2-Phospha[3]ferrocenophanes with planar chirality: Synthesis and use in enantioselective organocatalytic [3 + 2] cyclizations

Article abstract of DOI:10.1021/ja806060a

Planar chiral phosphines displaying a new ferrocenophane scaffold have been prepared via a stereoselective approach. The P-cyclohexyl substituted phosphine affords high levels of asymmetric induction in the organocatalytic [3 + 2] annulation reaction between allenes and electron-poor olefins. Copyright

Full text of DOI:10.1021/ja806060a

Published on Web 10/04/2008
2-Phospha[3]ferrocenophanes with Planar Chirality: Synthesis and Use in
Enantioselective Organocatalytic [3 + 2] Cyclizations
Arnaud Voituriez, Armen Panossian, Nicolas Fleury-Bre´geot, Pascal Retailleau, and
Angela Marinetti*
Institut de Chimie des Substances Naturelles, CNRS UPR 2301 - 1, aV. de la Terrasse, 91198 Gif-sur-YVette, France
Received June 3, 2008; E-mail: angela.marinetti@icsn.cnrs-gif.fr
Scheme 1. Synthesis of the Planar Chiral 2-Phospha-
[3]ferrocenophanes (S,S)-5 via Diastereoselective
ortho-Metalationa
Nucleophilic phosphine organocatalysis has emerged recently as
an attractive methodology in organic synthesis.1 Though a wide
variety of organic scaffolds are available by these methods,
comparatively few advances have been made in the development
of enantioselective variants of these reactions.2 Notably, major
contributions from Zhang,3 Fu,4 Miller5 and Jacobsen6 have
highlighted the most efficient catalysts for annulation reactions
disclosed so far. With the aim of further expanding the range of
chiral phosphines for enantioselective organocatalytic processes,
we have undertaken the development of a new class of specifically
tailored compounds, the planar chiral 2-phospha[3]ferrocenophanes
5. Relevant characteristics that make these phosphanes a priori
amenable to enantioselective organocatalysis are their cyclic
structure, with the related restricted conformational freedom, and
their electron-rich nature and potentially nucleophilic character.
The highly successful uses of many chiral phosphines with ferrocene
backbones in organometallic catalysis7 also supported our choice
of 5 as privileged targets. Here we describe a stereoselective
synthetic approach to the ferrocenophane scaffold as well as
applications of 5c as catalyst in highly enantioselective [3 + 2]
cyclizations of ethyl 2,3-butadienoate with R,ꢀ-unsaturated esters
and ketones.
a Reaction conditions: a) (S)-2-(methoxymethyl)pyrrolidine, NaBH3CN,
4 Å MS, MeOH, 63%; b) i. sBuLi, Et2O, -70 °C/-30 °C/-70 °C; ii.
TMSCl -70 °C to rt, 66%; c) Ac2O, 85 °C, 18 h, 87%; d) RPH2, AcOH,
60 °C, 16 h.
Our synthetic approach to 2-phospha[3]ferrocenophanes 5 implies
the building of an enantiomerically pure 1,1′,2,2′-tetrasubstituted
ferrocene bearing on its R-carbons suitable leaving groups (OAc)
that would allow introduction of the phosphorus function in the
final step (Scheme 1).
The 1,1′,2,2′-tetrasubstituted ferrocene moiety has been prepared
Via diastereoselective di-ortho-lithiation of (S,S)-28 bearing 2-(meth-
oxymethyl)pyrrolidine as the chiral directing groups.9 The bis-
lithiated intermediate obtained in Et2O at -30 °C with sBuLi as
the base, was conveniently quenched with TMSCl10 to afford
(S,SP)-3 in 66% yield, with excellent diastereoselectivity (dr > 98:
2). In the next step, the chiral auxiliaries have been removed, and
the required leaving groups have been introduced in a single process,
by heating compound 3 in acetic anhydride at 85 °C. The cyclization
step leading to 5 was performed then in acidic conditions11 Via
two consecutive SN1 substitutions on the R-carbons by a primary
Figure 1. ORTEP view of phosphine 5b.
Having in hand a suitable access to phosphines 5a-c, their use
as nucleophilic catalysts has been investigated then as a privileged
potential application. Phosphines 5 have been evaluated in the [3
+ 2] annulations of ethyl 2,3-butadienoate with R,ꢀ-unsaturated
esters and ketones,1d leading to functionalized cyclopentenes with
up to two contiguous stereogenic centers (see Table 1). These
processes involve activation of the allenoate by addition of the
nucleophilic phosphorus derivative to the central carbon, followed
by stepwise formal [3 + 2] cycloadditions of the intermediate 1,3-
dipole on the olefins.15
12
phosphine (PhPH2, l-MenthylPH2 or C6H11PH2). Compounds 5
represent the first known phosphines with a planar chiral
2-phospha[3]ferrocenophane scaffold.13
The trivalent phosphines 5 (TMS-FerroPHANEs) showed good
air stability in both solution14 and solid state. Their structures as
well as the expected (S)-configuration9a of the planar chiral
ferrocene moiety have been unambiguously established by X-ray
diffraction studies (Figure 1). In the solid state, the Cp rings of 5b
are almost perfectly eclipsed in a syn-periplanar conformation with
a torsion angle of 2.0°. They are only slightly tilted toward each
other (5.9°), which suggests a very low degree of ring strain induced
by the three-atom tether.
Initial experiments and optimization of the reaction conditions have
been performed on the reaction between ethyl 2,3-butadienoate 6 and
diethyl fumarate 7a,16,3 in the presence of a 10% amount of phosphines
5a-c. The reactions yielded the trans-stereoisomer of cyclopentene
8a as the single product, implying that the process takes place, as
expected, with retention of the stereochemistry of the starting olefin.
The nature of the phosphorus substituent in 5 proved to be a crucial
structural factor with respect to both conversion rates and enantiose-
lectivity. The P-cyclohexyl substituted phosphine 5c ([Cy]-TMS-
9
14030 J. AM. CHEM. SOC. 2008, 130, 14030–14031
10.1021/ja806060a CCC: $40.75
2008 American Chemical Society

C O M M U N I C A T I O N S
Table 1. [3 + 2] Annulation Reactions of Ethyl 2,3-Butadienoate 6
with the Unsaturated Esters 7a,b and Enones 7c-k Promoted by
Phosphine 5c
nophane scaffold, and we have highlighted the efficiency of phosphine
5c as enantioselective nucleophilic organocatalyst in model [3 + 2]
annulation reactions. In these reactions, phosphine 5c compares
favorably with the previous best catalysts.3,4a,5 Its practical utility
should rely on, among others, its good air-stability and ease of handling,
combined with a yet satisfying nucleophilicity. The modular nature
of ferrocenophanes 5 as well as the versatile synthetic approach should
allow subtle and extensive variations of both the phosphorus substituent
and the cyclopentadienyl substituents as a key to the fine-tuning of
single organic and organometallic catalytic processes.
entry
R1
R2
8:9 ratio
yield 8+9
cmpd
eeg (%)
1a
CO2Et
OEt
OEt
OEt
Ph
-
-
68
28
53
65
87
71
63
71
85
68
75
70
8a
8a
90
93
2a,b CO2Et
3c
4d
5d
6d
7e
H
Ph
1:1.5
20:1
>20:1
>20:1
10:1
8:1
8b/9b 88/84
Supporting Information Available: Complete experimental pro-
cedures, characterization data, ee determinations, and crystallographic
data for (S,S)-5b (CCDC 686645) and (S,S)-5c (CCDC 686646). This
material is available free of charge via the Internet at http://pubs.acs.org.
8c
8d
8e
8f
8g
8h
8i
92
96
93
92
93
95
89
87
90
1-naphth
4-MeOC6H4 Ph
4-NO2C6H4 Ph
Ph
8d,f 2-furyl
Ph
9d
Ph
4-MeOC6H4 >20:1
4-NO2C6H4 >20:1
Ph
Ph
10e Ph
References
11e 2-quinolyl
12e Ct CC5H11
20:1
15:1
8j
8k
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1.2:1. f In acetone. g Enantiomeric excesses have been measured by
chiral HPLC.
Scheme 2. [3 + 2] Annulation Reaction on a Trisubstituted Enone
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FerroPHANE) gave the highest conversion rates17 and enantiomeric
excesses,18 with a 90% ee for reactions performed in toluene at room
temperature (entry 1). The enantiomeric excess could be further
increased to 93% for reactions run with 5c at 0 °C (entry 2). These
are the highest ee’s reported so far for cyclization reactions between
ethyl 2,3-butadienoate and fumarate esters.3
Following these initial successful experiments, the annulation
reactions of ethyl 2,3-butadienoate, 6, with ethyl acrylate 7b and various
enones, 7c-k, were surveyed in the presence of a 10% amount19 of
phosphine 5c (entries 3-12). With such unsymmetrical alkenes as the
dipolarophiles, two regioisomeric [3 + 2] cycloadducts 8 and 9 can
be obtained, following γ- and R-addition modes of the intermediate
phosphine-allene adduct to the olefins. In the presence of 5c, the
annulation reaction with ethyl acrylate afforded indeed the expected
cyclopentenes as a 1:1.5 mixture of regioisomers 8b and 9b, in 88%
and 84% ee, respectively (entry 3). An (S)-absolute configuration has
been assigned to 9b, based on [R]D values.3,20
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Marinetti, A. Eur. J. Inorg. Chem. 2007, 3853.
Starting from the R,ꢀ-unsaturated enones 7c-k,4a,5 the correspond-
ing cyclopentenes were produced with high regioselectivity (8:9 ratios
from 8:1 to >20:1), Via preferential γ-addition. Cyclopentenes 8c-k
were obtained in 87-96% ee from both electron-rich and electron-
deficient chalcone derivatives. Enones 7g and 7j bearing heterocyclic
substituents could be also converted into the corresponding cyclo-
pentenes in 87-93% ee (entries 8 and 11). The possible use of
ꢀ-alkynyl-substituted enones in the annulation reactions has been
typified by converting 7k into the corresponding cyclopentene 8k in
90% ee (entry 12).21
Finally, high regioselectivity (20:1 regioisomeric ratio) and sub-
stantial enantiocontrol were observed in the synthesis of the spirocyclic
derivative 114a,5 from the corresponding exocyclic enone 10 (Scheme
2).
In summary, we have developed a stereoselective access to a new
class of chiral phosphines based on a planar chiral 2-phospha[3]ferroce-
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amount of the phosphine oxide, after 24 h at rt in air.
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tentatively ascribed to a lower nucleophilic character for 5a and to an
increased steric hindrance for 5b.
(18) In analogous conditions phosphine 5a afforded 8a in 11% ee, while 5b
gave a 12% ee for reactions run at 90 °C.
(19) The catalyst amount can be reduced, while retaining a significant catalytic
activity and the same levels of enantiocontrol: for reaction in entry 5,
conversion rates of 74% and 40% were observed after 40 h at rt, at catalysts
amounts of 5% and 1% respectively (96% ee).
(20) For preliminary considerations on the sense of asymmetric induction and
a model for the phosphine-allene adduct, see Supporting Information.
(21) Conversion rates lower than 10% were obtained in the annulations between
ethyl butadienoate and both ethyl maleate and the alkyl-substituted enone
C5H11CHdCHCOPh.
JA806060A
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J. AM. CHEM. SOC. VOL. 130, NO. 43, 2008 14031