Alkaloid-Catalyzed Enantioselective [3 + 2] Cycloaddition of Ketenes and Azomethine Imines

Article abstract of DOI:10.1021/acs.orglett.6b02038

A new asymmetric synthesis of bicyclic pyrazolidinones through an alkaloid-catalyzed formal [3 + 2] cycloaddition of in situ generated ketenes and azomethine imines is described. The products were formed in good to excellent yields (52-99% for 17 examples), with good to excellent diastereoselectivity (dr 5:1 to 27:1 for 11 examples), and with excellent enantioselectivity in all cases (≥96% ee). This method represents the first unambiguous example of an enantioselective reaction between ketenes and a 1,3-dipole.

Full text of DOI:10.1021/acs.orglett.6b02038

Letter
pubs.acs.org/OrgLett
Alkaloid-Catalyzed Enantioselective [3 + 2] Cycloaddition of Ketenes
and Azomethine Imines
†
‡
,†
Mukulesh Mondal, Kraig A. Wheeler, and Nessan J. Kerrigan*
†Department of Chemistry, Oakland University, 2200 North Squirrel Road, Rochester, Michigan 48309-4477, United States
‡Department of Chemistry, Eastern Illinois University, 600 Lincoln Avenue, Charleston, Illinois 61920-3099, United States
*
S Supporting Information
ABSTRACT: A new asymmetric synthesis of bicyclic pyrazolidinones through an
alkaloid-catalyzed formal [3 + 2] cycloaddition of in situ generated ketenes and
azomethine imines is described. The products were formed in good to excellent
yields (52−99% for 17 examples), with good to excellent diastereoselectivity (dr
5
:1 to 27:1 for 11 examples), and with excellent enantioselectivity in all cases
(
≥96% ee). This method represents the first unambiguous example of an
enantioselective reaction between ketenes and a 1,3-dipole.
he synthesis of bicyclic pyrazolidinones has recently
seminal contribution, Fu’s group reported a Cu(I)/chiral
phosphaferrocene oxazoline-catalyzed asymmetric synthesis of
the closely related bicyclic pyrazolines from azomethine imines
T
attracted attention due to the presence of the pyrazolidi-
none structural motif in many biologically active complex
1
4
molecules. Some examples include anti-Alzheimer’s disease
and alkynes. On the other hand Studer and co-workers showed
molecule 1 and related bicyclic pyrazolidinone derivatives tha1t
exhibit herbicidal, pesticidal, and antibiotic activity (Scheme 1).
However, the catalytic asymmetric synthesis of pyrazolidinones
that structurally novel pyrazolidinones 2 containing a tetrahydro-
isoquinoline moiety could be assembled through a chiral
benzotetramisole-catalyzed 1,3-dipolar cycloaddition of azome-
2
6
of structure 1 has proven an elusive target. Enantioselective
thine imines with mixed anhydrides. Although very high
access to pyrazolidinone motifs could be envisaged through a
chiral catalyst-controlled 1,3-dipolar cycloaddition of an
enantioselectivity could be obtained with this method, it is
notably limited to the tetrahydroisoquinoline-containing imines,
and as such is unable to provide access to the bicyclic
pyrazolidinones represented by 1 or related fused bicyclic five-
membered ring systems. It is also restricted to aryl substituents
(from the anhydride) at the stereogenic center α to the imide
carbonyl. This reaction is proposed to involve an ammonium
enolate intermediate, most likely accessed through deprotona-
tion of an acyl ammonium precursor. Ye and co-workers more
recently reported the N-heterocyclic carbene-catalyzed reaction
3
azomethine imine with a suitable dipolarophile reactant partner.
4
−8
A number of research groups have followed that strategy. In a
Scheme 1. Plan for Synthesis of Bicyclic Pyrazolidinones
of α-chloroaldehydes with azomethine imines to give pyrazoli-
7
dinones 2 with excellent enantioselectivity in most cases. Brier
̀
e
and co-workers demonstrated that a related and unexpected
regioisomer of a pyrazolidinone (3) could be prepared through
the (DHQ) PHAL-catalyzed Knoevenagel−aza-Michael cyclo-
2
condensation reaction of Meldrum’s acid with various
azomethine imines, albeit with just one example formed in
8
≥
90% ee. A significant drawback of this method is its restriction
to Meldrum’s acid, and as a result the lack of a versatile
diastereoselective variant, and moreover the lack of consistently
high enantioselectivity across a range of examples. It should be
noted that in all of these prior literature examples of
organonucleophile-catalyzed enantioselective [3 + 2] cyclo-
Received: July 13, 2016
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b02038
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
additions, ketenes were not demonstrated to be involved as a
reactant partner.
Table 1. Optimization of Alkaloid-Catalyzed [3 + 2]
Cycloaddition of Ketenes with Azomethine Imines
As part of our interest in the development of new
methodologies for the asymmetric synthesis of five-membered
ring structures from ketenes, we proposed that the pyrazolidi-
none motif 1 could be straightforwardly assembled through a
chiral nucleophile-catalyzed formal [3 + 2] cycloaddition of
azomethine imines of type 4 with in situ generated ketenes 5. Our
results described herein represent the first unambiguous example
of an enantioselective reaction between ketenes and a 1,3-dipole,
and only the second example of an asymmetric [3 + 2]
a
b
c
entry
cat.
temp (°C)
% yield
dr
% ee
1
2
3
4
5
6
6
7
6
7
8
9
9
−25
−25
−78
−25
−25
−25
−25
80
1:1
1.5:1
1:1
98
98
9
,10
cycloaddition reaction involving ketenes (Scheme 1).
63
We began our studies by investigating alkaloid and phosphine
catalysts which we and others had previously found to be
successful for promoting formal [2 + 2] cycloadditions of ketenes
(70)
(40)
(25)
90
1.5:1
2:1
1
0−13
with various coupling partners.
In stark contrast to
3:1
99
d
phosphines, alkaloid catalysts were found to be very successful
7
85
3:1
99
a
promoters under the reaction conditions tested (in CH Cl , − 25
Isolated yield for both diastereomers. Conversion as determined by
b
2
2
1
°
C, in situ ketene generation, acyl chloride added slowly). Slow
addition of the acyl chloride over 10 h to the reaction solution
GC-MS in parentheses. dr determined by H NMR or HPLC analysis
c
of crudes. (R,S)-isomer = major in most cases. ee determined by
chiral HPLC or chiral GC analysis for major diastereomer. 2.5 mol %
d
(
containing catalyst, azomethine imine, and Hunig’s base) was
̈
of catalyst used.
found to be beneficial to the yield of bicyclic pyrazolidinone and
limited both ketene homodimerization and aldehyde forma-
1
2,14
tion.
Initially Me-quinidine and TMS-quinine were found to be
effective catalysts for providing high enantiocontrol, albeit
accompanied by poor diastereoselectivity (Table 1, entries 1
and 2). A number of Lewis acid salt additives were investigated in
an attempt to improve diastereoselectivity, but all attempts met
with failure (see Supporting Information (SI)). Among the many
other alkaloid catalysts investigated (DHQ) PHAL was found to
2
be optimal, providing the desired product in excellent yield, with
excellent enantioselectivity, and, significantly, with improved
diastereoselectivity (entry 6). A catalyst loading of as low as 2.5
mol % was found to be effective in terms of providing the desired
product in good yield, dr, and ee (entry 7). Indeed, it was only
when the reaction was run using a 1 mol % catalyst loading that a
significant drop in yield (to ca. 45%) was observed, although with
preservation of excellent enantioselectivity (94% ee).
2, entries 1−11). The major diastereomer of the products was
determined to be the trans-isomer by X-ray crystallographic
analysis of the major isomer of 1f (see SI). The major enantiomer
We then went on to evaluate the substrate scope of the
(
DHQ) PHAL-catalyzed methodology using 10 mol % of the
2
catalyst to ensure complete conversion and limit formation of
from the (DHQD) PHAL 10-catalyzed formation of 1f was
2
1
4
aldehyde byproduct. The method displayed excellent tolerance
of substrate variation with respect to changes in the ketene
substituent; methyl, ethyl, n-propyl, n-hexyl, and acetoxy
substituents were all found to proceed with excellent
enantioselectivity. In most cases, high yields were obtained
determined to be the (2S,3R)-enantiomer by X-ray crystallog-
raphy. By analogy, the products of all 10-catalyzed reactions were
assigned the (2S,3R)-configuration, while products of all the 9-
catalyzed reactions were assigned the (2R,3S)-configuration. The
absolute stereochemical outcome is consistent with models
previously proposed by the Calter and Lectka groups for related
(
typically 70−99%), but it appears that AcO-substituted
1
0a,15
pyrazolidinones are somewhat acid-sensitive and that the slightly
lower isolated yields (52−69%) are due to decomposition during
purification on silica. The method was compatible with a variety
of substituents on the aryl ring of the imines; both electron-
donating and -withdrawing substituents were tolerated with
excellent enantioselectivity obtained in all cases. Importantly,
both enantiomers of bicyclic pyrazolidinone products can be
alkaloid-catalyzed reactions.
Examples obtained with
moderate diastereoselectivity could be enriched to high
diastereopurity through simple recrystallization; For example,
1f (dr 3:1) was recrystallized from CH Cl /pentane to provide 1f
2
2
in good yield (67%) and with excellent diastereomeric purity (dr
37:1). Interestingly, when an OAc substituent was present on the
ketene, excellent levels of diastereoselectivity were obtained
(entries 12−17). The origin of this increase in diastereoselec-
tivity is currently under investigation.
accessed by employing the pseudoenantiomeric (DHQ) PHAL
2
9
and (DHQD) PHAL 10 (see entries 3−6 and 12−17).
2
Remarkably, for all examples examined during the study of
substrate scope, an enantioselectivity lower than 96% ee was
never observed.
Our proposed mechanism for the (DHQ) PHAL-catalyzed
2
formation of bicyclic pyrazolidinones involves addition of the
alkaloid catalyst to the less sterically hindered side of the
monosubstituted ketene to afford an ammonium enolate I in
stereoselective fashion (in accord with previous mechanistic
Diastereoselectivity favoring formation of the trans (anti)-
diastereomer was moderate to good (dr up to 6.5:1) in most
cases when an alkyl substituent was present on the ketene (Table
10,11
proposals) (Scheme 2).
Addition of the ammonium enolate
B
DOI: 10.1021/acs.orglett.6b02038
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Table 2. Scope of Alkaloid-Catalyzed [3 + 2] Cycloaddition of
Ketenes with Azomethine Imines
when propionyl chloride and i-Pr NEt were used. Significantly
2
the major isomer was formed with the same sense of enantio- and
diastereoselectivity as was observed for the in situ generated
ketene case. Other mechanistic observations included the
following: (1) Reaction of azomethine imine with propionyl
chloride was examined under typical reaction conditions (−25
°
C, in CH Cl , but with no catalyst) and resulted in no product
2 2
formation, thus suggesting that formation of azomethine imide
followed by enolization is an unlikely mechanistic pathway. (2)
entry/1
cat.
R1
Me
R2
% yield
a
dr
b
% ee
c
In an experiment where (DHQ) PHAL and azomethine imine
2
were dissolved in CD Cl , no evidence for interaction of
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
/1a
9
Ph
90
94
85
80
99
97
95
93
74
81
84
58
55
64
52
69
64
3:1
5:1
99
98
99
99
99
99
98
99
98
99
99
99
96
99
99
99
96
2
2
1
(
DHQ) PHAL with azomethine imine was observed by H
/1b
9
Me
4-MeC H
2
6
4
4
4
NMR spectroscopy. (3) In the absence of the alkaloid catalyst, a
complex mixture of products resulted.
/1c
9
Me
2-MeC H
5:1
6
/1d
10
9
Me
2-MeC H
4:1
6
The formation of the major diastereomer of the product with
trans-relative stereochemistry may be rationalized through a
transition state in which the attacking ammonium enolate is
oriented gauche to the CN of the iminium electrophile
/1e
Me
4-MeOC H
6.5:1
3:1
6
4
/1f
10
9
Me
4-MeOC H
6
4
/1g
Me
4-FC H
4:1
6
4
/1h
10
9
Me
4-FC H
3:1
6
4
(
Scheme 3). This arrangement is presumably stabilized relative
/1i
Et
4-MeOC H
4:1
6
4
4
4
4
4
0/1j
1/1k
2/1l
3/1m
4/1n
5/1o
6/1p
7/1q
9
n-Pr
n-Hex
OAc
OAc
OAc
OAc
OAc
OAc
4-MeOC H
5:1
6
9
4-MeOC H
6:1
Scheme 3. Model for Diastereoselection
6
9
4-MeOC H
27:1
18:1
22:1
19:1
16:1
6
10
9
4-MeOC H
6
4-MeC H
6
4
10
9
4-MeC H
6
4
Ph
Ph
10
12:1
a
b
1
Isolated yield for both diastereomers. dr determined by H NMR or
c
HPLC analysis of crudes. ee determined by chiral HPLC or chiral GC
analysis for major diastereomer. (R,S)-isomer is the major isomer from
the 9-catalyzed reaction. (S,R)-isomer is the major isomer from the 10-
catalyzed reaction.
Scheme 2. Proposed Mechanism for Catalytic Asymmetric
Synthesis of Bicyclic Pyrazolidinones
to competing antiperiplanar arrangements, due to Coulombic
attraction between the negatively charged oxygen of the enolate
16
and the positively charged nitrogen of the imine. When an OAc
1
substituent was present on the ketene (R = OAc in Scheme 3),
very good to excellent levels of diastereoselectivity were obtained
(
Table 2, entries 12−17). We speculate that a favorable
interaction between lone pairs on the carbonyl oxygen of the
OAc group and the positively charged imine further stabilizes the
putative gauche arrangement in the transition state (Scheme 3)
leading to a greater preference for formation of the trans-isomer.
In summary, we have developed an alkaloid-catalyzed
asymmetric synthesis of bicyclic pyrazolidinones, which
represents the first unambiguous enantioselective [3 + 2] of
ketenes with a 1,3-dipole. Pyrazolidinones were formed from in
situ generated ketenes and azomethine imines, with excellent
enantioselectivity in all cases (17 examples). Future work will
involve applications of the reported methodology and the
development of other new nucleophile-catalyzed enantioselec-
tive [3 + 2] cycloaddition reactions of ketenes.
ASSOCIATED CONTENT
Supporting Information
■
to the azomethine imine provides access to zwitterionic species
II, which subsequently undergoes 5-exo-trig cyclization to afford
pyrazolidinone 1, along with simultaneous regeneration of the
alkaloid catalyst. The participation of a ketene rather than an acyl
chloride in reaction with the alkaloid catalyst was supported by
the following experimental observations: The use of pregen-
erated methylketene (rather than propionyl chloride) led to the
formation of bicyclic pyrazolidinone 1e in virtually the same
enantiomeric excess (98% ee) and diastereoselectivity (7:1) as
*
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.6b02038.
Experimental procedures (PDF)
spectroscopic data, chromatograms for all new com-
pounds (PDF)
Crystallographic data for 1f (CIF)
Crystallographic data for 1p (CIF)
C
DOI: 10.1021/acs.orglett.6b02038
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: kerrigan@oakland.edu.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Support has been provided by the National Science Foundation
and the National Institutes of Health: Grant Nos. CHE-1213638,
CHE-1463728, and R15GM107800 to N.J.K.
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DOI: 10.1021/acs.orglett.6b02038
Org. Lett. XXXX, XXX, XXX−XXX