Synthesis of functionalized cyclopentenes through catalytic asymmetric [3+2] cycloadditions of allenes with enones

Article abstract of DOI:10.1002/anie.200503312

(Chemical Equation Presented) A phosphepine catalyst mediates enantioselective [3+2] cycloadditions of allenes with a variety of β-substituted α,β-unsaturated enones to produce highly functionalized cyclopentenes that contain two contiguous stereocenters (see scheme). Surprisingly, opposite regioisomers are produced as compared to reactions with β-unsubstituted enones.

Full text of DOI:10.1002/anie.200503312

Communications
Asymmetric Synthesis
DOI: 10.1002/anie.200503312
Synthesis of Functionalized Cyclopentenes
through Catalytic Asymmetric [3+2]
Cycloadditions of Allenes with Enones**
Jonathan E. Wilson and Gregory C. Fu*
Five-membered carbocycles are a common substructure in a
wide array of natural and nonnatural products.[1] Among this
family of compounds, cyclopentenes are particularly impor-
tant targets, in part because derivatization of the olefin often
occurs with good diastereoselectivity, thereby providing
access to highly functionalized, stereochemically complex
cyclopentanes. Although considerable progress has been
described in developing methods for the asymmetric synthesis
of cyclopentenes, the number of effective catalytic enantiose-
lective processes is comparatively small.[2]
Recently, nucleophilic catalysis by phosphines has
emerged as a powerful tool in synthetic organic chemistry.[3]
For example, tertiary phosphines catalyze a variety of
annulation reactions, including Luꢀs [3+2] cycloaddition of
allenes with olefins to generate cyclopentenes.[4] In 1997,
Zhang et al. reported a pioneering study in which he
established that a chiral phosphine can furnish good enantio-
selectivity in this process; with respect to scope, only
unsubstituted acrylate esters and diethyl maleate react with
the allene to form the target cyclopentenes in high enantio-
meric excess (ee) [Eq. (1) and (2)].[5]
[*] J. E. Wilson, Prof. Dr. G. C. Fu
Department of Chemistry
Massachusetts Institute of Technology
Cambridge, MA 02139 (USA)
Fax: (+1)617-324-3611
E-mail: gcf@mit.edu
[**] We thank Luke Firmansjah and Dr. Peter Mueller for assistance (X-
ray crystallography) and the Jamison group for a sample of (R)-
nmdpp. Support has been provided by the NIH (National Institute
of General Medical Sciences: R01-GM57034; National Cancer
Institute: training grant CA009112), Merck Research Laboratories,
and Novartis. Funding for the MIT Department of Chemistry
Instrumentation Facility has been furnished in part by NSF CHE-
9808061 and NSF DBI-9729592.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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Table 1: Survey of chiral phosphine catalysts for the [3+2] cycloaddition
of allenes with enones.[a]
Entry
Phosphine[b]
Yield [%][c]
ee [%][d]
A:B
13:1
–
>20:1
11:1
6:1
1
2
3
4
5
6
7
(R)-2
(S)-binapine
(R)-binap
(R)-nmdpp
(R,R)-Me-bpe
(R,R)-ferrotane
(R,R)-Et-DuPhos
64
0
2
88
–
50
À4
À4
11
58
4
61
64
61
7:1
7:1
[a] All data are the average of two experiments. [b] binap
= 2,2’-
In general, there has been only very limited progress to
date in the development of effective phosphine-based meth-
ods for asymmetric nucleophilic catalysis.[6] We recently
reported that phosphepine 2, which was originally designed
as a ligand for metal-catalyzed processes,[7] catalyzes [4+2]
annulations of allenes with imines to generate piperidine
derivatives with good enantioselectivity.[6c,8] Since that initial
study, we have been exploring the utilization of this phos-
phepine for a wide array of nucleophile-catalyzed reactions.
Herein, we establish that 2 catalyzes enantioselective [3+2]
cycloadditions of allenes with a variety of b-substituted a,b-
unsaturated enones to produce highly functionalized cyclo-
pentenes that contain two contiguous stereocenters [Eq. (3)].
Bis(diphenylphosphanyl)-1,1’-binaphthyl, nmdpp = neomenthyldiphe-
nylphosphine. Molecular structures of (S)-binapine, (R,R)-Me-bpe, (R,R)-
ferrotane, and (R,R)-Et-DuPhos are shown in Ref. [17]. [c] Yield of
isolated A and B. [d] Enantiomeric excess of A. A negative value for ee
signifies that the shown enantiomer of cyclopentene A is the minor
product, rather than the major.
Table 2: Synthesis of functionalized cyclopentenes through catalytic
asymmetric [3+2] cycloadditions.[a]
Entry
R
R1
Yield [%][b] ee [%][c] A:B
1
2
3
4
Ph
Ph
Ph
Ph
Ph
64
88
82
87
88
13:1
7:1
20:1
4-chlorophenyl 76
4-methylphenyl 61
4-methoxy-
phenyl
54
>20:1
5
6
4-chlorophenyl Ph
74
67
87
87
9:1
10:1
4-methoxy-
phenyl
Ph
7
2-furyl
Ph
Ph
69
52
54
88
88
89
3:1
20:1
>20:1
In a preliminary investigation, we surveyed the use of
phosphepine 2 and a variety of commercially available mono-
and bisphosphines as catalysts for the asymmetric cyclo-
addition of ethyl-2,3-butadienoate and chalcone (Table 1).
Whereas 2 furnishes the target cyclopentene in good yield, ee,
and regioselectivity (Table 1, entry 1), the other phosphines
are either ineffective as catalysts (Table 1, entries 2–4) or
provide relatively poor enantiomeric excess (Table 1,
entries 5–7).
Phosphepine 2 catalyzes the asymmetric [3+2] cyclo-
addition of allenes with a wide array of enones (Table 2).[9] It
is worth noting that these are the first such processes that
employ b-substituted a,b-unsaturated carbonyl compounds
(other than diethyl maleate)[10] and that the opposite regio-
isomer is produced preferentially as compared with substrates
that lack a b substituent [cf. Eq. (1)].[4,5]
8[d] 2-quinolyl
9[d] 4-chlorophenyl 2-(5-methyl-
furyl)
10
11
12
13
Ph
2-thienyl
Ph
Ph
74
65
90
85
87
75
6:1
6:1
>20:1
>20:1
ꢀ
C CC5H11
ꢀ
C CTES
70
C5H11
Ph
39[e]
[a] All data are the average of two experiments. All cycloadditions
employed 1.2 equiv of allene, except for entries 4, 6, 7, and 13, for which
2.0 equiv was used. [b] Yield of isolated A and B. [c] Enantiomeric excess
of A. [d] Because of the low solubility of the enone in toluene, CH2Cl2 was
employed as a co-solvent. [e] The enone can be recovered in 56% yield.
tions of electron-rich substrates proceed somewhat less
efficiently and therefore require additional allene (2.0
equivalents, rather than 1.2; Table 2, entries 4 and 6). The
method tolerates heterocyclic substituents in either the b
position (Table 2, entries 7 and 8) or attached to the carbonyl
group (Table 2, entries 9 and 10) of the enone.
The desired cyclopentene is generated in good enantio-
meric excess for both electron-rich and electron-poor chal-
cone derivatives (Table 2, entries 2–6), although cycloaddi-
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This process is not limited to b-(hetero)aryl enones. For
example, phosphepine 2 catalyzes cycloadditions of enones
that bear a b-alkynyl group with good enantiomeric excess
(Table 2, entries 11 and 12). Under our standard conditions, if
an alkyl substituent occupies the b position, formation of the
cyclopentene proceeds sluggishly, but with fairly good selec-
tivity (Table 2, entry 13).
Catalyst 2 can achieve the enantioselective synthesis of
spirocyclic compounds through reactions of trisubstituted
enones, thereby generating adjacent quaternary[11] and ter-
tiary stereocenters [Eq. (4); a single regioisomer is pro-
enones. We have determined that b-substituted enones
undergo reaction with a different regiochemical preference
compared with previously described cycloadditions of b-
unsubstituted a,b-unsaturated carbonyl compounds. We have
applied our method to reactions of trisubstituted olefins,
thereby generating adjacent quaternary and tertiary stereo-
centers. Finally, we have established that the product cyclo-
pentenes can be stereoselectively derivatized to provide
cyclopentanes that bear four contiguous stereocenters. Ongo-
ing efforts are directed at further expanding the currently
limited range of enantioselective processes catalyzed by chiral
phosphine nucleophiles.
duced].[12–14] This method is not entirely general—the cyclo-
addition of an indanone proceeds in excellent yield, however,
the reaction of a closely related tetralone is considerably less
efficient [but highly enantioselective; Eq. (4)].[15]
Dienones are also suitable substrates, undergoing a single
phosphine-catalyzed [3+2] cycloaddition [Eq. (5) and (6);
Received: September 17, 2005
Published online: January 30, 2006
Keywords: asymmetric synthesis · cycloaddition ·
.
homogeneous catalysis · phosphanes
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[2] For recent examples of processes in which the asymmetry is
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[4] a) C. Zhang, X. Lu, J. Org. Chem. 1995, 60, 2906 – 2908; b) Z. Xu,
X. Lu, Tetrahedron Lett. 1999, 40, 549 – 552; c) X. Lu, C. Zhang,
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only one regioisomer is observed]). Although for symmetrical
dienones there is no issue of site selectivity, this complication
does arise for unsymmetrical compounds. Interestingly,
phosphepine 2 can achieve enantioselective cycloadditions
with complete site selectivity [Eq. (6)].
We had anticipated that the enantiomerically enriched
cyclopentenes generated in these asymmetric [3+2] cyclo-
additions should be attractive substrates for further function-
alization. An example of such a process, which produces a
diastereomerically pure cyclopentane that bears four contig-
uous stereocenters, is illustrated in Equation (7).[16]
[5] G. Zhu, Z. Chen, Q. Jiang, D. Xiao, P. Cao, X. Zhang, J. Am.
Chem. Soc. 1997, 119, 3836 – 3837.
[6] a) E. Vedejs, O. Daugulis, S. T. Diver, J. Org. Chem. 1996, 61,
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Chem. Soc. 2005, 127, 3790 – 3800; c) R. P. Wurz, G. C. Fu, J. Am.
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[7] a) S. Gladiali, A. Dore, D. Fabbri, O. De Lucchi, M. Manassero,
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Riermeier, U. Dingerdissen, M. Beller, Angew. Chem. 2004, 116,
In summary, we have described the first nucleophile-
catalyzed asymmetric [3+2] cycloadditions of allenes with
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5176 – 5179; Angew. Chem. Int. Ed. 2004, 43, 5066 – 5069, and
references therein.
[8] For the initial report of this annulation method, see: X.-F. Zhu, J.
Lan, O. Kwon, J. Am. Chem. Soc. 2003, 125, 4716 – 4717.
[9] Notes: a) Under these conditions, a,b-unsaturated ketones in
which R1 = alkyl or alkynyl or R = alkenyl (Table 2), a,b-
unsaturated esters that bear a b substituent, p-benzoquinone,
and N-phenylmaleimide are not suitable coupling partners.
Benzyl and allyl-2,3-butadienoate are less reactive than ethyl-
2,3-butadienoate. b) If access to racemic cyclopentenes is
desired, PPh3 or PBu3 can be employed as the catalyst. c) Use
of THF or CH2Cl2 as the solvent leads to poorer yield and
regioselectivity. d) At lower temperature, the rate of cyclo-
addition decreases significantly, with only a small gain in ee.
e) According to 31P NMR spectroscopy, phosphepine 2 is the
predominant phosphorus-containing species that is present
during the [3+2] cycloaddition process. f) To the best of our
knowledge, the stereochemistry of the enone is preserved in the
cyclopentene.
[10] For non-asymmetric reactions, only maleates and fumarates
have been shown to be suitable substrates. Lu et al. (e.g.,
ref. [4a]) and Zhang et al. (ref. [5]) were unable to achieve
cycloadditions of other b-substituted a,b-unsaturated carbonyl
compounds.
[11] For a recent discussion of the challenge of developing catalytic
asymmetric methods for the synthesis of quaternary all-carbon
centers, see: C. J. Douglas, L. E. Overman, Proc. Natl. Acad. Sci.
USA 2004, 101, 5363 – 5367.
[12] Lu et al. have described phosphine-catalyzed [3+2] cycloaddi-
tions that generate spirocycles from enones that lack a b
substituent (refs. [4d] and [4e]). They observe predominant
formation of a different regioisomer (the two carbonyl groups
are in a 1,3 relationship on the cyclopentene ring) from that
depicted in Equation (4).
[13] For leading references to an example of a naturally occurring
spiroindanone that bears an all-carbon quaternary stereocenter
(fredericamycin A), see: Y. Kita, K. Higuchi, Y. Yoshida, K. Iio,
S. Kitagaki, K. Ueda, S. Akai, H. Fujioka, J. Am. Chem. Soc.
2001, 123, 3214 – 3222.
[14] For another recent example of a catalytic asymmetric method for
the synthesis of spirocyclic compounds wherein an all-carbon
quaternary stereocenter is established in the cyclization process,
see: M. Hatano, K. Mikami, J. Am. Chem. Soc. 2003, 125, 4704 –
4705.
[15] For the tetralone, a considerable quantity of unreacted starting
material was observed. Increasing the amount of allene did not
improve the yield.
[16] These conditions were developed by Nakamura and Kuwajima:
S. Matsuzawa, Y. Horiguchi, E. Nakamura, I. Kuwajima,
Tetrahedron 1989, 45, 349 – 362.
[17] Molecular structures of phosphine catalysts given in Table 1:
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