Tamura cycloaddition optimisation pro-
cess, see the preceding Communication in this issue) proved
less effective here (entry 2). Interestingly, use of Nagasawa’s
catalyst 20[16] (entry 3) led to only moderate product ee, where-
as a mixed urea/thiourea variant 21 allowed catalysis to pro-
ceed with substantially improved enantiocontrol (entry 4). This
prompted the evaluation of the bisurea analogue 13 (entry 5),
which allowed for the formation of 17 with near perfect diaste-
reocontrol and in 91%ee. Further investigation of the use of
both 18 and 13 at lower temperatures failed to deliver superi-
or stereocontrol (entries 6–8). It is interesting that 13—which
Seidel had shown to be an effective anion-binding-catalyst for
acyl transfer[17] but was a less effective chiral catalyst in the
Tamura chemistry in the preceding Communication in this
issue—is superior here. This is advantageous from a practical
perspective considering that 13 is readily prepared in a single
step from commercially available starting materials.
0
À15
1
[a] Determined by H NMR spectroscopy using p-iodoanisole as the inter-
nal standard. [b] Diastereomeric ratio (determined by 1H NMR spectrosco-
py). [c] Determined by CSP-HPLC (CSP=chiral stationary phase), see Sup-
porting Information. [d] Concentration 0.1m.
Attention next turned to the imine component (Scheme 2)
through the reaction of various imines 31 with the nitrophenyl
succinic anhydride 16 in the presence of catalyst 13 to afford
lactams of general type 31. Given that the mechanism most
likely proceeds via deprotonation of the anhydride by the
imine and organisation of the resulting ion pair by the catalyst
(vide infra),[10] it is perhaps unsurprising that lactams derived
from more electron-rich imines (i.e., 32 and 33) were formed
with excellent enantiocontrol. Again, these materials were
formed as a single diastereomer. The introduction of methoxy
substituents in the 3- and 5-positions (OMe, sM =0.10) attenu-
ated enantiomeric excess (i.e., 34 and 35): a single methoxy
group was tolerated but addition of a second led to a large re-
duction in product ee and slower product formation. The PMP-
protected imine derived from p-bromobenzaldehyde could un-
dergo cycloaddition with 16 to form lactam 36 in high ee. Sim-
ilar levels of enantiocontrol were observed when the imine
bore 5-membered aromatic heterocycles (i.e., 37 and 38). The
benzhydryl protecting group is also compatible: lactam 39 was
generated with similar (but marginally lower) levels of enantio-
A variety of substituted aryl succinic anhydrides are compati-
ble with the catalytic process. Substitution which facilitates
enolate formation allows for smooth catalyst-mediated forma-
tion of g-lactams 24 from the anisaldehyde-derived PMP-pro-
tected imine 22[18] and various anhydrides 23 (Scheme 1). In-
stallation of nitrile- (i.e., 25), bistrifluoromethyl- (i.e., 26 and
27), dibromo- (i.e., 28), nitro- (i.e., 29) and trifluoro-substituted
(i.e., 30) phenyl units on the succinic anhydride allowed the
isolation of the desired g-lactams in ꢀ90% yield, >99:1d.r.
and ꢀ95%ee in all cases.
&
&
Chem. Eur. J. 2019, 25, 1 – 6
www.chemeurj.org
2
ꢂ 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!

Communication
Scheme 1. Substrate scope: the anhydride component.
control to 32. At this juncture imines-derived from aliphatic al-
dehydes appear to provide products with dramatically reduced
enantioselectivity, albeit with high yield and excellent diaste-
reocontrol (i.e., 40)
Scheme 2. Substrate scope: the imine component.
A DFT study (M062X/6-311+G**//M062X/6-31G*, SMD-diiso-
propylether, 298 K) was useful in rationalising the formation of
the observed lactam antipodes. The free energy profile for the
formation of both enantiomers of 30 (Figure 2) indicates that
cyclisation is both essentially irreversible and rate determining.
The catalyst organises the iminium-enolate ion pair to facilitate
the Mannich-type step with a barrier associated with eventual
formation of the major product enantiomer 3.7 kcalmolÀ1
lower than that associated with the minor antipode. A similar
situation is calculated to arise at the cyclisation stage: ring-clo-
sure to the major enantiomer is characterised by a barrier
4.9 kcalmolÀ1 lower that its counterpart leading to the minor
product (Figure 2). Overall barriers are higher than
calculated for the asymmetric Tamura chemistry (see
the preceding Communication in this issue)—consis-
tent with the need for ambient temperature required
for lactam generation as opposed to the smooth cy-
cloadditions observed at À408C in the Tamura pro-
cess.
catalyst 13,which did not emerge as the optimum promoter
either our study on Tamura cycloadditions, was superior in this
process and also sheds light on the catalyst-substrate interac-
tions which render aromatic aldehyde-derived imines consider-
ably more amenable to highly enantioselective cycloaddition
than aliphatic analogues. Catalyst 13 forms a discernible hy-
drophobic “pocket” between its bis(trifluoromethyl)phenyl
rings in which the imine aromatic unit resides [and interacts
with through multiple p–p interactions identified by quantum
theory of atoms in molecules (QTAIM) calculations, see Sup-
To probe the origins of the observed sense of
asymmetric induction, we examined the transition
states associated with the key first stereocentre
forming Mannich-like step reaction step for both
major and minor enantiomers (Figure 3). The binding
mode was analogous to that calculated by Seidel
and Vetticat for anion binding catalysis involving
imines and homophthalic anhydride.[10]
Inspection of the calculated transition state lead-
ing to the major antipode (R,S)-30 (Figure 3, top)
allows for appreciation of why the simple bisurea
Figure 2. Calculated (DFT) free energy profile associated with the formation of both
enantiomers of 30.
Chem. Eur. J. 2019, 25, 1 – 6
www.chemeurj.org
3
ꢂ 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
&
These are not the final page numbers! ÞÞ

Communication
als—to afford stereochemically dense g-lactam products,
which are the core of natural products and molecules of phar-
macological value with outstanding diastereocontrol and high-
excellent enantiocontrol. DFT calculations indicate a catalyst
mode of action involving selective binding of the enolate and
iminium ion components and the creation of a pocket be-
tween the catalyst aromatic rings, in which the imine sits. This
allows for the rationalisation of the stereocontrol observed in
the process.
Acknowledgements
This publication has emanated from research supported by the
Science Foundation Ireland (SFI-12-IA-1645). We are grateful to
the Irish Centre for High-End Computing (ICHEC) for the provi-
sion of computational facilities. We are indebted to Dr. Goar
Sꢅnchez from ICHEC for the AIM graphical outputs.
Conflict of interest
The authors declare no conflict of interest.
Keywords: cyclic anhydrides · cycloadditions · DFT · imines ·
lactams
Figure 3. Calculated (DFT) lowest energy transition state structures associat-
ed with both enantiomers of 30.
[1] For a recent review concerning biologically active lactams see: J. Carua-
no, G. G. Mucciolib, R. Robiette, Org. Biomol. Chem. 2016, 14, 10134.
[2] W. Hartwig, L. Born, J. Org. Chem. 1987, 52, 4352.
[3] For a review see: S.-F. Chu, J.-T. Zhang, Acta Pharm. Sin. B 2014, 4, 417.
[4] P. Y. Ng, Y. Tang, W. M. Knosp, H. S. Stadler, J. T. Shaw, Angew. Chem. Int.
Ed. 2007, 46, 5352; Angew. Chem. 2007, 119, 5448.
[5] a) N. Castagnoli, J. Org. Chem. 1969, 34, 3187; b) N. Castagnoli, M.
Cushman, J. Org. Chem. 1971, 36, 3404; c) M. Cushman, N. Castagnoli, J.
Org. Chem. 1972, 37, 1268; d) M. Cushman, N. Castagnoli, J. Org. Chem.
1974, 39, 1546; e) M. Cushman, N. Castagnoli, J. Org. Chem. 1973, 38,
440.
[6] For an excellent review of the racemic process see: M. Gonzꢅlez-Lꢀpez,
J. T. Shaw, Chem. Rev. 2009, 109, 164.
[7] D. E. A. Raup, B. Cardinal-David, D. Holte, K. A. Scheidt, Nat. Chem. 2010,
2, 766.
[8] S. Dong, M. Frings, D. Zhang, Q. Guo, C. G. Daniliuc, H. Cheng, C. Bolm,
Chem. Eur. J. 2017, 23, 13888.
[9] For representative other NHC-catalysed methodologies for g-lactam
synthesis see: a) M. He, J. W. Bode, Org. Lett. 2005, 7, 3131; b) M.
Rommel, T. Fukuzumi, J. W. Bode, J. Am. Chem. Soc. 2008, 130, 17266;
c) X. Zhao, D. A. DiRocco, T. Rovis, J. Am. Chem. Soc. 2011, 133, 12466;
d) B. Zhang, P. Feng, L.-H. Sun, Y. X. Cui, S. Ye, N. Jiao, Chem. Eur. J.
2012, 18, 9198; e) H. Lv, B. Twari, J. Mo, C. Xing, Y. G. Chi, Org. Lett.
2012, 14, 5412.
[10] C. L. Jarvis, J. S. Hirschi, M. J. Vetticatt, D. Seidel, Angew. Chem. Int. Ed.
2017, 56, 2670; Angew. Chem. 2017, 129, 2714.
[11] S. A. Cronin, A. G. Collar, S. Gundala, C. Cornaggia, E. Torrente, F.
Manoni, A. Botte, B. Twamley, S. J. Connon, Org. Biomol. Chem. 2016, 14,
6955.
[12] N. Mofaddel, N. Bar, D. Villemin, P. L. Desbꢆne, Anal. Bioanal. Chem.
2004, 380, 664.
[13] Representative recent reviews on anion-binding catalysis: a) J. Lacour,
D. Moraleda, Chem. Commun. 2009, 7073; b) Z. Zhang, P. R. Schreiner,
Chem. Soc. Rev. 2009, 38, 1187; c) S. Beckendorf, S. Asmus, O. G. Man-
porting Information] in the transition state. This, together with
the binding of the iminium ion NÀH proton to one of the urea
carbonyl groups, aligns the electrophile. This may explain why
imines incorporating more electron-rich aromatic rings provide
products with higher ee, considering that could better interact
with the catalyst relatively electron-deficient bis(trifluorome-
thyl)phenyl substituents which comprise the boundary of the
pocket. The other catalyst urea moiety is involved in stabilising
the nucleophilic reaction component via double hydrogen
bond donation to the enolate oxygen atom and its neighbour.
The transition state leading to the minor (S,R)-30 enantiomer
(Figure 3, bottom) occurs considerably later (i.e. the CÀC dis-
tance for the forming bond is 0.08 ꢃ shorter in the transition
state leading to (S,R)-30 than the corresponding distance in
the transition state leading to (R,S)-30). The anhydride enolate
must be bound through its less basic oxygen atoms to achieve
a Bꢄrgi–Dunitz trajectory. In addition, the PMP group occupies
the now less pronounced “pocket” and interacts only weakly
with the catalyst aromatic rings (see Supporting Information),
which likely contributes to the 3.7 kcalmolÀ1 difference in barri-
er heights calculated.
In summary, the development of the first highly enantiose-
lective cycloaddition reactions between imines and succinic
anhydrides is reported. This broadens the scope beyond dihy-
droisoquinolone products for the first time. The reaction does
not require specialised imines incorporating electron-with-
drawing (basicity dampening) groups at nitrogen. Aromatic N-
PMP imines react with a-aryl succinic anhydrides in the pres-
ence of an exceedingly simple catalyst—which can be pre-
pared in one step from commercially available starting materi-
ˇ
cheno, ChemCatChem 2012, 4, 926; d) R. J. Phipps, G. L. Hamilton, F. D.
Toste, Nat. Chem. 2012, 4, 603; e) J.-F. Briꢆre, S. Oudeyer, V. Dalla, V. Le-
vacher, Chem. Soc. Rev. 2012, 41, 1696; f) M. Mahlau, B. List, Angew.
Chem. Int. Ed. 2013, 52, 518; Angew. Chem. 2013, 125, 540; g) K. Brak,
&
&
Chem. Eur. J. 2019, 25, 1 – 6
www.chemeurj.org
4
ꢂ 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!

Communication
E. N. Jacobsen, Angew. Chem. Int. Ed. 2013, 52, 534; Angew. Chem. 2013,
125, 558; h) D. Seidel, Synlett 2014, 25, 783; i) N. H. Evans, P. D. Beer,
Angew. Chem. Int. Ed. 2014, 53, 11716; Angew. Chem. 2014, 126, 11908;
j) N. Busschaert, C. Caltagirone, W. Van Rossom, P. A. Gale, Chem. Rev.
2015, 115, 8038.
Commun. 2017, 53, 8874; g) R. Claveau, B. Twamley, S. J. Connon, Chem.
Commun. 2018, 54, 3231; h) M. L. Aiello, U. Farid, C. Trujillo, B. Twamley,
S. J. Connon, J. Org. Chem. 2018, 83, 15499; i) H. Xu, F. Sha, Q. Li, X. Y.
Wu, Org. Biomol. Chem. 2018, 16, 7214.
[16] Y. Sohtome, A. Tanatani, Y. Hashimoto, K. Nagasawa, Tetrahedron Lett.
2004, 45, 5589.
[17] a) C. K. De, E. G. Klauber, D. Seidel, J. Am. Chem. Soc. 2009, 131, 17060;
b) N. Mittal, K. M. Lippert, C. K. De, E. G. Klauber, T. J. Emge, P. R. Schrein-
er, D. Seidel, J. Am. Chem. Soc. 2015, 137, 5748.
[14] For the use of these anhydrides in mechanistically distinct catalytic
asymmetric cycloadditions with aldehydes see: F. Manoni, C. Cornaggia,
J. Murray, S. Tallon, S. J. Connon, Chem. Commun. 2012, 48, 6502.
[15] For related catalytic asymmetric reactions involving enolisable anhy-
drides see: a) C. Cornaggia, F. Manoni, E. Torrente, S. Tallon, S. J.
Connon, Org. Lett. 2012, 14, 1850; b) F. Manoni, S. J. Connon, Angew.
Chem. Int. Ed. 2014, 53, 2628; Angew. Chem. 2014, 126, 2666; c) C. Cor-
naggia, S. Gundala, F. Manoni, N. Gopalasetty, S. J. Connon, Org. Biomol.
Chem. 2016, 14, 3040; d) F. Manoni, U. Farid, C. Trujillo, S. J. Connon,
Org. Biomol. Chem. 2017, 15, 1463; e) U. Nath, S. C. Pan, J. Org. Chem.
2017, 82, 3262; f) C. Trujillo, I. Rozas, A. Botte, S. J. Connon, Chem.
[18] N-Allyl- and N-benzhydryl imines provided products with considerably
lower enantiomeric excess (>40%ee).
Manuscript received: March 5, 2019
Version of record online: && &&, 0000
Chem. Eur. J. 2019, 25, 1 – 6
www.chemeurj.org
5
ꢂ 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
&
These are not the final page numbers! ÞÞ

Communication
COMMUNICATION
The scope of the asymmetric cycload-
dition between simple imines and anhy-
drides has been expanded to include
highly enantioselective synthesis of g-
lactams for the first time.
&
Synthetic Methods
A. G. Collar, C. Trujillo, B. Lockett-Walters,
B. Twamley, S. J. Connon*
&& – &&
Catalytic Asymmetric g-Lactam
Synthesis from Enolisable Anhydrides
and Imines
&
&
Chem. Eur. J. 2019, 25, 1 – 6
www.chemeurj.org
6
ꢂ 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!