Organocatalytic enantioselective desymmetrization of cyclic enones via phosphine promoted [3+2] annulations

Article abstract of DOI:10.1039/c0cc03164j

Phosphine catalyzed enantioselective [3+2] cyclizations on 4-substituted 2,6-diarylidenecyclohexanones and 2,4-diarylidene-bicyclo[3.1.0]hexan-3-ones take place with high diastereo- and enantioselectivity levels. The process affords spirocyclic compounds with excellent stereochemical control of up to five stereogenic centres.

Full text of DOI:10.1039/c0cc03164j

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Organocatalytic enantioselective desymmetrization of cyclic enones via
phosphine promoted [3+2] annulationsw
Nathalie Pinto, Pascal Retailleau, Arnaud Voituriez and Angela Marinetti*
Received 10th August 2010, Accepted 12th October 2010
DOI: 10.1039/c0cc03164j
Phosphine catalyzed enantioselective [3+2] cyclizations on
4-substituted 2,6-diarylidenecyclohexanones and 2,4-diarylidene-
bicyclo[3.1.0]hexan-3-ones take place with high diastereo- and
enantioselectivity levels. The process affords spirocyclic
compounds with excellent stereochemical control of up to five
stereogenic centres.
has been applied recently to the challenging synthesis of
spirocyclic cyclopentenes, leading to good stereochemical
control of two stereogenic carbons, including the quaternary
carbon at the ring junction (Scheme 1b).6b,7a,8
The efficient stereochemical control attained in these
annulation reactions makes them well suitable for implementing
desymmetrization processes. Therefore, as a further step
toward enantiomerically enriched molecules of increased
complexity, we have envisioned application of the organo-
catalytic [3+2] cyclizations to the prochiral cyclic enones 1
and 4. Our aim is to control the stereogenicity of the prochiral
ring carbons, in order to create up to five stereogenic centres
by a single process.
Desymmetrization is one of the most powerful synthetic tools
for the stereocontrolled preparation of chiral molecules from
simple and easily available starting materials. Among
others, enantioselective organocatalytic methods have been
successfully applied to these processes. Relevant recent
examples are the desymmetrizations of prochiral cyclohexanones
and cyclohexadienones via aldol or Michael type reactions
which are performed in the presence of chiral Brønsted acids,1
nitrogen bases2 or ionic liquids.3 As an extension of this
strategy, we disclose here the first desymmetrization of cyclo-
hexanone derivatives based on enantioselective phosphine
organocatalysis.
The first series of targeted substrates have been the
4-substituted 2,6-bis(benzylidene)cyclohexanones 1,9 which
display two enantiotopic olefin functions and a prochiral
carbon in the 4-position. To probe the viability of the cyclization
process, enones 1a–d have been submitted to annulations with
ethyl allenoate in the presence of the achiral catalyst
(C6H11)PPh2 (Scheme 2 and Table 1, entries 1–4).
Our approach starts from the [3+2] annulations of allenic
esters and electron-poor olefins into functionalized cyclo-
pentenes, also known as the Lu’s reaction (Scheme 1a).4 The
well established synthetic potential of this methodology5
mainly relates to the easy availability of the starting materials,
to a simple experimental procedure as well as to the high
regio- and diastereoselectivity levels. Moreover, high enantio-
selectivities have been attained by using chiral catalysts made
of either cyclic phosphines with conformationally rigid molecular
scaffolds6 or acyclic multifunctional phosphines.7 The method
The reactions afforded the spirocyclic compounds 2a–d
(R1 = Et) in over 80% yield, with high regioselectivity and
diastereoselectivity levels. Compounds 2 result from C–C
bond formation between the g-carbon of the allene and the
b-olefinic carbon (g-addition products). The corresponding
Scheme
2 Phosphine-catalyzed [3+2] annulations on prochiral
arylidene cyclohexanones.
Table 1 [3+2] annulations promoted by (C6H11)PPh2
Scheme 1 (a) The Lu’s phosphine-promoted [3+2] cyclizations
between allenoates and electron-poor olefins. (b) Representative spiro-
cyclic cyclopentenes available through enantioselective cyclizations.
Entry
Product
R1
R2
Yielda (%)
drb
1
2
3
4
5
6
7
8
2a
2b
2c
2d
3a
3b
3c
3d
Et
Et
Et
Et
t-Bu
t-Bu
t-Bu
t-Bu
Me
i-Pr
t-Bu
Ph
Me
i-Pr
t-Bu
Ph
95
92
94
86
90
91
87
64
90 : 10
85 : 15
>95 : 5
90 : 10
85 : 15
70 : 30
90 : 10
85 : 15
Institut de Chimie des Substances Naturelles, CNRS UPR 2301,
Centre de Recherche de Gif. 1, av. de la Terrasse, 91198 Gif-sur-Yvette,
France. E-mail: angela.marinetti@icsn.cnrs-gif.fr;
Fax: +33 (0)1 69 07 72 47; Tel: +33 (0)1 69 82 30 36
w Electronic supplementary information (ESI) available: Experimental
procedures and characterization data. CCDC 787941. For ESI and
crystallographic data in CIF or other electronic format see DOI:
10.1039/c0cc03164j
a
b
1
Reactions performed at 40 1C. By H NMR of the crude reaction
mixture.
c
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a-addition products have never been unambiguously observed
in the reaction mixtures.
Table
(Scheme 2)
2
Enantioselective [3+2] cyclizations on enones 1a–d
The spirocyclic cyclohexanones 2 are formed as mixtures of
two diastereomers with opposite relative configurations of the
stereogenic centres of the cyclohexanone moiety. Isomers
ratios depend on the nature or the R2 substituent which is
expected, indeed, to dictate facial discrimination. Diastereomeric
ratios are of approximatively 9 : 1 for 2a, 2b and 2d
(R2 = Me, i-Pr and Ph, entries 1, 2 and 4 in Table 1), while
the tert-butyl-substituted cyclohexanone 2c was isolated as a
single isomer (entry 3).
Entry Cat. Product R1
R2
Yielda (%) dr
eeb (%)
1
2
A
A
A
A
A
A
A
B
B
B
2a
2b
2c
2d
3a
3b
3c
2a
2c
3a
Et
Et
Et
Et
Me 91
i-Pr 44
t-Bu 98
80 : 20
80 : 20
>95 : 5 92
75
82
3
4
Ph
98
85 : 15
80 : 20
70 : 30
90 : 10
85 : 15
92
90c
86
95
82
5
6
7
t-Bu Me 86
t-Bu i-Pr 60
t-Bu t-Bu 71
8
9
10
Et
Et
Me 75
t-Bu 50
>95 : 5 92
80 : 20 86
t-Bu Me 20
The structure of the major diastereomer of 2a was assigned
by X-ray diffraction studies (Fig. 1a). X-Ray data show that
the favoured cyclization product results from the addition of
the allenoate syn to the R2 substituent. It can be assumed that,
in the favoured conformer of the substrate, the R2 substituent
occupies an equatorial position. Then, the phosphine–
allenoate adduct gives syn-addition in order to minimize the
steric interactions between the incoming nucleophile and the
axial H-substituent (Fig. 1b). In other words, the preferred
conformation of the substrate prefigures the geometry of the
final cyclization product 2a.
a
b
Reactions performed at 80 1C. Ee’s have been measured by chiral
HPLC. (S,S)-FerroPHANE and (S)-Binepine give the same sense of
chiral induction.13 c Minor isomer, ee = 92%.
X-Ray data also show that the cyclisation takes place with
retention of the olefin E-configuration.
cyclohexanone. A satisfying level of stereoselectivity, that is a
>95 : 5 dr and a 92% ee, was attained in the synthesis of 2c from
ethyl allenoate and the t-Bu-substituted cyclohexanone 1c (entry
3). The 4-i-Pr- and 4-phenyl-substituted cyclohexanones 2b and
2d also gave high ees (82% and 92% ee respectively), with
however lower diastereomer ratios (entries 2 and 4). In the
starting allenoate, the ethyl group could be replaced by a t-Bu
group (entries 5–7): the corresponding annulation products 3a–c
(R1 = t-Bu) were produced with ees up to 95%, higher than
those obtained from ethyl allenoate.
In additional experiments, enones 1a–d were then reacted
with tert-butyl allenoate (entries 5–8 in Table 1). We noticed
that the increased steric hindrance of the allene tends to
decrease the diastereoselectivity of the cyclizations. For
instance, diastereomeric ratios of 85 : 15 and 70 : 30 have
been obtained, for compounds 3a and 3b respectively
(vs. 90 : 10 and 85 : 15 for the corresponding ethyl esters 2a,b).
We next considered asymmetric variants of these annulation
processes by using (S,S)-FerroPHANE, A,10 and (S)-t-
Bu-Binepine, B,11 as the privileged catalysts. Representative
results are compiled in Table 2.
In parallel experiments, (S)-t-Bu-Binepine, B, has been
evaluated as the catalyst for these cyclizations (entries 8–10).
This catalyst gave comparable levels of diastereo- and
enantioselectivity with respect to FerroPHANE. It displayed
however a lower catalytic efficiency and comparatively lower
yields.
The FerroPHANE catalyzed cyclization between 1a and
ethyl 2,3-butadienoate (entry 1) proceeded well, providing 2a
in good yield (91%), with only moderate diastereo- and
enantioselectivity (75% ee).12
Different substrates were examined then to test the scope of
the [3+2] cyclizations above. Specifically, variations of the
arylidene moiety have been performed on 4-t-Bu-substituted
cyclohexanones. A set of substrates of this class (1e–j) have
been prepared and reacted then with ethyl allenoate under
FerroPHANE catalysis. The corresponding spirocyclic
compounds 2e–j have been obtained as depicted in Table 3.
The cyclization reactions afford good yields (72–95%), good
diastereoselectivity and high enantioselectivity (85–94%) for
Ar = naphthyls and para-substituted aryls (entries 1–5). The
2-furyl-substituted enone 1j affords 2j in 57% yield and
a 75 : 25 diastereomeric ratio only, while the enantiomeric
excess remains fully satisfying (92% ee).
However, both the diastereo- and enantioselectivity
could be improved by varying the R2 substituent on the
A further step toward increased product complexity has
been taken then by considering the bicyclo[3.1.0]hexanes 4a
and exo-4b as the substrates. Compounds 414 have been
reacted with ethyl 2,3-butadienoate in the presence of the
chiral phosphorus catalysts A and B (Scheme 3).
Fig. 1 (a) X-Ray crystal structure of the major diastereomer of 2a
(CCDC 787941). (b) Schematic drawing of the preferred addition of
the phosphine–allenoate adduct to the enone.
The FerroPHANE promoted cyclizations led to the
4-spiro-bicyclo[3.1.0]hexanes 5a and 5b, which display four
c
1016 Chem. Commun., 2011, 47, 1015–1017
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Table 3 (S,S)-FerroPHANE catalyzed [3+2] cyclizations on 2,6-
diarylidene-4-tert-butyl-cyclohexanones
desymmetrization process based on phosphine promoted
cyclizations.
We thank the Institut de Chimie des Substances Naturelles,
the Agence Nationale de la Recherche (ANR) and the COST
action CM0802 ‘‘PhoSciNet’’ for supporting this work.
Notes and references
1 Q. Gu, Z.-Q. Rong, C. Zheng and S.-L. You, J. Am. Chem. Soc.,
2010, 132, 4056–4057.
Entry
Product
Ar
Yield (%)
dr
eec (%)
2 (a) X. Companyo, G. Valero, L. Crovetto, A. Moyano and
R. Rios, Chem.–Eur. J., 2009, 15, 6564–6568; (b) Y. Hayashi,
H. Gotoh, T. Tamura, H. Yamaguchi, R. Masui and M. Shoji,
J. Am. Chem. Soc., 2005, 127, 16028–16029; (c) J.-R. Chen,
Y.-Y. Lai, H.-H. Lu, X.-F. Wang and W.-J. Xiao, Tetrahedron,
2009, 65, 9238–9243; (d) J. Jiang, L. He, S.-W. Luo, L.-F. Cun and
L.-Z. Gong, Chem. Commun., 2007, 736–738.
1
2
3
4
5
6
2e
2f
2g
2h
2i
p-MeOC6H4
p-MeC6H4
p-ClC6H4
1-Naphthyl
2-Naphthyl
2-Furyl
91a
77a
86b
95a
72b
57b
>95 : 5
85 : 15
95 : 5
95 : 5
95 : 5
75 : 25
94
90
86
85
90
92
2j
3 (a) S. Luo, L. Zhang, X. Mi, Y. Qiao and J.-P. Cheng, J. Org.
Chem., 2007, 72, 9350–9352; (b) L. Zhang, L. Cui, X. Li, S. Luo
and J.-P. Cheng, Chem.–Eur. J., 2010, 16, 2045–2049.
a
b
Reaction time: 60 h. Reaction time: 18 h. By chiral HPLC.
c
Samples of racemic 2e–j have been obtained under CyPPh2 catalysis.
4 (a) C. Zhang and X. Lu, J. Org. Chem., 1995, 60, 2906–2908;
(b) X. Lu, C. Zhang and Z. Xu, Acc. Chem. Res., 2001, 34,
535–544.
5 (a) A. T. Ung, K. Schafer, K. B. Lindsay, S. G. Pyne,
K. Amornraksa, R. Wouters, I. Van der Linden, I. Biesmans, A.
S. J. Lesage, B. W. Skelton and A. H. White, J. Org. Chem., 2002,
67, 227–233; (b) X. Lu, Z. Lu and X. Zhang, Tetrahedron, 2006, 62,
457–460; (c) C. E. Henry and O. Kwon, Org. Lett., 2007, 9,
3069–3072; (d) J. L. Garcia Ruano, A. Nunez, M. R. Martin and
A. Fraile, J. Org. Chem., 2008, 73, 9366–9371; (e) L.-W. Ye,
J. Zhou and Y. Tang, Chem. Soc. Rev., 2008, 37, 1140–1152;
(f) R. A. Jones and M. J. Krische, Org. Lett., 2009, 11, 1849–1851;
(g) Y. Du and X. Lu, J. Org. Chem., 2003, 68, 6463–6465.
6 (a) G. Zhu, Z. Chen, Q. Jiang, D. Xiao, P. Cao and X. Zhang,
J. Am. Chem. Soc., 1997, 119, 3836–3837; (b) J. E. Wilson and
G. C. Fu, Angew. Chem., Int. Ed., 2006, 45, 1426–1429;
(c) A. Voituriez, A. Panossian, N. Fleury-Bregeot, P. Retailleau
and A. Marinetti, J. Am. Chem. Soc., 2008, 130, 14030–14031.
7 (a) B. J. Cowen and S. J. Miller, J. Am. Chem. Soc., 2007, 129,
10988–10989; (b) H. Xiao, Z. Chai, C.-W. Zheng, Y.-Q. Yang,
W. Liu, J.-K. Zhang and G. Zhao, Angew. Chem., Int. Ed., 2010,
49, 4467–4470.
8 (a) D. J. Wallace, R. L. Sidda and R. A. Reamer, J. Org. Chem.,
2007, 72, 1051–1054; (b) A. Voituriez, A. Panossian, N. Fleury-
Bregeot, P. Retailleau and A. Marinetti, Adv. Synth. Catal., 2009,
351, 1968–1976; (c) N. Pinto, M. Neel, A. Panossian, P. Retailleau,
G. Frison, A. Voituriez and A. Marinetti, Chem.–Eur. J., 2010, 16,
1033–1045; (d) A. Voituriez, N. Pinto, M. Neel, P. Retailleau and
A. Marinetti, Chem.–Eur. J., 2010, DOI: 10.1002/chem.201001791.
9 (a) H. Frey, Synthesis, 1992, 387–390; (b) J. R. Dimmock,
M. P. Padmanilayam, G. A. Zello, K. H. Nienaber, T. M. Allen,
C. L. Santos, E. De Clercq, J. Balzarini, E. K. Manavathu and
J. P. Stables, Eur. J. Med. Chem., 2003, 38, 169–177.
Scheme 3 Enantioselective [3+2] cyclizations on the 2,5-dibenzyl-
idene-bicyclo[3.1.0]hexanes 4.
and five stereogenic carbons, respectively, with good diastereo-
selectivity. 5a was isolated as a 9 : 1 mixture of isomers, while
for 5b only one out of eight possible isomers is produced in
significant amount. The structures of the major isomers of 5a,b
have been tentatively assigned as shown in Scheme 3, by
assuming that the cyclization takes place following the same
stereochemical pathway as for substrates 2, with the allenoate
approaching the less hindered, exo-face of the bicyclic moiety.
Under FerroPHANE catalysis, compounds 5a (R2 = H) and
5b (R2 = Me) are formed in comparable ee, showing that the
additional Me substituent of 5b does not affect the enantio-
control. Under t-Bu-Binepine A catalysis, the bicyclic spiranic
compound 5a is obtained in a satisfying 86% ee, however the
conversion rate is of only 22% after 18 h at 80 1C.
In summary, we have developed an efficient, highly
stereoselective synthetic approach to the spirocyclic
compounds 2, as well as to the unique spiranic scaffolds 5,
involving the stereocontrolled formation of up to five
stereogenic carbon centres in a single process. As far
as we know, this is the first example of an enantioselective
10 For uses of FerroPHANE in [3+2] cyclizations on bis-
(benzylidene)-cyclopentanones and cyclohexanones, see ref. 8b,c.
11 The use of (R)-t-Bu-Binepine in [3+2] cyclizations on 2,5-
dibenzylidenecyclohexanone (93% ee) has been reported in ref. 6b.
12 In previous studies, the analogous cyclization on the 4-unsubstituted
2,6-dibenzylidenecyclohexanone gave a 85% ee. See ref. 8c.
13 If we assume that FerroPHANE displays the same sense of chiral
induction as previously demonstrated for analogous cyclization
reactions,8c,d compounds
configurations.
2 and 3 should have 4R,5R,9R
14 (a) M. L. Kearley and P. M. Lahti, Tetrahedron Lett., 1991, 32,
5869–5872; (b) M. L. Kearley, A. S. Ichimura and P. M. Lahti,
J. Am. Chem. Soc., 1995, 117, 5235–5244.
c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 1015–1017 1017