One-pot asymmetric cyclocarbohydroxylation sequence for the enantioselective synthesis of functionalised cyclopentanes

Article abstract of DOI:10.1039/c0cc01940b

A new method has been developed for the enantioselective synthesis of highly functionalised cyclopentanes bearing up to three stereogenic centres with very high stereoselectivity. This one-pot process combines an enantioselective organocatalytic Michael addition with a highly diastereoselective [3+2]-cycloaddition-fragmentation step.

Full text of DOI:10.1039/c0cc01940b

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One-pot asymmetric cyclocarbohydroxylation sequence for the
enantioselective synthesis of functionalised cyclopentanesw
´
Wilfried Raimondi, Gregory Lettieri, Jean-Pierre Dulcere, Damien Bonne* and
Jean Rodriguez*
Received 17th June 2010, Accepted 26th July 2010
DOI: 10.1039/c0cc01940b
A new method has been developed for the enantioselective
synthesis of highly functionalised cyclopentanes bearing up to
three stereogenic centres with very high stereoselectivity. This
one-pot process combines an enantioselective organocatalytic
Michael addition with
a highly diastereoselective [3+2]-
cycloaddition–fragmentation step.
Scheme 1 Strategy for the one-pot stereoselective construction of
The development of organocatalytic enantioselective methods
to access enantiopure molecules has received much attention
in the last ten years due to the many advantages in terms of
efficiency, selectivity and environmental benefits offered by
organocatalysis.1 When the method involves simple starting
materials and is associated with one-pot multiple bond-forming
transformations (MBFTs),2 the resulting tools are particularly
useful for reaching a high level of structural complexity and
functional diversity.
functionalised cyclopentanes.
C–O bond and the control of up to three stereogenic centres
with very high diastereo- and enantioselectivites.9,10
We first started to investigate the organocatalytic Michael
addition and catalysts I,11 II12 and III4b were screened under
standard conditions (Table 1). Catalysts I and III bearing two
different hydrogen bond donor sites respectively, in toluene or
THF, were the most efficient (entries 1 and 4) although I
showed a reduced activity in THF (entry 2). Catalyst II in
toluene, showed a good selectivity but slightly lower yield
(entry 3). Finally, when catalyst III was used in toluene instead
of THF, we observed a significant decrease in the yield which
could be due to its lower solubility (entry 5). We were also very
pleased to find that both enantiomers of 3a could be obtained
using structurally different catalysts I and III.
In this context, the asymmetric organocatalysed Michael
addition of various nucleophiles to nitroolefins represents a
very useful reaction.3 Although malonates have been used
most often in Michael addition,4 synthetic developments in a
sequential way, by further modification of the adducts, are
limited by the lack of reactivity of 2-substituted malonates. An
interesting recent example concerns the functional group
pairing of modular nitro scaffolds obtained from enantio-
selective Michael addition catalysed by Cinchona alkaloids.5
Given our interest in the reactivity of nitroalkenes6 and
domino processes,7 we envisioned a one-pot consecutive transfor-
mation consisting of an enantioselective organocatalytic
Michael addition between nitroalkenes 1 and 2-allylmalonates
2 followed by an in situ [3+2] nitronate cycloaddition–
fragmentation sequence leading to highly functionalised cyclo-
pentanone oximes 4 (Scheme 1). The resulting intramolecular
carbohydroxylation of the non-activated double bond with
formation of the oxime function has been rarely exploited to
date8 and this would constitute the first example of an
enantioselective version. Herein, we disclose our results on
this one-pot consecutive cyclopentannelation with a remote
hydroxylation leading to highly functionalised five-membered
rings with concomitant creation of two C–C bonds, one
Table 1 Screening of reaction conditions for the enantioselective Michael
addition of dimethyl 2-allylmalonate (2a) to b-nitrostryrene (1a)a
Entry
Catalyst
Solvent
Yield (%)b
Ee (%)c
1
2
3
4
5
I
I
II
III
III
Toluene
THF
Toluene
THF
Toluene
95
95d
78
94
67
92 (S)
88 (S)
90 (R)
90 (R)
87 (R)
´
UMR CNRS 6263 iSm2, Aix-Marseille Universite,
Centre Saint Jerome, service 531, 13397 Marseille Cedex 20, France.
E-mail: jean.rodriguez@univ-cezanne.fr,
damien.bonne@univ-cezanne.fr; Fax: (+33) 491 289 187;
Tel: (+33) 491 289 187
w Electronic supplementary information (ESI) available: Complete
experimental procedures and characterisation of all compounds.
CCDC 764561. For ESI and crystallographic data in CIF or other
electronic format see DOI: 10.1039/c0cc01940b
´ ˆ
a
Reaction conditions: 1 mmol of 1a, 2 mmol of 2a and catalyst I, II or
mL of solvent at room temperature for
III (10 mol%) in 2
48 h. Isolated yield by flash chromatography. Determined by
d
HPLC on a chiral stationary phase. 7 days of reaction time.
b
c
c
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Chem. Commun., 2010, 46, 7247–7249 7247

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total transfer of chirality to furnish the transient isoxazolidine
A through the preferred nitronate conformation B. Treatment
with aqueous HCl did not result in its fragmentation but led to
the known isoxazoline 5a with 70% yield in diastereomerically
pure form.15 More interestingly, using tetrabutylammonium
fluoride (TBAF) provoked the expected selective fragmenta-
tion affording the corresponding hydroxymethyl oxime 4a also
in a highly stereoselective manner16 probably through the
tautomeric nitroso intermediate.13g The absolute configura-
tion was unambiguously determined to be (E)-(2S,4S) by
X-ray crystallographic analysis of 4a.w
The overall cyclocarbohydroxylation in a one-pot con-
secutive manner with organocatalysts I and III has been
extended to various substrates (Table 2). Pleasingly, in all
cases, this led to the formation of the desired cyclopentanone
oximes 4a–n in good to excellent yields and with high diastereo-
and enantioselectivities.17 This allowed the one-pot creation of
a five-membered ring and the control of two stereogenic
centres starting from commercially available acyclic achiral
substrates and operated a remote hydroxylation. The use of
catalysts I and III allowed the formation of both enantiomers
with comparable efficiencies (entries 1, 2 and 13, 14). Aromatic
nitroalkenes bearing electron-withdrawing and electron-
donating groups reacted well in the reaction and gave all
excellent enantioselectivities (entries 3–8). However 4h was
obtained in moderate yield (entry 9, 57%) due to the lower
electrophilic character of the corresponding electron rich
nitroalkene 1h. Heteroaromatic nitroolefins proved also to
be very good substrates affording the desired products 4i–l
(entries 10–13) in good yields (72–95%) and excellent enantio-
selectivities (93–97%). The (R,S)-enantiomer of 4l was also
easily obtained using catalyst I, although with a somewhat
Scheme 2 Cyclocarbohydroxylation sequence.
Scheme 3 Diastereoselective reduction of oximes.
We next turned our attention to the carbohydroxylation
via an intramolecular [3+2]-silylnitronate olefin cyclisation
(ISOC)-fragmentation sequence (Scheme 2).13 In the first
attempt, generation of the silylnitronate resulted in a highly
stereoselective process driven by a 1,3-allylic strain6,14 with a
Table 2 Scope of the enantioselective cyclocarbohydroxylation sequencea
Entry
R1
Malonate 2
Catalyst
Product
Yield (%)b
Ee (%)c
1
2
3
4
5
6
7
8
Ph (1a)
Ph (1a)
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2b
(E)-2c
(Z)-2c
III
I
III
III
I
III
III
III
III
III
III
III
III
I
(R,R)-4a
(S,S)-4a
(R,R)-4b
(R,R)-4c
(R,S)-4d
(R,R)-4e
(S,R)-4f
(R,R)-4g
(R,R)-4h
(R,R)-4i
(R,R)-4j
(R,R)-4k
(S,R)-4l
92
74
81
73
80
99
97
82
57
95
80
77
72
71
60
84
74
91
97
93
97
93
88
92
98
94
93
96
97
95
89
92
91
94
4-FC6H4 (1b)
4-MeOC6H4 (1c)
2-BrC6H4 (1d)
4-MeC6H4 (1e)
2-Cl-6-FC6H4 (1f)
2-NO2C6H4 (1g)
3,4,5-(MeO)3C6H4 (1h)
2-Furyl (1i)
9
10
11
12
13
14
15
16
17
3-Furyl (1j)
2-Thienyl (1k)
2-Pyridinyl (1l)
2-Pyridinyl (1l)
Ph (1a)
Ph (1a)
Ph (1a)
(R,S)-4l
III
III
III
(R,R)-4m
(R,R,S)-4n
(R,R,R)-4n
a
b
Reaction conditions: 1 mmol of 1, 2 mmol of 2 catalyst in 2 mL of solvent (toluene with I, THF with III). Isolated yield by flash
c
chromatography. Determined by HPLC on a chiral stationary phase.
c
7248 Chem. Commun., 2010, 46, 7247–7249
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reduced efficiency (entry 14). When dimethyl 2-methallyl-
malmate (2b) was employed, the consecutive process allowed
the formation and control of an all-carbon quaternary stereo-
genic centre18 in the final product 4m with 92% ee (entry 15).
Finally, when (E)-2c was used as the starting malonate, the
consecutive reaction sequence afforded the cyclopentanone
oxime 4n with the stereospecific control of a third stereogenic
centre in high yield and selectivity (entry 16). Starting
from (Z)-2c gave the single diastereomer of 4n with opposite
configuration of the carbon bearing the hydroxy function
(entry 17).
4 For selected exemples of organocatalytic enantioselective
addition of malonates on nitroolefins, see: (a) T. Okino,
Y. Hoashi, T. Furukawa, X. Xu and Y. Takemoto, J. Am.
Chem. Soc., 2005, 127, 119–125; (b) H. Li, Y. Wang,
L. Tang and L. Deng, J. Am. Chem. Soc., 2004, 126, 9906–9907;
(c) H. Li, Y. Wang, L. Tang, F. Wu, X. Liu, C. Guo,
B. M. Foxman and L. Deng, Angew. Chem., Int. Ed., 2006, 44,
105–108; (d) S. H. McCooey and S. J. Connon, Angew.
Chem., Int. Ed., 2005, 44, 6367–6370; (e) J. Ye, D. J.
Dixon and P. S. Hynes, Chem. Commun., 2005, 4481–4483;
(f) M. Terada, H. Ube and Y. Yaguchi, J. Am. Chem. Soc.,
2006, 128, 1454–1455.
5 E. Comer, E. Rohan, L. Deng and J. A. Porco, Jr., Org. Lett.,
2007, 9, 2123–2126.
6 E. Dumez, A.-C. Durand, M. Guillaume, P.-Y. Roger, R. Faure,
J.-M. Pons, G. Herbette, J.-P. Dulcere, D. Bonne and
J. Rodriguez, Chem.–Eur. J., 2009, 15, 12470–12488.
7 For recent examples, see: (a) M. Presset, Y. Coquerel and
J. Rodriguez, Org. Lett., 2009, 11, 5706–5709; (b) C. Allais,
T. Constantieux and J. Rodriguez, Chem.–Eur. J., 2009, 15,
12945–12948.
Oximes are an important class of compounds with potential
pharmaceutical properties19 and constitute versatile building
blocks since they can be easily transformed into various
functional groups.20 As an illustration of their synthetic
potential, oximes 4a, 4c and 4i were reduced with NaBH3CN
affording the corresponding hydroxylamines 6a, 6b and 6c
as single diastereomers in good yields where a supplementary
stereogenic centre was created (Scheme 3). Here again,
depending on the catalyst used in the consecutive enantio-
selective reaction, both configurations of the new created
stereogenic centre can be accessed.
8 For
a
diastereoselective intramolecular carbohydroxylation
reaction, see: A. V. Stepanov and V. V. Veselovsky, Russ. Chem.
Bull., 2002, 51, 359–361.
9 For selected examples of enantioselective organocatalysed construc-
tion of cyclopentanes, see: (a) D. Enders, C. Wang and J. W. Bats,
Angew. Chem., Int. Ed., 2008, 47, 7539–7542; (b) B. Tan, P. J. Chua,
X. Zeng, M. Lu and G. Zhong, Org. Lett., 2008, 10, 3489–3492;
(c) V. Nair, B. P. Babu, S. Vellalath, V. Varghese, A. E. Raveendran
and E. Sures, Org. Lett., 2009, 11, 2507–2510.
10 We previously described a three-step sequence affording fused-
isoxazolines from aldehydes and nitroalkenes: D. Bonne,
L. Salat, J.-P. Dulcere and J. Rodriguez, Org. Lett., 2008, 10,
5409–5412.
11 (a) T. Okino, Y. Hoashi and Y. Takemoto, J. Am. Chem. Soc.,
2003, 125, 12672–12673; (b) A. Berkessel and B. Seelig, Synthesis,
2009, 12, 2113–2115.
12 (a) B. Vakulya, S. Varga, A. Csampai and T. Soos, Org. Lett.,
2005, 7, 1967–1970; (b) B. Vakulya, S. Varga and T. Soos, J. Org.
Chem., 2008, 73, 3475–3480.
13 (a) I. N. N. Namboothiri, A. Hassner and H. E. Gottlieb, J. Org.
Chem., 1997, 62, 485–492; (b) A. Hassner, O. Friedman and
W. Dehaen, Liebigs Ann./Recl., 1997, 587–594; (c) S. Ghorai,
R. Mukhopadhyay, A. P. Kundu and A. Bhattacharjya, Tetra-
hedron, 2005, 61, 2999–3012; (d) J. L. Duffy and M. J. Kurth,
J. Org. Chem., 1994, 59, 3783–3785; (e) T. Ishikawa, Y. Shimizu,
T. Kudoh and S. Saito, Org. Lett., 2003, 5, 3879–3882;
(f) T. Kudoh, T. Ishikawa, Y. Shimizu and S. Saito, Org. Lett.,
2003, 5, 3875–3878; (g) P.-Y. Roger, A.-C. Durand, J. Rodriguez
and J.-P. Dulcere, Org. Lett., 2004, 6, 2027–2029.
In conclusion, we have identified two structurally different
and complementary organocatalysts for the successful enantio-
divergent cyclocarbohydroxylation sequence allowing the
construction of highly functionalised and optically pure func-
tionalised cyclopentanes with the creation and control of up to
three stereogenic centres. The high efficiency and the practical
simplicity of the method make it an important platform for the
stereoselective formation of complex molecules.
This research was supported by the Universite Paul Cezanne
and the CNRS (iSm2 – UMR 6263). W.R. thanks the Ministere
de l’Enseignement Superieur et de la Recherche for a doctoral
fellowship. We thank Dr N. Vanthuyne (iSm2 – UMR 6263) for
chiral HPLC analysis and M. Giorgi (www.spectropole.fr) for
X-ray structure.
Notes and references
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2 Y. Coquerel, T. Boddaert, M. Presset, D. Mailhol and
J. Rodriguez, in Ideas in Chemistry and Molecular Sciences:
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14 R. W. Hoffmann, Chem. Rev., 1989, 89, 1841–1860.
15 Only one diastereomer can be detected in proton NMR spectra.
For one isolated example of
a related two-step Michael
addition–nitrile oxide cycloaddition leading to 5a with very low
diastereoselectivity, see ref. 5.
16 Phenyl and CH2OH substituents in 4a were exclusively trans.
Besides, the oxime 4a was isolated as a 96 : 4 E/Z ratio.
17 When 2-alkyl-substituted nitroalkenes were used as substrates,
only traces of products were formed. This non reactivity of
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Y.-N. Xuan, S.-Z. Nie, L.-T. Dong, J.-M. Zhang and M. Yan,
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c
This journal is The Royal Society of Chemistry 2010
Chem. Commun., 2010, 46, 7247–7249 7249