An intramolecular organocatalytic cyclopropanation reaction

Article abstract of DOI:10.1002/anie.200454007

Nucleophilic tertiary amines catalyze an intramolecular cyclopropanation reaction to give [n.1.0]bicycloalkanes in good yield (see scheme). The reaction is tolerant of a wide range of functional groups and is highly diastereoselective. Furthermore, when a

Full text of DOI:10.1002/anie.200454007

Angewandte
Chemie
molecular cyclopropanation reaction that forms synthetically
versatile [n.1.0]bicycloalkanes by using a nucleophilic tertiary
amine catalyst.
The synthesis of these bicycloalkanes is most commonly
carried out by inter- or intramolecular metal-catalyzed
carbene transfer of diazo compounds to electron-rich alkenes
[Eq. (1)].[5] Other than these methods there are few general
alternatives to form [n.1.0]bicycloalkanes.[5c,6] [n.1.0]Bicy-
cloalkanes offer many exciting applications in complex
molecule synthesis due to the high levels of stereochemistry
and latent reactivity inherent within their structure.[7] There-
fore, new complementary methods for their catalytic enan-
tioselective synthesis are very important. We have identified
an interesting organocatalytic intramolecular cyclopropana-
tion process that is stereoselective and produces highly
functionalized bicycloalkanes that contain three stereocen-
tres, two rings, and three levels of orthogonal functionality in
a single step from linear building blocks [Eq. (2)].
Intramolecular Cyclization
An Intramolecular Organocatalytic
Cyclopropanation Reaction**
In this approach an a-chloroketone with a tethered
electron deficient alkene reacts through a catalytically
generated ammonium ylide to form the bicyclic structure
[Eq. (2)]. This organocatalytic strategy precludes the use of
highly sensitive diazo compounds. It should also offer a wider
scope of substrates owing to compatibility with the metal-free
catalyst, and produce bicylcoalkanes with higher levels of
functionality. Furthermore, there are many readily available
chiral tertiary amines from which an enantioselective process
can be developed.
Nadine Bremeyer, Stephen C. Smith, Steven V. Ley, and
Matthew J. Gaunt*
Catalytic processes that form functionalized cyclic molecules
represent a key transformation for synthetic organic chemis-
try.[1,2] Recently, a number of organocatalytic processes have
emerged that often provide excellent levels of both enantio-
and diastereocontrol for the synthesis of cyclic molecules.[3,4]
Our recent studies have identified the utility of ammoni-
um ylides for carbon–carbon bond formation. Herein we
describe the development of a new organocatalytic intra-
A proposed catalytic cycle is shown in Scheme 1. The
amine catalyst I displaces the chloride in 1 to give the
[*] N. Bremeyer, Prof. Dr. S. V. Ley, Dr. M. J. Gaunt
Department of Chemistry, University of Cambridge, Lensfield Road,
Cambridge, CB2 1EW (UK)
Fax: (+44)122-333-6442
E-mail: mjg32@cam.ac.uk
Dr. S. C. Smith
Syngenta, Jealott's Hill International Research Centre, Bracknell,
Berkshire, RG42 6EY (UK)
[**] We gratefully acknowledge financial support from Syngenta UK for
Industrial Case Award (to N.B.), the Novartis Research Fellowship
(to S.V.L.) and the Ramsay Memorial Trust and Magdalene College
for Research Fellowship (to M.J.G.).
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
Scheme 1. Proposed catalytic cycle.
Angew. Chem. Int. Ed. 2004, 43, 2681 –2684
DOI: 10.1002/anie.200454007
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2681

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quaternary ammonium salt II. Deprotonation forms the
Grubbs second-generation catalyst, formed the desired sub-
strate 1 in good yield.[10] Furthermore, the functional-group
sensitivity of alkenyl a-chloroketones clearly demonstrates
the mild nature of the alkene cross-metathesis process
(Table 2).
ammonium ylide III and intramolecular conjugate addition
forms IV and finally the bicycloalkane 2 is generated through
displacement of the ammonium group, concurrently regener-
ating catalyst I.
To assess the viability of this intramolecular process, a
range of reaction conditions were investigated by using
alkenyl chloroketone 1a, the results of which are summarized
in Table 1. At room temperature little or no reaction was
observed in dichloromethane when 20 mol% of 1,4-diazabi-
Table 2: Synthesis of alkenyl chloroketones 1.
Alkene-cross metathesis
Table 1: Effect of reaction conditions for the conversion of 1a into 2a.
Entry
Alkene
t [h]
Yield
1
2
3
4
12
12
9
82
83
80
85
Entry
Solvent
T [8C]
H22
H45
E
t [h]
Yield
d.r.
18
1
2
3
4
C
C
2Cl2
2Cl2
48
48
60
<10
45
18
>95:5
>95:5
>9915:5
>95:5
[a] 2 equiv ClCH2I, 1.5 equiv MeLi, Et2O, À788C, 0.5 h; [b] the Grubbs
second-generation catalyst (2.5 mol%), 1.5 equiv Alkene, CH2Cl2, 458C.
EWG=electron withdrawing group.
DC
MeCN
80
5
84
The scope of the intramolecular cyclopropanation reac-
tion was subsequently investigated under the optimized
conditions.[11] The results in Table 4 (next page) demonstrate
that the reaction is applicable with many types of function-
ality and all examples produced a single diastereoisomer.
The most reactive substrates were enones 1a–c, which
form the cyclopropanes 2a–c in excellent yields. The reaction
with enoate 1e also progressed well in MeCN at 808C to
afford 2e. Unsaturated sulfone 1 f delivered the desired
product 2 f in moderate yield, however, most pleasing was the
formation of aldehyde 2d isolated in 82% yield from 1d. This
demonstrates that even sensitive functional groups are
compatible with this process. Moreover, aldehyde 2d is a
versatile scaffold for subsequent elaboration. The reaction
also worked with diene 1g to form the vinyl cyclopropane 2g
in 72% yield. [3.1.0]Bicyclohexanes that contained a five-
membered ring system could also be formed as single
diastereoisomers. Heteroatoms were compatible with the
reaction and amide derivative 1i gave the heterocycle 2i in
81% yield. In all examples no background cyclopropanation
was observed in the absence of catalyst.
cyclo[2.2.2]octane (DABCO) as catalyst and 1.3 equivalents
of sodium carbonate as base were used (entry 1). At elevated
temperature (458C) the yield rose to 45%, but the reaction
was slow (entry 2). With 1,2-dichloroethane (DCE) as solvent
and reaction at 608C a 91% yield of 2a was isolated after 18 h
(entry 3). A similar yield was obtained for reaction in
acetonitrile (MeCN) at 808C with a reduced reaction time
of 5 h. Catalytic quantities of quinuclidine could also be used,
thus producing similar results to DABCO, although few other
tertiary amines gave acceptable reaction. The choice of base
was important due to a potential background reaction. After
screening a range of organic and inorganic bases, sodium
carbonate was found to be the optimal choice. Importantly, a
single diastereoisomer was formed and no background
reaction was observed in the absence of the catalyst. There-
fore, in a single transformation this catalytic process effects
the stereocontrolled formation of three stereocenters, two
carbon–carbon bonds, and two rings from an acyclic molecule.
Once an intramolecular cyclopropanation process had
been identified, a reliable and operationally simple two-step
synthesis of the precursors 1 was
developed. Alkenyl a-chloroke-
Table 3: Enantioselective organocatalytic cyclopropanation.[a]
tone 4 was formed by using a
modification of the procedure
reported by Barluenga et al.,[9] in
which lithiochloromethane (gener-
ated in situ through the addition of
methyllithium to
chloroiodomethane) reacts with a
Weinreb amide to form the
a solution of
Entry
Catalyst loading
t [h]
Additive
Yield [%]
ee [%]
3
desired chloroketone 4 in excellent
yield. Alkene cross-metathesis
between the alkenyl a-chloroke-
tone 4 and an electron-deficient
alkene by using 2.5 mol% of the
1
2
3
4
20 mol% 5
20 mol% 5
20 mol% 5
20 mol% 6
96
24
24
24
-
67
61
64
48
64 (+)
94 (+)
95 (+)
94 (À)
40 mol% NaBr
40 mol% NaI
40 mol% NaBr
[12]
[a] Reagents and conditions: catalyst, 1.3 equiv Na2CO3, MeCN, 808C , 24 h.
2682
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Chemie
Table 4: Scope of the intramolecular cyclopropanation reaction under optimal conditions.
excellent result represents the first
enantioselective organocatalytic
intramolecular cyclopropantion
reaction. The use of NaI as an
additive gave a similar yield and
enantiomeric excess. Moreover,
with amine 6 as catalyst, the oppo-
site cyclopropane enantiomer was
obtained with an excellent ee value
(94%), thus demonstrating the
potential efficacy of this organo-
catalytic process (see Table 3).
Entry
1[a]
Substrate
Time
18
Product
Yield%
1a
1b
1c
1d
1e
1 f
2a
2b
2c
2d
2e
2 f
91
2[a]
3[b]
4[b]
5[b]
6[b]
2
95
90
82
65
42
In summary, we have devel-
oped an organocatalytic intramo-
lecular cyclopropanation reaction
for the formation of synthetically
versatile [n.1.0]bicycloalkanes as
single diastereoisomers. This pow-
erful catalytic process effects the
controlled formation of three ster-
eocenters, two carbon–carbon
bonds, and two rings in a single
transformation. The reaction is
enantioselective with a catalytic
amount of chiral amine and can
form either enantiomer. We are
currently exploring the scope of
the catalytic enantioselective proc-
ess and applications towards the
synthesis of complexmolecules.
7
2
9
18
7[b]
1g
11
9
2g
72
50
Received: February 12, 2004 [Z54007]
Published Online: April 28, 2004
8[b]
1h
1i
2h
2i
Keywords: cyclization ·
.
cyclopropanation ·
diastereoselectivity ·
enantioselectivity · homogeneous
catalysis
9a[b]
9b[b]
9
9
48
65[c]
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2684
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