Enantioselective organocatalytic cyclopropanation via ammonium ylides

Article abstract of DOI:10.1002/anie.200460234

Highly functionalized cyclopropanes can be produced with excellent enantioselectivity through an a mine-catalyzed organocatalytic cyclopropanation process (see scheme). Catalytically generated asymmetric ammonium ylides mediate the reaction, and the cyclopropane products can be produced as either enantiomer by using quinine- or quinidine-derived catalysts.

Full text of DOI:10.1002/anie.200460234

Angewandte
Chemie
Cyclopropanations
cyclopropanation reaction via ammonium ylides. This process
produces a range of functionalized molecules with excellent
diastereo- and enantioselectivity and as either enantiomer
[Eq. (3)].
Enantioselective Organocatalytic
Cyclopropanation via Ammonium Ylides**
This enantioselective catalytic cyclopropanation process
via ammonium ylides[4] has a number of advantages over its
counterparts: There are no transition metals involved in the
reaction, and the starting materials are readily available and
conveniently handled.[5] Furthermore, the number of known
chiral amines represents a significant pool from which
potential catalysts can be selected.
In this system, an a-bromo carbonyl compound 1 under-
goes SN2displacement with the tertiary amine catalyst 3 to
form a quaternary ammonium salt I. Deprotonation with mild
base forms the ylide II, which undergoes conjugate addition
to alkene 2 to form III. Finally, 3-exo-tet cyclization generates
the cyclopropane 4 and reforms the catalyst (Scheme 1).
Charles D. Papageorgiou, Maria A. Cubillo de Dios,
Steven V. Ley, and Matthew J. Gaunt*
The cyclopropane motif is a common feature in the synthesis
of complex molecules and in medicinal chemistry owing to a
unique combination of reactivity and structural properties.[1]
These properties have made the preparation of cyclopropanes
an attractive target for new methodology development.
Despite the many processes for the synthesis of functionalized
cyclopropanes, there are surprisingly few general catalytic
enantioselective methods.[2] Of the methods available, the
carbenoid-mediated reactions[2c–e] are most often utilized
[Eqs. (1,2)]; however, there are isolated examples of cata-
lytic-ylide-based enantioselective cyclopropanations.[2a,b,e]
Scheme 1. Proposed catalytic cycle.
To assess the viability of this intermolecular process,
reaction conditions were investigated with phenacyl bromide
(1a), acrylate 2a, and a stoichiometric quantity of quinine
derivative 3a (Table 1). By screening bases it became
apparent that the larger the metal cation (Na!Cs), the
better the yield of cyclopropane 4a, although the enantiose-
lectivity was lower. However, reversing the role of the starting
Recently, we described a cyclopropanation process with a
reaction that was mediated by a stoichiometric quantity of a
nucleophilic tertiary amine through the formation of an
ammonium ylide.[3] We also developed an intramolecular
version of this reaction that forms [n.1.0]bicyloalkanes as
single diastereomers.[3b] Herein, we report the evolution of
our studies and the resulting development of a general and
practical intermolecular enantioselective organocatalytic
Table 1: Optimization of reaction conditions.
[*] C. D. Papageorgiou,M. A. Cubillo de Dios,Prof. Dr. S. V. Ley,
Dr. M. J. Gaunt
Department of Chemistry
University of Cambridge
Entry
Base
Yield [%]
ee [%]
Lensfield Road,Cambridge,CB2 1EW (UK)
Fax: (+44)1223-336-442
E-mail: mjg32@cam.ac.uk
1
2
3
4
5
6
NaOH
Na2CO3
Na2CO3,[15]crown-5
K2CO3
Rb2CO3
58
19
57
61
77
84
94
96
86
86
74
71
[**] We gratefully acknowledge Pfizer Global Research and Development
(Dr. Blanda Stammen,Sandwich (UK)) and the EPSRC for an
Industrial Case Award (to C.D.P),Novartis (to S.V.L.),and
Magdalene College and Ramsay Memorial Trust (to M.J.G.) for
Research Fellowships.
Cs2CO3
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
Angew. Chem. Int. Ed. 2004, 43, 4641 –4644
DOI: 10.1002/anie.200460234
ꢀ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4641

Communications
materials so that tert-butyl bromoacetate (1b) reacted with
was used. Most importantly, when the amount of tertiary
amine was decreased to 0.2equivalents, the reaction pro-
duced the cyclopropane 4a in 96% yield with 86% ee (same
enantiomer as Table 1, entry 6).[6]
phenyl enone 2b in the presence of 3a resulted in a dramatic
change to the outcome of the reaction: cyclopropane 4a was
isolated in 96% yield with 90% ee when 1 equivalent of 3a
Table 2: Enantioselective organocatalytic cyclopropanantion.
Entry[a]
1
R1
Alkene
Product[b]
Catalyst
Yield [%]
ee [%]
OtBu (1b)
3a
3b
96
92
86 (+)
88 (ꢀ)
2b
2c
4a
4b
2
OtBu (1b)
3a
3b
73
73
84 (+)
84 (ꢀ)
3
4
OtBu (1b)
NEt2 (1c)
2d
2b
4c
4d
4e
3a
83
85 (+)
3a
3b
94
85
97 (+)
97 (ꢀ)
5
6
NMe(OMe) (1d)
NMe(OMe) (1d)
2d
2e
3c
3d
67
74
96 (+)
97 (ꢀ)
3c
3d
60
60
96 (+)
97 (ꢀ)
4 f
7
OtBu (1b)
2 f
2g
2h
2i
4g
4h
4i
3a
3a
63
75
92 (+)
80 (+)
8
9
OtBu (1b)
OtBu (1b)
3a
3d
3a
90
97 (+)
90 (ꢀ)
96 (+)
83
53[c]
10
NMe(OMe) (1d)
NMe(OMe) (1d)
3a
3d
65
77
96 (+)
92 (ꢀ)
4j
11[d]
3c
3d
74
84
95 (+)
94 (ꢀ)
2j
4k
[a] 1 (1 equiv) and 2 (1.1 equiv) were added to Cs2CO3 and 3 (20 mol%) in MeCN (0.25m) and stirred at 808C for 24 h. [b] (+)-enantiomer shown.
[c] 3a: 1 mol%. [d] 1d: 2 equiv. Boc=tert-butoxycarbonyl.
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Chemie
Having identified an asymmetric process, its scope was
investigated with the aim of producing a general catalytic
enantioselective cyclopropanation reaction. Table 2shows the
range of cyclopropanes that can be formed by this method. A
range of readily available cinchona alkaloids catalyzed the
reaction. Importantly, both enantiomers of the cyclopropanes
can be accessed in excellent yield and enantioselectivity by
using either of the pseudoenantiomeric quinine or quinidine
derivatives.[7] Interestingly, the use of alkaloid derivatives 3c
and 3d[7] (10 mol%) often gave improved yield and enantio-
selectivity when 3a or 3b failed to give good results.
Scheme 2. Synthesis of biscyclopropanes.
Bromoacetate 1b reacts with a range of aryl vinyl ketones
to form cyclopropanes 4a–c in good yield and with excellent
ee in the presence of 20 mol% of catalyst 3a. The opposite
enantiomer is also accessible by using the quinidine-derived
catalyst 3b (Table 2, entries 1–3). The role of these catalysts in
the stereochemical outcome of the reaction is currently under
investigation. It was also noticed that in some cases the slow
addition of 1 and 2 to a solution of the catalyst resulted in
higher yields. Changing the bromoacetate reagent 1b to
acetamide 1c in the reaction with enone 2b gave cyclo-
propane 4d in excellent yield with 93% ee. The more versatile
Weinreb amide derivative 1d also produces the cyclopro-
panes with excellent ee values for 4e–f.[8] High levels of
substitution can be incorporated into the cyclopropane by
using disubstituted enones or acrylates. For example, trisub-
stituted cyclopropane 4g is produced in good yield and with
high enantioselectivity. Aminocyclopropane 4i was also
formed in excellent yield and enantioselectivity, thus reflects
the power of this process, which generates a high level of
functionalization and stereocontrol on the cyclopropane core.
The catalyst loading could also be lowered to 1 mol%,
producing cyclopropane 4i in 53% yield (53 catalyst turn-
overs) after 48 h without compromising the enantioselectivity.
Cyclopropanation with bromomethyl alkyl ketones (1; R1 =
alkyl) was problematic and produced the cyclopropane in low
yields. However, the application of the alkyl-substituted
enones, such as 2i, alleviated this problem, furnishing 4j in
excellent yield and enantioselectivity. Finally, the indole-
derived cyclopropane 4k was formed in good yield and with
very high ee values, demonstrating the suitability of the
reaction for the preparation of medicinally relevant com-
pounds. To the best of our knowledge these results represent
the first general intermolecular enantioselective organocata-
lytic cyclopropanation reaction.
Although it was not possible to form diketocyclopropanes
directly by using the described method, they were accessible
from the amide 4j.[6] Thus, enone 5 could be readily generated
and subjected to a second cyclopropanation reaction to form
structurally and functionally complex biscyclopropanes 6 and
7 through reaction with 1d (Scheme 2). Interestingly, catalyst
3c produced 6 as a single diastereomer (d.r. ꢁ 99:1), whereas
catalyst 3d gave only 7 (d.r. 97:3), suggesting that the
stereoselectivity is controlled completely by the catalyst.
In summary, we have developed a new enantioselective
organocatalytic cyclopropanation reaction. Importantly, the
cyclopropanes can be produced as either enantiomer by using
the quinine or quinidine series of cinchona alkaloid catalysts.
The reaction is applicable to a range of substrates with a
variety of versatile functional groups. We are currently
investigating expansion of the scope of the reaction and
applications to the synthesis of natural and non-natural
products.
Received: April 6, 2004
Keywords: asymmetric synthesis · cyclopropanation ·
.
nitrogen heterocycles · organocatalysis · ylides
[1] a) H.-U. Reissig, R. Zimmer, Chem. Rev. 2003, 103, 1151; b) J.
Pietruszka, Chem. Rev. 2003, 103, 1051; c) W. A. Donaldson,
Tetrahedron 2001, 57, 8589.
[2] For examples of asymmetric ylide-mediated cyclopropanation
reactions, see: a) V. K. Aggarwal, E. Alonso, G. Fang, M. Ferrara,
G. Hynd, M. Porcelloni, Angew. Chem. 2001, 113, 1482; Angew.
Chem. Int. Ed. 2001, 40, 1433; b) W.-W. Lioa, K. Li, Y. Tang, J.
Am. Chem. Soc. 2003, 125, 13030; for examples of carbenoid-
mediated processes, see: c) S. E. Denmark, S. P. OꢀConnor, S. R.
Wilson, Angew. Chem. 1998, 110, 1162; Angew. Chem. Int. Ed.
1998, 37, 1149, and references therein; d) A. B. Charette, C.
Molinaro, C. Brochu, J. Am. Chem. Soc. 2001, 123, 12168; e) for a
review, see: H. Lebel, J.-F. Marcoux, C. Molinaro, A. B. Charette,
Chem. Rev. 2003, 103, 977.
[3] a) C. D. Papageorgiou, S. V. Ley, M. J. Gaunt, Angew. Chem.
2003, 115, 852; Angew. Chem. Int. Ed. 2003, 42, 828; b) N.
Bremeyer, S. C. Smith, S. V. Ley, M. J. Gaunt, Angew. Chem.
2004, 116, 2735; Angew. Chem. Int. Ed. 2004, 43, 2681.
[4] a) S. S. Bhattacargee, H. Ila, H. Junjappa, Synthesis 1982, 301;
b) A. Jonczyk, A. Konarska, Synlett 1999, 1085.
[5] a) P. I. Dalko, L. Moisan, Angew. Chem. 2001, 113, 3840; Angew.
Chem. Int. Ed. 2001, 40, 3726; b) S. P. Brown, M. P. Brochu, C. J.
Sinz, D. W. C. MacMillan, J. Am. Chem. Soc. 2003, 125, 10800;
c) P. Chandrakala, H. Linh, N. Vignola, B. List, Angew. Chem.
2003, 115, 2891; Angew. Chem. Int. Ed. 2003, 42, 2785, and
references therein.
[6] See Supporting Information for full experimental information
relating to stereochemical assignment and the determination of ee
values. General experimental procedure: One-pot method: The
catalyst 3a, 3b (0.2equiv) or 3c, 3d (0.1 equiv), was added to a
solution of the a-bromo carbonyl compound (1.0 equiv), the
alkene (1.2equiv), and Cs 2CO3 (1.2equiv) in MeCN (0.25 m) and
stirred at 808C for 24 h. The reaction was quenched with aqueous
HCl (1m) and extracted three times with Et2O or EtOAc. The
combined organic phases were washed with a saturated aqueous
solution of NaHCO3, dried (MgSO4), and concentrated under
reduced pressure. The residue was purified by flash column
chromatography. Slow addition method: A solution of the a-
bromo carbonyl compound (1.0 equiv) and the alkene (1.2equiv)
in MeCN (0.25m with respect to the a-bromo carbonyl com-
Angew. Chem. Int. Ed. 2004, 43, 4641 –4644
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Communications
pound) was added to a solution of the catalyst 3a, 3b (0.2equiv)
or 3c, 3d (0.1 equiv) and Cs2CO3 (1.2equiv) in MeCN (0.25 m) at
808C over 20 h by means of a syringe pump. The syringe was
rinsed with MeCN and the reaction mixture stirred for a further
4 h. The reaction was quenched with aqueous HCl (1m) and
extracted three times with Et2O or EtOAc. The combined organic
phases were washed with a saturated aqueous solution of
NaHCO3, dried (MgSO4), and concentrated under reduced
pressure. The residue was purified by flash column chromatog-
raphy.
[7] For a recent review, see: S. France, D. J. Guerin, S. J. Miller, T.
Leckta, Chem. Rev. 2003, 103, 2985.
[8] The amide derivatives 1c–d give higher enantioselectivities (5–
10%) than reactions with 1b, although the yields are slightly
lower (10–20%).
4644
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Angew. Chem. Int. Ed. 2004, 43, 4641 –4644