Diastereoselective Synthesis of and Mechanistic Understanding for the Formation of 2-Piperidinones from Imines and Cyano-Substituted Anhydrides

Article abstract of DOI:10.1002/chem.201504424

2-Piperidinones are synthesized in a single step from imines and 2-cyano glutaric anhydrides. The reaction provides the products in good diastereoselectivity and generates a quaternary stereogenic center. Substitutions on the anhydride skeleton are well tolerated to provide 2-piperidinones with three stereogenic centers from a single transformation. The pertinent transition structures have also been computed using quantum mechanics and reveal the key interactions controlling the stereochemical outcome of the reaction.

Full text of DOI:10.1002/chem.201504424

DOI: 10.1002/chem.201504424
Full Paper
&
Synthetic Methods
Diastereoselective Synthesis of and Mechanistic Understanding
for the Formation of 2-Piperidinones from Imines and Cyano-
Substituted Anhydrides
Michael J. Di Maso,[a] Kevin M. Snyder,[b] Fµbio De Souza Fernandes,[a, c]
Ommidala Pattawong,[b] Darlene Q. Tan,[a] James C. Fettinger,[a] Paul Ha-Yeon Cheong,*[b] and
Jared T. Shaw*[a]
Abstract: 2-Piperidinones are synthesized in a single step
from imines and 2-cyano glutaric anhydrides. The reaction
provides the products in good diastereoselectivity and gen-
erates a quaternary stereogenic center. Substitutions on the
anhydride skeleton are well tolerated to provide 2-piperidi-
nones with three stereogenic centers from a single transfor-
mation. The pertinent transition structures have also been
computed using quantum mechanics and reveal the key in-
teractions controlling the stereochemical outcome of the re-
action.
Introduction
only recently have other substituted anhydrides been shown
to work in the reaction and provide high levels of diastereose-
lectivity; furthermore, nearly all reactions of this type have fo-
cused on the use of succinic anhydrides to form 2-pyrrolidones.
Recently, we reported on reactions of sulfone-substituted
succinic and glutaric anhydrides with imines to provide lac-
tams in high yields and diastereoselectivity.[5] This was the first
report using an activated glutaric anhydride in a Castagnoli-
type reaction. The success of those studies paired with our
previous work on synthesis of g-lactams (2-pyrrolidinones)
from cyanosuccinic anhydrides prompted us to explore the re-
actions of glutaric anhydrides, which would form d-lactams (2-
piperidinones). These products, which would have a quaternary
stereogenic center at the 5-position of the ring, are a common
motif seen in Aspidosperma and Kopsia alkaloids along with
other useful compounds (Figure 1).[2d]
Lactams and their reduced nitrogen heterocycle counterparts
are found in a variety of natural products and pharmaceutical
compounds.[1] The six-membered ring version of these cores
(2-piperidinones and piperidines) are particularly prevalent in
natural products and bioactive small molecules. Additionally
these structures have found use as protein secondary structure
mimics, which can act to disrupt protein–protein interac-
tions.[1d] The prevalence and utility of this simple core has re-
sulted in the development of many synthetic methods.[2]
The diastereoselective synthesis of these core structures has
driven the research in our group for several years.[3] The formal
cycloaddition of imines with substituted anhydrides provides
these valuable core structures. While anhydrides are typically
relegated to acylating alcohols and amines, their use as a nucle-
ophilic source of carbon dates back to the work of Perkin in
1868.[4] The reaction to form lactams was discovered by Cas-
tagnoli and developed significantly by Haimova and Cush-
man.[4] While this reaction has successfully been used for sever-
al applications using substituted homophthalic anhydride,[4e]
Our computational studies into the mechanism of the
cyano-substituted succinic anhydride-Mannich reaction (AMR)
suggest that the enol-tautomer of the anhydride (enol-4)
reacts with the imine (Scheme 1A)[6] in a Mannich fashion
which can provide either diastereomer of product 6.[7] The two
diastereomers then undergo an intramolecular acylation cycli-
zation to furnish the lactams. Scheme 1B shows the relevant
torsional interactions that drive the overall diastereoselectivity
of the reaction. The large eclipsing interactions in 6b prevent
the molecule from adopting the required geometry to under-
go acylation, thus leading to selective formation of 7-syn. We
thus determined that the selectivity in these reactions result
from a combination of torsional steering, hyperconjugation,
stabilizing electrostatic and transannular steric effects
(Scheme 1B).
[a] M. J. Di Maso, F. De Souza Fernandes, Dr. D. Q. Tan, Dr. J. C. Fettinger,
Prof. J. T. Shaw
Department of Chemistry, University of California, Davis
One Shields Avenue Davis, CA 95616 (USA)
E-mail: jtshaw@ucdavis.edu
[b] K. M. Snyder, O. Pattawong, Prof. P. H.-Y. Cheong
Department of Chemistry Oregon State University
153 Gilbert Hall Corvallis, OR 97331 (USA)
[c] F. De Souza Fernandes
Current address: Department of Chemistry, Federal University of Juiz de
Fora, Campus Martelos Juiz de Fora, MG 36036-330 (Brazil)
Herein, we describe the synthesis of 2-piperidones with
a quaternary stereogenic center along with additional support
for our working mechanistic hypothesis.
Supporting information and the ORCID identification numbers for the au-
thors of this article can be found under http://dx.doi.org/10.1002/
chem.201504424.
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forms the double alkylation product, we were able to synthe-
size multigram quantities of the desired diester. Hydrolysis of
the diester with lithium hydroxide followed by dehydration
with trifluoroacetic anhydride (TFAA) provided the anhydride
on multigram scale [Eq. (1)].
With the anhydride in hand, we tested a variety of solvents
in the reaction with commercially available N-benzylidene-
methylamine (Table 1). Use of tetrahydrofuran, the optimal sol-
vent for reaction of cyanosuccinic anhydride, provided the an-
ticipated d-lactam product in good yield with little diastereose-
lectivity. A variety of solvents provided only minor variations in
the diastereoselectivity, so we continued our studies using tet-
rahydrofuran.
Figure 1. A) Natural products and pharmaceutical active synthetic com-
pounds containing 2-piperidinones or 2-piperidines with a quaternary ste-
reogenic center at the 5-position B) Synthesis of 2-piperidinones from substi-
tuted glutaric anhydrides.
Table 1. Initial solvent screen for the cyano-glutaric AMR.[23]
Entry
Solvent
d.r.
Yield [%]
1
2
3
4
5
6
THF
53:47
67:33
46:54
57:43
57:43
56:44
90
CH3CN
CHCl3
CH2Cl2
Et2O
n.d.
n.d.
n.d.
n.d.
n.d.
EtOH
n.d.=not determined.
Our computed results for the AMR reaction involving N-ben-
zylidenemethylamine (1a) and cyano-glutaric anhydride 2a are
summarized in Figure 2. All geometry optimizations were car-
ried out at the B3LYP[9]/6-31G*[10]/PCM(THF)[11] level of theory,
as implemented in the Gaussian09 suite of programs.[12] The
[14]
energy refinements were performed at SCS-MP2[13]/def2-1
as implemented in ORCA.[15] Final solvation corrections were
computed at the B3LYP/6-31+G**/PCM(THF) level of theory.[16]
The Mannich is the rate-determining step (RDS) for the
major diastereomeric product (DDG° =6.6 kcalmolÀ1), whereas
the acylation is the RDS for the minor (DDG° =7.2 kcalmolÀ1).
Theory predicted much poorer diastereoselectivity in this case
(glutaric anhydride AMR, DDG° =0.6 kcalmolÀ1) compared to
the succinic anhydride AMR (DDG° =1.8 kcalmolÀ1).[6]
Scheme 1. A) The computed mechanism for the cyano-substituted succinic
anhydride Mannich reaction. B) The major torsional interaction responsible
for diastereoselectivity (cyano-substituent omitted for clarity).
Results and Discussion
We began our studies with the synthesis of cyano-substituted
glutaric anhydride 2a for use in AMR. Synthesis of the anhy-
dride was realized by the enolate alkylation of ethyl cyanoace-
tate with ethyl bromopropionate.[8] While this reaction quickly
The selectivity of this reaction is determined by the compari-
son between the Mannich step of the major product and the
acylation of the minor. The selectivity in the Mannich step is
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Table 2. Effects of the steric demand of the N-substituent on the diaste-
reoselectivity of the reaction.[23]
Entry
Product
R1
d.r.
Yield [%]
1
2
3
4
5
3b
3c
3d
3e
3 f
nPr
iPr
Ph
p-OCH3-C6H4
p-Et-C6H4
55:45
68:32
87:13
91:9
84
79
45
59
59
94:6
We explored a variety of anilines and aldehydes to test their
effects on the diastereoselectivity of the reaction (Table 3).
Recent studies in our group have revealed that isolation and
purification of the imines results in increased yields in the sub-
sequent AMR reaction;[5] therefore, we applied this approach
to our current system and noticed a similar increase in yield.
The reaction tolerates a variety of electron-donating and elec-
tron-withdrawing substituents around the aldehyde or aniline
component; however, very electron-rich systems (entries 1 and
11) provide significant reductions in the reaction yield. Use of
the regioisomeric m-anisaldehyde (entry 4) provides product in
high yield. The ortho-substitution on the aniline increased the
diastereoselectivity. Adding
a
second ortho-substituent
(entry 8) provided a single diastereomer of product. Additional-
ly, cinnamaldehyde (entry 5) worked well in the reaction, albeit
with a decrease in the diastereoselectivity that, presumably,
stems from the decreased steric demand near the reacting
atoms of the imine.
The computed diastereoselectivity of the reaction between
N-benzylideneaniline and cyano-glutaric anhydride 2a is
4.5 kcalmolÀ1 (Figure 3). Theory (SCS-MP2//B3LYP) predicted
Figure 2. Computed Mannich and acylation transition states involving N-
benzylidenemethylamine (1a) and cyano-glutaric anhydride (2a).[17]
nearly nonexistent, as observed previously.[6] The selectivity in
the acylation is determined by two factors in the Minor-Acyla-
tion-TS (Figure 2): 1) torsional steering: the eclipsing interac-
tion between the phenyl and the adjacent methyl group,
which accounts for the majority of selectivity in the succinic
anhydride AMR; 2) transannular steric interactions (shown in
red).[7] The reduced selectivity is due to reduced eclipsing
around the former imine CÀN bond, resulting in diminished
torsional steering effect in the six-membered glutaric anhy-
dride transition state compared to the five-membered succinic
anhydride system.
Table 3. Substrate scope for the cyano-glutaric AMR.
Entry Product R1
R2
d.r.
Yield [%]
1
2
3
4
5
6
7
8
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
3q
p-OCH3-C6H4
p-OCH3-C6H4
p-OCH3-C6H4
p-OCH3-C6H4
p-OCH3-C6H4
C6H5
p-OCH3-C6H4
p-NO2-C6H4
2-furyl
m-OCH3-C6H4
(E)-PhCHCH
p-OCH3-C6H4
p-OCH3-C6H4
72:28 20
90:10 53
89:11 72
83:17 65
80:20 51
84:16 67
We proceeded to synthesize a variety of N-substituted
imines to determine if increasing steric demand around the ni-
trogen would affect the diastereoselectivity (Table 2). Although
the increased steric demand of various alkyl groups showed
modest improvement, aniline-derived imines were immediately
more selective, which suggests that there might be a dual
steric and electronic origin to the observed diastereoselectivity.
p-Et-C6H4
92:8
59[a]
64[a]
2,5,-OCH3-4-Cl-C6H2 p-OCH3-C6H4 >95:5
9
10
11
3,4-OCH2O-C6H3
3,5-diCl-C6H3
o-OCH3-C6H4
p-OCH3-C6H4
p-OCH3-C6H4
p-OCH3-C6H4
87:13 53[a]
90:10 76[a]
87:13 38
[a] Yield of major diastereomer.
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the experimental stereoisomer but over-predicted the diaste-
reoselectivity by 3.4 kcalmolÀ1. We investigated whether this
overestimation was the result of inadequacy of the final
energy refinement methods (Table 4). We therefore computed
the B2GP-PLYP[18]/def2-1 energies—a high accuracy double
hybrid DFT method, which occupy the fifth rung of Jacob’s
ladder in DFT hierarchy[19]—in addition to Truhlar’s 87M06-
2X.[20] However, the resulting computed diastereoselectivities
deviated even more significantly, leading us to believe that the
error may be the result of the inability of B3LYP geometry to
capture dispersion interactions between the two adjacent
phenyl rings observing in transition state.[21] Indeed, re-optimi-
zation coupled with SCS-MP2 single points resulted in impres-
sive correlation between the experimental and theoretical se-
lectivity for 3d (À0.3 vs. À0.4 kcalmolÀ1 experiments). Howev-
er, this method predicted the wrong diastereomeric product
for the previously published succinic anhydride analogue of
3a by 1.7 kcalmolÀ1, and was unsuitable for this study.
tivity mainly arises from torsional steering effects around the
now proximal substituents of the imine and increased transan-
nular steric repulsion in the minor acylation transition structure
(Minor-Acylation-TS-3d, Figure 3).
With a firmer grasp on the origins of selectivity in this reac-
tion, we wondered if the acylation step could be attenuated
by the addition of substituents along the anhydride backbone.
Michael addition of ethyl cyanoacetate to four different acry-
late esters provided diester precursors to additional anhydrides
with methyl or phenyl substituents in the b- or g-positions.
These Michael reactions provide a mixture of diastereomers
that are carried forward to the final anhydrides. The lack of dia-
stereoselectivity in the Michael addition is inconsequential
given that one stereogenic center undergoes enolization
during the anhydride Mannich reaction. Hydrolysis of the
esters with lithium hydroxide followed by dehydration with tri-
fluoroacetic anhydride provided our desired anhydrides
[Eq. (2)].
Interestingly, the SCS-MP2//B3LYP//PCM(THF) method was
superior to all other methods studied, including any combina-
tion involving B2GP-PLYP or M06-2X, regardless of whether the
geometries were B3LYP or M06-2X based (Table 4). In any case,
the computed Mannich and acylation transition structures in-
volving N-benzylideneaniline showed that the diastereoselec-
To determine effects on the diastereoselectivity, these substi-
tuted anhydrides were treated with a variety of imines (Table 5
and Table 2). Although the methyl substituted anhydrides pro-
vided the lactam in good yield, mixtures of all four possible
diastereomers were observed in the case of both b- and g-
methyl substitution. Phenyl-substituted anhydrides provided
interesting and divergent results.
Substitution at the b-position provided the desired lactams
in the highest diastereoselectivities we have observed. Even
some larger alkyl substituents (benzyl, and isopropyl) provided
product in good to excellent diastereoselectivity, thus provid-
ing evidence for a more rigid acylation geometry. Substitution
at the g-position proved more cumbersome. Analysis of the
crude NMR spectra of these compounds often showed poor
diastereoselectivity except in the case of a highly substituted
anilines. These observations suggest that while substitution at
the b-carbon of the anhydride enforces a rigid acylation geom-
etry, substitution at the g-carbon not only provides no stabili-
zation, but may destabilize the acylation geometries of the var-
ious Mannich products.
Next, we computationally studied the effect of substituents
at the b-position of cyano-glutaric anhydride on the diastereo-
selectivity (Figure 4), specifically the reaction involving cyano-
glutaric anhydride 2c (d.r. 96:4:0:0, Table 5, entry 4). The Man-
nich and acylation steps are both partially rate-determining for
the major product, while the RDS for the minor is the Mannich.
The computed diastereoselectivity of 1.8 kcalmolÀ1 is in good
agreement with experiment (1.3 kcalmolÀ1).
The Major-Mannich-TS-8d-(S,S,R) is the most stable of all
Mannich transition structures. It experiences the strongest sta-
bilizing attraction from CH···N between base N-amine and
Figure 3. Computed transition structures of the AMR involving N-benzylide-
neaniline and cyano-glutaric anhydride 2a.[16]
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Table 4. Comparison of observed and computed selectivities of AMR reaction under various levels of theory.[a]
Products
Experimental selectivity
DDG° [kcalmolÀ1
]
1.5
0.1
1.1
Geometries+solvation
Energy refinement
B3LYP/6-31G*/PCM(THF)
B3LYP/6-31G*/PCM(THF)
3.5 (2.0)
3.7 (3.6)
8.5 (7.4)
+ B3LYP/6-31+G**/PCM(THF)
“
“
“
SCS-MP2/def2-1
1.8 (0.3)
4.6 (3.1)
4.6 (3.1)
0.6 (0.5)
5.4 (5.3)
6.3 (6.2)
4.5 (3.4)
7.9 (6.8)
8.4 (7.3)
B2GP-PLYP/def2-1
M06-2X/6-311+ +G(2df,p)/PCM(THF)
M06-2X/6-31G*/PCM(THF)
+M06-2X/6-31+G**/PCM(THF)
M06-2X/6-31G*/PCM(THF)
À1.8 (À3.3)
À2.7 (À2.8)
4.2 (3.1)
“
“
“
SCS-MP2/def2-1
À0.2 (À1.7)
3.7 (2.2)
3.5 (2.0)
À0.3 (À0.4)
3.7 (3.6)
5.3 (5.2)
1.3 (0.2)
8.4 (7.3)
7.7 (6.6)
B2GP-PLYP/def2-1
M06-2X/6-311+ +G(2df,p)/PCM(THF)
[a] Values in parenthesis are errors with respect to experiments. See Table S4.1 in the Supporting Information for comparisons using SMD solvation.
to the major due to the axial orientation of one of the phenyl
Table 5. Synthesis of 2-piperidinones with a b-substituted anhydride.[23]
groups. Minor-Acylation-TS-8d-(R,S,S), which has both phenyl
groups in the axial orientation, experiences the most transan-
nular strain and is therefore the most destabilized.
Finally, we studied the effect of substituents at the g-posi-
tion of cyano-glutaric anhydride on the diastereoselectivity
(Figure 5), specifically the reaction involving cyano-glutaric an-
hydride 2e (d.r. 90:10:0:0, Table 6, entry 5). The computed dia-
stereoselectivity of 1.9 kcalmolÀ1 is in good agreement with
experiments (1.3 kcalmolÀ1).
Entry Product R1
R2
R3
d.r.
80:20[b]
92:8:0:0
70:30:0:0
96:4:0:0
>95:<5:0:0 83[a]
Yield
[%]
1
2
3
4
5
8a
8b
8c
8d
8e
Ph
Ph
Ph
Ph
Ph
iPr
Bn
Ph
CH3
Ph
Ph
99
75[a]
50[a]
77[a]
Interestingly, the Major-Mannich-TS-9e-(S,S,S), which is the
RDS for the formation of the major diastereomeric product, is
not the most stable of the Mannich transition structures due
to several steric contacts (shown in red) and relatively poorer
stabilization afforded from the electrostatic interaction be-
tween the iminium proton and the anhydride cyano. The most
Ph
PMP 2,5-OCH3-4-Cl-C6H2 Ph
[a] Yield of major diastereomer. [b] Major/sum of minor diastereomers.
acidic proton on b-carbon of the anhydride (1st row, Figure 4).
While, the Minor-Mannich-TS-8d-(S,S,S), leading to the minor
product, experiences weaker electrostatic stabilization from
NH···p between the iminium proton and the cyano group (2nd
row, Figure 4).
Table 6. Synthesis of 2-piperidinones with a g-substituted anhydride.
In the acylation step, the Major-Acylation-TS-8d-(S,S,R) is
also in the most stable conformation where all the phenyl
groups are in equatorial position. It experiences the most elec-
trostatic stabilizations from CH···O[10] and hydrogen bonding in-
teractions (green, Figure 4).
Entry Product R1
R2
R4
CH3 80:20[b]
d.r.
Yield [%]
It also experiences the least transannular steric destabiliza-
tion (red, Figure 4). Replacing the b-(R)-phenyl group with
methyl decreases the selectivity (d.r. 80:20, Table 5, entry 1),
presumably due to the loss of more stabilizing CH···O stabiliz-
ing interaction (DE for CH3ÀH···OꢀÀ0.1 kcalmolÀ1).[6a] Minor-
Acylation-TS-8d-(S,S,S) and -(R,S,R) are destabilized compared
1
2
3
4
5
9a
9b
9c
9d
9e
Ph
PMP Ph
Ph
Ph
Ph
68
80
Ph
Ph
Ph
95:5:0:0
47:33:13:7 52
34:33:32:0 44[a]
Bn
Ph
PMP 3,5-diCl-C6H3 Ph
90:10:0:0
60[a]
[a] Yield of major diastereomer. [b] Major/sum of minor diastereomers.
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Figure 4. Computed Mannich and acylation transition states involving N-
benzylideneaniline and b-substituted cyano-glutaric anhydride 2c.[16]
Figure 5. Computed Mannich and acylation transition states involving (E)-
3,5-dichloro-N-(4-methoxybenzylidene)aniline and g-substituted cyano-gluta-
ric anhydride (2e).[16]
stable Mannich transition state is Minor-Mannich-TS-9e-
(R,S,S), which leads to a minor diastereomer product. More-
over, in this transition structure, the iminium proton is involved
in a CH···O stabilization[22] with the anhydride enolate oxygen
(shown in blue).
Figure 5). Minor-Acylation-TS-9e-(S,S,R) leads to the minor
diastereomeric product, and is destabilized compared to the
major due to transannular interaction between the axial
proton at the b-carbon and the g-phenyl. Minor-Acylation-TS-
9e-(R,S,S) and -(R,S,R) are destabilized to even greater degrees
by torsional effects between vicinal aryl groups and transannu-
lar steric interactions.
The preference for the observed major product arises from
the instability of all acylation transition structures that lead to
the minor product formation. Major-Acylation-TS-9e-(S,S,S) is
in the most stable configuration where all the aryl groups are
in equatorial positions. It also experiences the greatest degree
of electrostatic stabilizations from CH···O and hydrogen bond-
ing interactions, the least torsional steering and transannular
steric destabilization (green, yellow and red, respectively,
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the mixture was concentrated under reduced pressure. This was re-
peated three times to ensure the removal of trace amounts of tri-
fluoroacetic anhydride. This process provided 2a–e.
Conclusions
We have successfully developed a novel route to synthesizing
2-piperidinones from readily available substituted glutaric an-
hydrides and imines. This new method provides these prod-
ucts in high diastereoselectivity with a quaternary carbon and
up to three contiguous stereogenic centers. These studies into
the synthesis and reactions of cyano-glutaric anhydrides sup-
port our continued efforts into the understanding of the anhy-
dride Mannich reaction. Our various anhydrides provided val-
uable information for our continued efforts in utilizing the
AMR to quickly access densely substituted lactam cores. Addi-
tionally, extending this methodology to use glutaric anhydrides
accesses a class of anhydride that has been underutilized in all
studies of this class of nucleophiles. Our computational work is
consistent with our results from the succinic anhydride in iden-
tifying torsional steering and transannular strain in the acyla-
tion step as the major contributors to the diastereoselectivity
of this reaction.
General procedure B for the synthesis of d-lactams
To a solution of amine (1 equiv), aldehyde (1 equiv) in THF (0.2m)
was added triethyl orthoformate (1.6 equiv) and the reaction mix-
ture was stirred at room temperature for 16 h. Anhydride 2a–
e (1 equiv) was added to the reaction mixture, which was then
stirred for 3 h at room temperature. The solvent was removed
under vacuum and the residue was dissolved in acetone (0.05m
based on the amine). K2CO3 (4 equiv) and iodomethane (4 equiv)
were then added and the reaction was stirred for 16 h. The solvent
was removed under reduced pressure and the residue was taken
up in CH2Cl2 and water and the layers were separated. The aque-
ous layer was extracted twice more with CH2Cl2. The combined or-
ganics were dried over Na2SO4, filtered, and concentrated in vacuo.
Purification by column chromatography afforded the desired lac-
tams.
Further studies in the use of these anhydrides for complex
molecule synthesis and in rendering these reactions enantiose-
lective are ongoing in our laboratory and will be reported in
due course.
General procedure C for the synthesis of d-lactams (3, 8,
and 9)
To a solution of imine in THF (0.2m) was added anhydride 2a–
e (1 equiv). The solution was then stirred for 3 h at room tempera-
ture. The solvent was removed under vacuum and the residue was
dissolved in acetone (0.05m). K2CO3 (4 equiv) and iodomethane
(4 equiv) were then added and the reaction was stirred for 16 h.
The solvent was removed under reduced pressure and the residue
was purified by column chromatography (conditions given for
each compound) to afford the desired lactam.
Experimental Section
General information
Unless otherwise specified, all commercially available reagents
were used as received. All reactions using dried solvents were car-
ried out under an atmosphere of argon in flame-dried glassware
with magnetic stirring. Dry solvent was dispensed from a solvent
purification system that passes solvent through two columns of
dry neutral alumina. 1H NMR spectra and proton-decoupled
13C NMR spectra were obtained on a 400 or 600 MHz Varian NMR
spectrometer. Chemical shifts (d) are reported in parts per million
(ppm) relative to residual solvent (CHCl3, s, d=7.26 ppm). Multiplic-
ities are given as: s (singlet), d (doublet), t (triplet), dd (doublet of
doublets), m (multiplet), brs (broad singlet). 13C NMR chemical
shifts are reported relative to CDCl3 (t, d=77.23 ppm) unless other-
wise noted. Accurate mass measurements were recorded on posi-
tive ESI mode in methanol or acetonitrile. Silica gel chromato-
graphic purifications were performed by flash chromatography
with silica gel (Silicycle, 40–63 mm) packed in glass columns. The
eluting solvent for each purification was determined by thin layer
chromatography (TLC) on glass plates coated with EMD silica gel
50 F254 and visualized by ultraviolet light or by staining ceric am-
monium molybdate (CAM) stain followed by gentle heating. The
following abbreviations are used throughout: ethyl acetate
(EtOAc), hexanes (hex), dichloromethane (CH2Cl2).
Acknowledgements
J.T.S. acknowledges support from the National Science Founda-
tion in the form of CAREER (CHE-0846189) and SusChEM (CHE-
1414298) awards. M.J.D. acknowledges UCD and US Depart-
ment of Education for a fellowship from the GAANN program
(P200A120187) and UCD for the R. Bryan Miller Graduate Fel-
lowship. F.S.F. was supported by a fellowship from CAPES (Co-
ordination for the Improvement of Higher Education Personnel
in Brazil; 99999.002792/2014-01). The authors from UCD also
acknowledge support from the NSF (CHE-0840444) for a dual
source X-ray diffractometer. P.H.Y.C. gratefully acknowledges fi-
nancial support from the Stone Family and the National Sci-
ence Foundation (NSF, CHE-1352663). K.M.S. acknowledges the
Tartar research support. O.P., K.M.S. and P.H.Y.C. also acknowl-
edge computing infrastructure in part provided by the NSF
Phase-2 CCI, Center for Sustainable Materials Chemistry (NSF
CHE-1102637).
General procedure A for the synthesis of anhydrides (2a–e)
The requisite diester was dissolved in THF/water (0.3m, 7:3 v/v)
and LiOH (6 equiv) was added to the solution. The mixture was
stirred for 2.5 h at room temperature and then acidified with 1m
aq. HCl. The mixture was diluted with water and EtOAc. The layers
were separated and the organic layer was washed with water and
brine. The organic layer was dried over Na2SO4, filtered, and con-
centrated in vacuo to afford the diacid, which was suspended in
trifluoroacetic anhydride (0.24m) for 16 h. Toluene was added and
Keywords: alkaloids · anhydrides · imine · lactams · Mannich
reaction
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Received: November 3, 2015
Published online on March 1, 2016
Chem. Eur. J. 2016, 22, 4794 – 4801
www.chemeurj.org
4801
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim