Palladium-mediated annulation of vinyl aziridines with michael acceptors: Stereocontrolled synthesis of substituted pyrrolidines and its application in a formal synthesis of (-)-α-kainic acid

Article abstract of DOI:10.1002/anie.201101389

Just add salt: Vinyl aziridines have been treated with methyl vinyl ketone or ethyl thioacrylate in the presence of Pd⁰ to give pyrrolidines with moderate to good diastereoselectivity. The presence of nBu₄NCl was critical to successf

Full text of DOI:10.1002/anie.201101389

Communications
DOI: 10.1002/anie.201101389
Annulation Reactions
Palladium-Mediated Annulation of Vinyl Aziridines with Michael
Acceptors: Stereocontrolled Synthesis of Substituted Pyrrolidines and
Its Application in a Formal Synthesis of (À)-a-Kainic Acid**
Martin A. Lowe, Mehrnoosh Ostovar, Serena Ferrini, C. Chun Chen, Paul G. Lawrence,
Francesco Fontana, Andrew A. Calabrese, and Varinder K. Aggarwal*
Dedicated to Professor Yun-Shan Lin
The rapid increase in molecular complexity from simple
precursors is a major goal in organic synthesis.[1] Within this
context, the palladium-mediated annulation reaction of
Michael acceptors with vinyl epoxides,[2] and aziridines,[3]
offers significant potential for the synthesis of heterocycles,
but to date, this reaction has not been well developed
(Scheme 1).[4] As we had established a simple, asymmetric
singly activated enones/acrylates, and we were able to control
stereochemistry in the annulation process, then we could
potentially utilize this methodology in synthesis. Herein, we
describe our success in simultaneously meeting these two
significant challenges and also describe its application in a
formal synthesis of (À)-a-kainic acid 1.
Our initial efforts at promoting reaction between vinyl
aziridine 2a and methyl vinyl ketone (MVK, A) using
[Pd2(dba)3·CHCl3], (p-FC6H5)3P in THF (conditions
employed by Yamamoto[3a]), however, were fruitless—we
only observed decomposition. Using trimethylsilyl-substi-
tuted trans vinyl aziridine 2e, we now observed isomerization
to a mixture of trans/cis aziridines (1:20).[9] With this sub-
strate, clearly the Pd was performing its role in generating the
p-allyl palladium complex as this resulted in isomerization of
the vinyl aziridine. However, the amide anion that was
generated did not react with the enone. This result reinforced
the observations by Yamamoto and Knight[2,3] that doubly
activated Michael acceptors were required to capture the
relatively unreactive amide anion. We reasoned that ion
pairing of the amide anion with the cationic Pd complex might
compromise its reactivity, and that increased nucleophilicity
should therefore be possible with an anionic Pd complex
instead (Scheme 2).
Scheme 1. Palladium-catalyzed annulation reaction of vinyl epoxides/
aziridines with Michael acceptors. EWG=electron-withdrawing group,
Ts =4-toluenesulfonyl.
route to vinyl epoxides[5] and vinyl aziridines[6] via chiral
sulfur ylides,[7] we were keen to develop their potential in
synthesis further.[8]
It had been reported that palladium-catalyzed reactions of
vinyl epoxides and aziridines with doubly activated Michael
acceptors gave tetrahydrofurans and pyrrolidines in good
yield but usually with poor stereocontrol.[2,3] However,
related reactions with singly activated Michael acceptors
were not effective.[2a,3b] Nevertheless, we recognized that if we
could find a way of coercing vinyl aziridines to react with
[*] Dr. M. A. Lowe, Dr. M. Ostovar, Dr. S. Ferrini, C. C. Chen,
P. G. Lawrence, Dr. F. Fontana, Prof. V. K. Aggarwal
School of Chemistry, University of Bristol
Cantock’s Close, Bristol, BS8 1TS (UK)
Fax: (+44)117-925-1295
E-mail: v.aggarwal@bristol.ac.uk
Dr. A. A. Calabrese
Pfizer Limited
Scheme 2. Possible origin of low reactivity of amide towards MVK.
Ramsgate Road, Sandwich, Kent, CT13 9NJ (UK)
[**] We thank Pfizer and EPSRC for support of a studentship (MAL).
C.C.C. thanks the University of Bristol for a Centenary Scholarship.
F.F. thanks “Universitꢀ degli Studi di Milano” for funding. V.K.A.
thanks the Royal Society for a Wolfson Research Merit Award and
EPSRC for a Senior Research Fellowship. We thank Prof. G. Lloyd-
Jones and Prof. V. Rawal for useful discussions.
We therefore added nBu4NCl[10] and were immediately
rewarded with success.[11] A 1:1 diastereomeric mixture of
pyrrolidines was obtained albeit in low yield (Table 1,
entry 1). Increasing the amount of MVK resulted in increased
yield and diastereoselectivity (Table 1, entry 2). Further
optimization of reaction conditions focused on variation of
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201101389.
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Angew. Chem. Int. Ed. 2011, 50, 6370 –6374

Table 1: Optimization of the annulation reaction.[a]
Entry
Phosphine
Solvent
Yield [%][b]
d.r.
(3aA/4aA)
Scheme 3. Annulation of aziridine 2e with MVK and ethyl thioacrylate.
1[c]
2
3
4
5
6
7
8
9
(4-FC6H4)3P
(4-FC6H4)3P
Ph3P
(2-furyl)3P
(o-tolyl)3P
(o-tolyl)3P
(o-tolyl)3P
(o-tolyl)3P
(o-tolyl)3P
THF
THF
THF
THF
THF
Et2O
Pentane
Pent/Et2O[d]
Pent/TBME[d]
21
38
36
56
38
60
60
65
66
50:50
68:32
65:35
69:31
83:17
92:8
93:7
93:7
93:7
pyrrolidine products. Alternative aryl groups in the terminal
position of the vinyl aziridine 2b could be used, albeit with
decreased diastereoselectivity (Table 2, entry 2).[13] The
parent vinyl aziridine 2c was also a suitable substrate, but
this time, the 2,3-cis-3,4-trans-substituted pyrrolidine 5cAwas
the major diastereomer (Table 2, entry 3). The a-methyl vinyl
aziridine 2d was also effective in this process, furnishing 2,3-
trans-3,4-trans-substituted pyrrolidine 4dA, but with low
diastereoselectivity (Table 2, entry 4). Investigation of alter-
native Michael acceptors revealed that although ethyl acry-
late was unreactive towards the aziridines, ethyl thioacry-
late[14] (B) was effective (Table 2, entries 5 and 6), and gave
the pyrrolidines 3aB and 5cB with moderate diastereoselec-
tivity and good yield.
The trimethylsilyl-substituted vinyl aziridine 2e could also
be employed in the annulation reaction with MVK but,
surprisingly, the 2,3-cis-3,4-trans pyrrolidine bearing a Z ole-
fin (7eA; Scheme 3) was now the major diastereomer
formed—exactly opposite to that obtained from the phenyl-
substituted aziridine 2a (2,3-trans-3,4-cis bearing an E olefin
was the major diastereomer; Table 2, entry 1). A further
surprise emerged with ethyl thioacrylate (B), which gave rise
to the all-cis isomer 8eB as the major diastereomer. The
relative configuration of the major diastereomers 3aA, 7eA,
and 8eB were determined by X-ray crystal structure analysis
(see the Supporting Information).[15]
[a] All reactions conducted at 0.1m, 208C, with 10 equivalents of MVK.
[b] Yield of isolated product. [c] 2 equivalents of MVK was used. [d] 3:1
mixture of solvents was used. dba=trans,trans-dibenzylideneacetone,
Pent=pentane, TBME=tBuOMe, THF=tetrahydrofuran.
the phosphine and solvent and representative results are
summarized in Table 1. Of the phosphine reagents examined
(Table 1, entries 2–5), the most sterically hindered, (o-tolyl)3P,
led to the highest diastereoselectivity but still only with
moderate yield (Table 1, entry 5). Further improvements in
diastereoselectivity and yield were achieved using nonpolar
solvents, for example, pentane, diethyl ether, or diethyl ether/
pentane mixtures (Table 1, entries 6–9). Resubjection of the
pyrrolidine products to the reaction conditions did not change
the diastereomeric ratio indicating that the reactions were
under kinetic control.[12]
Having found conditions that gave workable yields and
high diastereoselectivity in this novel annulation reaction, we
briefly explored alternative aziridines and Michael acceptors
(Table 2 and Scheme 3). The aziridines were easily prepared
in high e.r. using our sulfur ylide methodology[5c] (e.g. as
illustrated in Scheme 5) and the e.r. was maintained in the
The stereoselectivity observed can be rationalized by
considering the transition states involved in the final ring
closure of the enolate onto the p-allyl palladium complex
Table 2: Annulation of aziridines with Michael acceptors.[a]
Entry
Aziridine
R1
e.r.
Acceptor
Phosphine
Solvent
Product type (d.r)
Yield [%][b]
2
R2
3
4
5
6
1
2
3
4
5
6
2a
2b
2c
2d
2a
2c
Ph
4-ClC6H4
H
H
Ph
H
H
H
H
Me
H
99:1
99:1
94:6
99:1
99:1
94:6
A
A
A
A
(o-tolyl)3P
(o-tolyl)3P
(o-tolyl)3P
(4-FC6H4)3P
(2-furyl)3P
(2-furyl)3P
Pent/TBME[c]
Pentane
Pentane
Et2O
93
80
–
14
75
–
7
20
–
58
25
–
–
–
80
28
–
–
–
20
–
–
66
60
52
57
50
59
B[d]
B[d]
Pent/TBME[c]
Et2O
H
66
33
[a] All reactions conducted at 0.1m, 208C, with 5 mol% of [Pd2(dba)3·CHCl3], 0.25 equivalents of phosphine, 1 equivalents of nBu4NCl and
10 equivalents of MVK. [b] Total yield of isolated products. [c] 3:1 mixture of solvents was used. [d] 5 equivalents of ethyl thioacrylate was used.
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6371

Communications
(Scheme 4). In the four transition states proposed, the phenyl
formal synthesis of the natural product, (À)-a-kainic acid.
Kainic acid has been a popular target in synthesis,[18,19] not
only because of its structure, but also because of its unique
biological properties, as it is widely used as a tool in
pharmacology for the investigation of a variety of neuro-
logical disorders.[20] However, a shortage of the natural
material through commercial extraction[21] has led to a
significant impediment to these studies, therefore fuelling a
real need for a practical asymmetric synthesis.
group is positioned in a pseudoaxial position to minimize
steric interactions with the PdLn moiety, as previously pro-
posed in related systems.[16] In the case of aryl-substituted
Our synthesis of (À)-a-kainic acid (Scheme 5) began with
the enantio- and diastereoselective aziridination of imine 9
using our chiral sulfur ylide methodology.[5c] Thus, treatment
Scheme 5. Reagents and conditions: a) NaHCO3, CH3CN, RT, 85%,
99% ee; b) [Pd2(dba)3·CHCl3], nBu4NCl, P(o-tolyl)3, pentane, 62%,
10:1 d.r; c) NBS, H2O, acetone, RT, 95%; d) nBu3SnH, ACCN, ben-
zene, reflux, 90%. e) NaIO4/H5IO6, RuCl3, H2O/CCl4/CH3CN (2:1:1);
then TMSCHN2, MeOH, toluene, RT, 37%. ACCN=1,1’-azobis(cyclo-
hexanecarbonitrile). NBS=N-bromosuccinimide, Tf=trifluorometha-
nesulfonyl, TMS=trimethylsilyl.
Scheme 4. Rationalization of stereochemical outcome of annulation
reactions.
vinyl aziridines, the E p-allyl palladium complexes are
favored, thus leading to TS1 or TS2. Of the two transition
states, TS1 may benefit from attractive interactions between
the electron-rich p system of the enolate and the electron-
poor p system of the p-allyl Pd complex, thus leading to the
major products 3aA, 3bA, and 3aB. In the case of terminal
vinyl aziridine 2c (R1, R2 = H), all transition states are
accessible but TS3 suffers from the least steric hindrance
and is favored leading to 5cA and 5cB. An unusual situation
arises for the silyl-substituted vinyl aziridine 2e (R1 = SiMe3),
where now it seems that both E and Z p-allyl palladium
of sulfonium salt 10 with imine 9 gave the vinyl aziridine 2a in
85% yield and 99% ee (step a). Palladium-catalyzed annula-
tion with MVK furnished pyrrolidine (+)-3aA in good yield
and high diastereoselectivity, and a single diastereoisomer
was obtained after recrystallization (step b). Conversion of
the styryl group into a carboxylic ester was achieved through
halohydrin formation (step c),[22] radical debromination
(step d),[23] RuCl3/H5IO6/NaIO4 oxidation,[24] and esterifica-
tion (step e). The last steps also converted the 2-phenyl group
into a carboxylic ester. Although the simultaneous oxidative
cleavage of both the styryl and phenyl groups was rather low
yielding (step e), the high regioselectivity and brevity in the
conversion of 3aA into 13 is noteworthy. Diester 13 has been
converted into (À)-a-kainic acid by Scott and Lautens in
three steps involving olefination, ester hydrolysis, and
removal of protecting groups.[18m] As diester 13 was identical
in all respects to Lautensꢀ diester, a formal synthesis of (À)-a-
kainic acid 1 has been completed. Diester 13 was obtained in a
total of only six synthetic steps from cinnamaldehyde with
high diastereo- and essentially complete enantiocontrol.
In conclusion, we have described novel methodology
which converts vinyl aziridines into pyrrolidines with good
complexes are equally accessible, perhaps as a result of the
[17]
À
longer C Si bond length. With MVK, TS3 is favored as it
suffers the least steric hindrance, thus leading to 7eA.
Whereas with the thiol ester, an attractive interaction
between the soft S atom and the p-allyl palladium complex
may now favor TS4, thus leading to 8eB. Alternatively,
favorable interactions between the anionic oxygen atom of
the enolate and the silyl group may also be present, thus
promoting TS3 and TS4.
The stereoselective formation of densely functionalized
pyrrolidines 3aA, 3aB, 5cA, 7eA, or 8eB—depending on the
aziridine and Michael acceptor employed—provides a power-
ful synthetic method for synthesis. This is exemplified in the
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Angew. Chem. Int. Ed. 2011, 50, 6370 –6374

Chem. Soc. 2003, 125, 10926 – 10940; c) O. Illa, M. Arshad, A.
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132, 1828 – 1830.
diastereoselectivity to furnish 2,3-trans-3,4-cis, or 2,3-cis-3,4-
trans or the all-cis isomer—depending on the starting materi-
als employed. Because vinyl aziridines are readily available
with high enantiomeric purity from simple precursors using
sulfur ylides, this combined methodology shows significant
potential. The synthetic utility of the methodology has been
demonstrated in one of the shortest (formal) syntheses of (À)-
a-kainic acid to date.
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Received: February 24, 2011
Revised: April 18, 2011
in Stereoselective Synthesis
2 (Eds.: J. G. de Vries, G. A.
Published online: May 27, 2011
Molander, P. A. Evans) Georg-Thieme, Stuttgart, 2010, Chap-
ter 2.6, pp. 311 – 347.
Keywords: annulation · aziridines · palladium · pyrrolidines ·
synthetic methods
.
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see: a) H. Ohno in Aziridines and Epoxides in Asymmetric
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[11] nBu4NOAc, nBu4NF KCl, LiCl, and ZnCl2 were also tested but
,
found to be ineffective.
[12] Resubjection of a 93:7 mixture of 3aA/4aA to the standard
reaction conditions for 14 hours resulted in a final ratio of 96:4.
Resubjection of a 24:76 mixture of 3aA/4aA to the standard
reaction conditions resulted in a final ratio of 23:77, even after
extended reaction time (48 h). These results indicate that the
reaction is essentially under kinetic control. We thank one of the
[5] a) V. K. Aggarwal, I. Bae, H.-Y. Lee, D. T. Williams, Angew.
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Communications
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substrates as the vinyl aziridine compounds were rather unstable
and were difficult to isolate in pure form.
[14] A. W. V. Ziji, J. Minnaard, B. L. Feringa, J. Org. Chem. 2008, 73,
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[15] CCDC 826528 (3aA), 826526 (7eA), and 826527 (8eB) contain
the supplementary crystallographic data for this paper. These
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