Organocatalytic Mukaiyama Mannich Reactions of 2,5-Bis(trimethylsilyloxy)furan

Article abstract of DOI:10.1021/acs.orglett.9b01664

The organocatalytic synthesis of densely substituted mono- and bis-?-lactams involving the Mukaiyama Mannich addition of 2,5-bis(trimethylsilyloxy)furan to imines is described. Use of a ditoluenesulfonylimide catalyst produces ?-lactams from monoaddition, whereas a more acidic catalyst (triflic acid) produces fused bis-lactams from double addition. Optimized organocatalytic conditions allow for the selective synthesis of either desired core as well as the one-pot, multicomponent assembly of the trisubstituted monolactams from aldehydes, amines, and bis-trimethylsilyloxyfuran. An examination of chiral acids found these organocatalysts to be highly active and diastereoselective in the monoaddition reaction, albeit with no enantioselectivity.

Full text of DOI:10.1021/acs.orglett.9b01664

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Organocatalytic Mukaiyama Mannich Reactions of 2,5-
Bis(trimethylsilyloxy)furan
Stephen W. Laws, Sara Y. Howard, Raquel Mato, Shuyu Meng, James C. Fettinger,
and Jared T. Shaw*
Department of Chemistry, University of California, One Shields Ave, Davis, California 95616, United States
S
* Supporting Information
ABSTRACT: The organocatalytic synthesis of densely substituted mono- and bis-γ-lactams involving the Mukaiyama Mannich
addition of 2,5-bis(trimethylsilyloxy)furan to imines is described. Use of a ditoluenesulfonylimide catalyst produces γ-lactams
from monoaddition, whereas a more acidic catalyst (triflic acid) produces fused bis-lactams from double addition. Optimized
organocatalytic conditions allow for the selective synthesis of either desired core as well as the one-pot, multicomponent
assembly of the trisubstituted monolactams from aldehydes, amines, and bis-trimethylsilyloxyfuran. An examination of chiral
acids found these organocatalysts to be highly active and diastereoselective in the monoaddition reaction, albeit with no
enantioselectivity.
been reported.6 Based on current mechanistic understanding,
he stereoselective synthesis of γ-lactams has been studied
Textensively due to the prevalence of this scaffold in we now call this the anhydride-Mannich reaction (AMR)
natural products and biologically relevant molecules.1 As a
because the key step involves the addition of an anhydride
enolate to an iminium ion. Recent contributions to this field
include the development of the first catalytic variants of the
AMR (Figure 1B).7 In these reports, selecting substrates with
inherently slow thermal AMR rates allowed base and/or
hydrogen-bond-donating organocatalytic activation of the
anhydride to form the key enolate intermediate. Despite
these successes, all reported catalytic examples of the AMR
involve reactions of homophthalic anhydride, the most readily
enolizable cyclic anhydride substrate. We have developed a
novel method for the Lewis acid catalyzed synthesis of
disubstituted γ lactams, and also report the first ever one-step
synthesis of fused bis-lactams.
result, a variety of methods for the synthesis of γ-lactams have
been developed.2 Our group and others have been interested
in the synthesis of lactams via formal [4 + 2] cycloadditions of
imines and cyclic, enolizable anhydrides for years (Figure 1A).3
This interest has led to many advances since the introduction
of the Castagnoli−Cushman reaction. A related four-
component reaction,4 the introduction of new anhydrides as
reaction substrates,5 and improved mechanistic insight have all
We envisioned a strategy for catalyzing the AMR in analogy
to the Mukaiyama aldol reaction (Figure 1C).8 Organocatalysis
has emerged as a useful tool for performing organic
transformations without the cost and toxicity associated with
transition-metal-catalyzed systems. The design of Brønsted
acid organocatalysts has seen significant exploration, largely
due to the successful application of BINOL-derived Brønsted
acids in asymmetric catalysis.9 Phosphoric acids,10 phosphor-
amides,11 disulfonic acids,12 and disulfonimides13 are among
the most commonly used Brønsted acidic catalytic moieties for
organocatalytic transformations. Although these Brønsted acids
are often used as proton donors in electrophile activation,
recent reports show that disulfonimides are also capable of
Figure 1. Reactions of imines and cyclic anhydrides or their
derivatives for the synthesis of lactams.
Received: May 10, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b01664
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Lewis acid activity in Mukaiyama aldol13,14 and Mannich14c,15
reactions. Based on this precedent, we proposed that
protodesilylation of anhydride-derived silyl ketene acetal 1
would allow access to Lewis acidic silylated disulfonimides,
enabling the organocatalytic Mukaiyama AMR (Scheme 1).
easily synthesized ditoluenesulfonimide catalyst with slightly
increased catalyst loadings, longer reaction times, and 2 equiv
of furan were selected.
With our optimized conditions in hand, we screened a
number of N-aryl imines in reactions with 1. All examined p-
substituted benzaldehyde-derived substrates were well toler-
ated, yielding a single trans diastereomer of lactam products in
good yield (Figure 2). Similarly, 3,5-dimethoxy-substituted and
Scheme 1. Proposed Mechanism of the Catalytic
Mukaiyama Anhydride Mannich Reaction
Initial triflic acid and disulfonimide catalyzed Mukaiyama
AMRs of bis(trimethylsilyloxy)furan 1 with variously N-
substituted, benzaldehyde-derived imines were carried out at
room temperature for 24 or 48 h (Table 1). Although the
Table 1. Effect of Imine N-Substituent and Catalyst on
Conversion and Diastereomeric Ratio of the Mukaiyama
AMR
a
a
entry
R
catalyst
time (h) % conv 5
dr 5
1
2
Boc (5a)
Boc (5a)
Boc (5a)
Cbz (5b)
Cbz (5b)
PMP (5c)
PMP (5c)
PMP (5c)
PMP (5c)
2 mol % TfOH
2 mol % Tf2NH
2 mol % o-BDSI
2 mol % Tf2NH
2 mol % o-BDSI
2 mol % TfOH
2 mol % Tf2NH
2 mol % Ts2NH
5 mol % Ts2NH
24
24
48
24
48
24
24
24
48
<5
<5
89
>95
>95
7
54
62
86
n.d
n.d.
b
3
74:26
>95:5
>95:5
n.d.
>95:5
90:10
93:7
b
4
b
5
6
7
8
c
9
a
1
As determined by H NMR spectroscopy of the unpurified reaction
b
c
mixture. Imine formed in situ from corresponding amidosulfone. 2
Figure 2. Scope of Mukaiyama AMR.
equiv of bis(trimethylsilyloxy)furan 1 used.
ortho-methoxy-substituted imines also afforded lactams 5i and
5j, respectively, in good yield with excellent diastereomeric
ratio. Notably, however, the organocatalytic reactions of 1 with
N-PMP imines derived from 2-napthaldehyde and mesitalde-
triflimide and ortho-benzenedisulfonimide (o-BDSI)-catalyzed
reactions of N-Boc and N-Cbz imines appeared promising, the
products of these reactions proved prohibitively difficult to
isolate, precluding further investigation. By comparison, the
lactam products of N-PMP imines proved easily isolable, albeit
with somewhat diminished conversion. While the triflic acid
catalyzed reaction of N-PMP imine showed nearly full
consumption of starting materials, only a small quantity of
1
hyde showed no conversion by H NMR spectroscopy of the
unpurified reaction mixture, suggesting a limit to the substrate
sterics tolerated by the reaction. N-Aryl substituents other than
N-PMP were also proven productive, albeit with slightly lower
yields and diastereoselectivities.
In hopes of expanding our scope to aliphatic aldehyde
derived imines, we turned our attention to the synthesis of
1
desired lactam was identified by H NMR of the unpurified
reaction mixture. Ultimately, optimized conditions using the
B
DOI: 10.1021/acs.orglett.9b01664
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
imines derived from isobutyraldehyde and hydrocinnamalde-
hyde. The isolation of these imines proved to be nontrivial, as
the imines decomposed prior to subjecting to reaction
conditions. Interested in overcoming this setback, we began
to screen the catalytic, multicomponent assembly of γ-lactams
by reaction of aldehydes, amines, and furan 1 in the presence
of desiccants (Figure 3). Lactam 5c, previously isolated in 74%
exclusive formation of 5c, confirming that these catalysts
exhibit similar reactivity to ditoluenesulfonimide. Although
imidodiphosphorimidate-type (IDPi) catalyst C3 is more
acidic than ditoluenesulfonimide, lactam 5c is still the only
observed product. This result suggests that the bulkier steric
environment of this catalyst may preclude the addition of a
second equivalent of imine. The complete lack of enantiose-
lectivity observed with two structurally distinct catalysts
suggests that this reaction may require a high level of
customization in order to realize useful levels of asymmetric
induction.
Having explored the scope of the diastereoselective,
organocatalytic method, we sought to further functionalize
lactam 5c (Scheme 2). Amidation and esterification of the
Scheme 2. Lactam Product Derivatization
Figure 3. Scope of the one-pot, three-component Mukaiyama AMR.
carboxylic acid moiety were achieved in high yield, and CAN-
mediated PMP-cleavage of esterified lactam 6c provided N−H
lactam 11 in good yield.
from the reaction of 1 with imine 2c, was formed from the
three-component reaction as a single diastereomer in 92% yield
following esterification (6c). Furthermore, the previously
unobserved aliphatic aldehyde-derived lactams could be
isolated in fair to excellent yield.
A preliminary screen of chiral catalysts revealed high
conversion and diastereoselectivity, albeit with no discernible
enantioselectivity (Table 2). Sulfonimides C1 and C2 showed
We revisited the results of our initial achiral catalyst screen
in order to better understand the divergent reactivity observed
in the triflic acid catalyzed reaction of 1 and 2c. Purification of
the crude reaction mixture by flash column chromatography
revealed the formation of two diastereomeric bis-γ-lactams, the
C2-symmetric 15a, and the C1-symmetric 16a. We hypothesize
that this uncommon core structure may be formed via two
successive Mukaiyama Mannich reactions followed by global
protodesilylation, intramolecular acylation, and amidation
(Scheme 3).16 Although the two products are formed in
Table 2. Mono-addition Reactions Using Chiral Catalysts
Scheme 3. Proposed Mechanism for the Synthesis of Bis-γ-
lactams
time
(h)
trans/cis
ab
,
a
c
entry
catalyst
% conv 5c
5c
er 5c
1
2
24
24
24
24
2 mol % 9a
2 mol % 10
5 mol % (S)-9b
5 mol % (S)-9b
95
94
100
100
>95:5
>95:5
>95:5
>95:5
50:50
50:50
50:50
50:50
d
3
de
,
similar quantities, no trace of the other four possible diastereomers
could be detected in the reaction mixture. This core structure has
only been previously observed once as a synthetic product and
once as the core of a natural product.17 The analogous fully
unsaturated heterocycle, i.e. diketopyrrolopyrrole (DPP), is a
common building block for photoactive dyes and polymers.18
4
a
1
As determined by H NMR spectroscopy of the unpurified reaction
b
c
mixture. No conversion to bis-γ-lactam product was observed. As
determined by chiral HPLC of the corresponding methyl ester.
equiv 4 Å MS added. 5 mol % 2,6-DTBP added.
d
2
e
C
DOI: 10.1021/acs.orglett.9b01664
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Organic Letters
Letter
Further reaction screening showed that triflic acid remains
catalytically active with the addition of equimolar 2,6-di-tert-
butylpyridine, when added as a pyridine salt, and when
replaced by catalytic trifluoromethanesulfonate (Table 3). This
and products were always formed as a mixture of two
diastereomers. Several attempts to employ sequential addition
of two different imines to produce completely unsymmetrical
bis-lactam products were unsuccessful. Although imines with
ortho-substituted N-aryl groups were found to be either
synthetically inaccessible or unproductive Mukaiyama-AMR
substrates, lactam 15e represents the first synthesis of the C2-
symmetrical bis-lactam core of natural product ( )-bisavenan-
thramide B-1.19
Table 3. Effect of Catalyst on Conversion to Bis-γ-lactams
In conclusion, we report the development of a new acid
catalyzed, organocatalytic Mukaiyama-variant of the anhydride
Mannich reaction. This method allows for highly diaster-
eoselective access to challenging trisubstituted lactam targets in
high yield. Although imines derived from alkyl aldehydes can
be synthetically inaccessible substrates, a three-component
reaction variation allows for the expansion of scope by forming
these electrophiles in situ. Additionally, excellent catalyst
control for single versus double Mukaiyama Mannich addition
was observed.
dr
a
a
entry
catalyst
2 mol % TfOH
2 mol % TfOH
20 mol % TfOH
20 mol % TfOH, 20 mol %
2,6-(t-Bu)2Py
20 mol % 2,6-(t-Bu)2Py·TfOH
20 mol % Py·TfOH
20 mol % TMSOTf
solvent
% conv
15:16
1
2
3
4
THF
80
62
81
78
55:45
61:39
51:49
51:49
CH3CN
CH3CN
CH3CN
5
6
7
CH3CN
CH3CN
CH3CN
84
85
77
48:52
48:52
53:47
ASSOCIATED CONTENT
* Supporting Information
■
S
a
1
As determined by H NMR spectroscopy of the unpurified reaction
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b01664.
mixture.
suggests that the catalytic activity of triflic acid in this reaction
is the result of Lewis, not Brønsted, acid activity, following in
situ silylation. While this reactivity is apparently similar to that
proposed for the disulfonimide catalysts, triflic acid presumably
must provide greater catalytic activation in order to selectively
effect two Mannich additions.
Despite efforts at optimization, the diastereomeric product
ratio appeared independent of reaction conditions. After
reoptimizing the reaction method to favor double addition
by increasing catalyst loading, employing anhydrous sodium
sulfate, and using 2 equiv of imine, we screened a small
number of reactions to probe the scope of double Mukaiyama
AMR (Figure 4). Yields were generally slightly lower than
those of the single addition reactions of corresponding imines,
Experimental procedures, computational NMR data, X-
ray crystallographic data, 1H and 13C NMR spectra
(PDF)
Accession Codes
CCDC 1903958−1903959 contain the supplementary crys-
tallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: jtshaw@ucdavis.edu.
ORCID
Sara Y. Howard: 0000-0001-9481-1928
Raquel Mato: 0000-0002-5157-961X
James C. Fettinger: 0000-0002-6428-4909
Jared T. Shaw: 0000-0001-5190-493X
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This work was supported by the National Science Foundation
(CHE-1764309-0, CHE-1414298). S.W.L. acknowledges
■
Professor Benjamin List (Max-Planck-Institut fur Kohlenfor-
̈
schung) for hosting laboratory work that was funded by an
NSF supplement (to CHE-1414298). R.M. acknowledges the
Basque Government Fellowship (Spain) for supporting
international graduate research. S.M. acknowledges the
Fudan University Overseas Summer Research Foundation for
supporting international undergraduate research. We also
acknowledge support from the NSF (CHE-0840444) for a
dual-source X-ray diffractometer. The authors thank Professor
Dean Tantillo, Carla Saunders, and Amy Bellinghiere
Figure 4. Scope of the double Mukaiyama AMR for the synthesis of
bis-γ-lactams.
D
DOI: 10.1021/acs.orglett.9b01664
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(University of California, Davis) for input into computational
NMR and preparation of the Supporting Information.
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