Iron and ruthenium Lewis acid catalyzed asymmetric 1,3-dipolar cycloaddition reactions between nitrones and enals

Article abstract of DOI:10.1021/ja017814f

The single coordination-site transition metal Lewis acids [CpM(BIPHOP-F)][SbF₆] (M = Fe, Ru) catalyze the [3+2] dipolar cycloaddition reaction between reactive nitrones and α,β-unsaturated aldehydes to give chiral isoxazolidines with ee values

Full text of DOI:10.1021/ja017814f

Published on Web 04/11/2002
Iron and Ruthenium Lewis Acid Catalyzed Asymmetric 1,3-Dipolar
Cycloaddition Reactions between Nitrones and Enals
†
§
,†
Florian Viton, G e´ rald Bernardinelli, and E. Peter K u¨ ndig*
UniVersity of GeneVa, Department of Organic Chemistry and Laboratory of X-ray Crystallography,
CH-1211 GeneVa 4, Switzerland
Received December 19, 2001
Enantiomerically pure isoxazolidines are direct precursors of
chiral 1,3-amino alcohols which are effective synthons for the
assigned to the nitrone complex 5. Signal integration indicated a
ratio of crotonaldehyde complex 4 to nitrone complex 5 of 7:3.
This ratio could be shifted further in favor of complex 4 by adding
more crotonaldehyde. The above observations attest to the prefer-
ence of aldehyde over nitrone coordination by the Ru complex and
to the reversibility of coordination of both substrates. They were
rendered possible because of the low reactivity of this nitrone toward
the Lewis acid coordinated crotonaldehyde. As only traces of
cycloaddition products were observed with these reaction partners,
we turned our attention toward more reactive nitrones.
assembly of biologically active compounds such as â-lactams,
1
â-amino acids, and alkaloids. With its potential for the control of
up to three contiguous stereogenic centers, the chiral Lewis acid
catalyzed 1,3-dipolar cycloaddition reaction between nitrones and
alkenes is a direct and versatile route to these compounds. Both
nitrone activation and the activation of R,â-unsaturated carbonyl
compounds have been developed successfully.2 The former is
essential in inverse electron-demand reactions while the latter is
required for normal electron-demand cycloadditions with two-point
3
binding substrates. The simpler R,â-unsaturated aldehydes would
be very attractive substrates but they have been shown to be poor
performers. With a one-point binding Lewis acid, coordination of
the nitrone is favored over coordination of the aldehyde and this
results in an effective blocking of the catalyzed reaction pathway.4
We wish to report here that this problem can be solved via the
judicious choice of the chiral Lewis acid and we here present the
first asymmetric Lewis acid catalyzed 1,3-dipolar cycloaddition
Confirming our starting hypothesis, the reaction of methacrolein
with C,N-diaryl nitrones 6a-c in the presence of catalysts 1-2
yielded the isoxazolidines endo-7a-c and endo-8a-c in moderate
to high enantio- and regioselectivities and complete endo/exo
selectivity. The pronounced endo preference of the reaction made
the highly exo-selective indenyl catalyst 3 unsuitable for this
5
reactions between nitrones and R,â-unsaturated aldehydes. We note
that this transformation has recently been achieved via an elegant,
efficient, and highly enantioselective organocatalyzed route.6
The readily prepared, mild Fe and Ru Lewis acids 1-3
effectively catalyze the asymmetric Diels-Alder reaction of dienes
7
7a
with enals. Structural and mechanistic studies have provided a
reaction, giving only poor yields of mixtures of endo/exo 7/8
8
detailed picture of enal coordination and chiral environment in these
reactions. We reasoned that the highly tuned aldehyde-selective
chiral Lewis acid site might be able to discriminate between enals
and nitrones and either favor coordination of the first or bind
nitrones in a readily reversible manner.
adducts. The low solubility of nitrones 6b-c resulted in much
longer reaction times. This turned out to be problematic with the
less stable Fe catalyst 1 and led us to explore a different set of
nitrones.
Table 1. Asymmetric 1,3-Dipolar Cycloadditions between
Methacrolein and Nitrones 6a-c
To test this hypothesis we first carried out qualitative 31P NMR
experiments of competitive nitrone-aldehyde Lewis acid coordina-
tion. The 31P NMR spectrum of the crotonaldehyde complex 4,
formed upon addition of 2 equiv of the aldehyde to complex 2 (1
entry
catalyst
nitrone
yield (%)
endo-7/endo-8
ee 7/8 (%)
1a
2
(R,R)-1
(R,R)-2
(R,R)-2
(R,R)-2
6a
6a
6b
6c
85
92
80
79
80/20
60/40
100/0
90/10
87/91
76/94
66/-
74/-
b
equiv) in CD
707 Hz, JAB ) 70 Hz). Upon addition of 10 equiv of
N-benzylidenebenzylamine N-oxide a new AB quartet grew in
2
Cl
2
consisted of an AB quartet at 126.3 ppm (∆νAB
3
4
)
a
Reaction performed in the presence of 2,6-lutidine (5 mol %, scavenger
(125.9 ppm, ∆νAB ) 332 Hz, JAB ) 69 Hz) and was tentatively
of acid impurities). b Reaction performed at 0 °C.
*
Corresponding author. E-mail: peter.kundig@chiorg.unige.ch.
Department of Organic Chemistry, 30 Quai Ernest Ansermet.
Laboratory of X-ray Crystallography, 24 Quai Ernest Ansermet.
First experiments with pyrrolidine N-oxide 9 and methacrolein
confirmed the high reactivity of this nitrone (Table 2, entry 1).
†
§
9
4968
9
J. AM. CHEM. SOC. 2002, 124, 4968-4969
10.1021/ja017814f CCC: $22.00 © 2002 American Chemical Society

C O MMU N I C A T I O N S
Presumably because of the background reaction the ee of the
reaction with an equimolar mixture of methacrolein and nitrone 9
in the presence of (R,R)-1 was a low 26% (entry 2). The improved
yield and the fact that 10 was formed as a nonracemic mixture
indicated, however, that the nitrone 9 was not blocking the Lewis
acid catalyst site. Varying the nitrone:methacrolein ratio showed
the expected variation in product enantioselectivity (entries 3-4).
In all reactions, isoxazolidine 10 was formed as a single regio-
and diastereoisomer. Recognizing the need to keep the nitrone
concentration low in order to suppress the background reaction, a
2 2
0.8 M solution of 9 in CH Cl was added slowly to the catalyst/
enal reaction mixture. This afforded product 10 in excellent yield
and high enantiomeric purity when the Fe catalyst (R,R)-1 was used
Figure 1. Endo addition of 9 to the alkene CR-Si-face or CR-Re-face in
+
[CpFe((R,R)-BIPHOP-F)(methacrolein)] (enal in s-trans conformation).
(
entry 5). It also allowed a reduction of the catalyst loading. The
7b
Ru catalyst (R,R)-2 is a slightly weaker Lewis acid than 1. It also
has a larger catalyst site and the two factors account for the inferior
performance of 2 compared to 1 in this reaction (entries 6-7).
dition through an endo approach of the nitrone minimizes steric
interactions between the nitrone ring, the enal methyl group, and a
C F
6 5
ring of the catalyst. Product 13 is formed in lower enantiomeric
purity. It can be argued that addition to the s-cis enal C -Re-face
R
becomes more important here because the reversed regiochemistry
of the reaction results in a more hindered endo approach of the
nitrone to the C -Si-face in the enal s-trans conformation.
R
In conclusion, we have shown that single coordination site
transition metal Lewis acids can efficiently promote enantioselective
1,3-dipolar cycloadditions of nitrones with R,â-unsaturated enals
and represent a rapid access to substrates of high synthetic potential.
Table 2. Fe- and Ru-Lewis Acid Catalyzed 1,3-Dipolar
Cycloadditions between Methacrolein and Nitrone 9
na
entry
catalyst (mol %)
yield (%)
ee (%)
45b
Acknowledgment. This work was supported by the Swiss
National Science Foundation (FNS grant 20-59374.99).
1
2
3
4
1.2
1.2
0.2
5.0
1.2
1.2
1.2
(R,R)-1 (10)
(R,R)-1 (10)
(R,R)-1 (10)
(R,R)-1 (5)
(R,R)-2 (5)
(R,R)-2 (5)
84
87
85
92
61
88
26
12
54
96
44
67
Supporting Information Available: Experimental procedures and
physical data of products 7, 8, 10, 12, 13, 15, and 16 (product of
reductive amination of (-)-(3S,5S)-10 with (1R,2S)-norephedrine) and
crystallographic data, bond lengths, bond angles, dihedral angles, and
hydrogen bonds (PDF); X-ray crystallographic file (CIF) for (-)-16.
This material is available free of charge via the Internet at http://
pubs.acs.org.
c
5
c
6
7
d
a
Enal/nitrone ratio. Isolated yield after 20 h. c Dropwise addition of 9
b
d
over 18 h. Dropwise addition of 9 over 36 h.
The superior level of asymmetric induction and the higher activity
of the Fe catalyst prompted us to select this catalyst for the
additional examples detailed in Table 3. The (R,R)-catalysts afforded
products (-)-endo-(3S,5S)-10 and (-)-endo-(3R,4S,5R)-13 (see
Supporting Information). The X-ray structure of the catalyst
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