Asymmetric phospha-Diels-Alder reaction: A stereoselective approach towards P-chiral phosphanes through diastereotopic face differentiation

Article abstract of DOI:10.1002/chem.201203671

Old principles, new chemistry: A facile stereoselective synthesis of P-chiral phosphanes is described in which the principle of enantiotopic and diastereotopic face differentiation used in carbon chemistry is extended to a phosphorus atom in a planar environment, that is, 2H-phospholes. Copyright

Full text of DOI:10.1002/chem.201203671

DOI: 10.1002/chem.201203671
Asymmetric Phospha-Diels–Alder Reaction: A Stereoselective Approach
towards P-Chiral Phosphanes through Diastereotopic Face Differentiation
Tobias Mçller,[a] Menyhꢀrt B. Sꢀrosi,[b] and Evamarie Hey-Hawkins*[a]
Chiral phosphanes are highly important as ligands in
asymmetric catalysis.[1] Most of them exhibit a chiral back-
bone, but P-chiral phosphanes are gaining increasing impor-
tance. Routes to P-chiral compounds include resolution of
racemates or diastereomers, dynamic–kinetic resolution, and
desymmetrization.[2] In contrast to asymmetric carbon chem-
istry, in which a carbon atom in a planar molecule is gener-
ally the prochiral species,[3] all of these methods start from a
phosphorus atom in a trigonal–pyramidal environment.
Herein we describe a facile synthetic approach, extending
the principle of enantiotopic and diastereotopic face differ-
entiation, to a phosphorus atom in a planar environment, in
particular by employing a P=C double bond as prochiral
motif.[4] This approach has attracted only little attention in
the development of P-chiral phosphanes,[5] as a major prob-
lem is the low stability of a P=C bond compared to a C=C
bond. Thus, sterically demanding and electronically stabiliz-
ing groups (e.g., metal–carbonyl fragments) are needed,[4,6]
and as a result such substrates may be expensive, less availa-
ble, and their substitution pattern less suitable for stereose-
lective syntheses. Consequently, only substrates with a chiral
substituent directly attached to the phosphorus atom have
been applied and shown to give good selectivities.[5]
The essential step in the synthesis of 3 and 4 is a [1,5]-sig-
matropic shift, which is strongly dependent on the migrating
group R1 and temperature.[8a,b,9a,c] The 2H-phospholes can
be generated directly from the corresponding 1H-phospho-
les[7a,d,12] or from their dimers by [4+2]-cycloreversion (Sche-
me 1).[8a,c,9b–e] Once formed, they immediately react with the
present dienophile, (5R)-(l-menthyloxy)-2ACTHNUTRGNEUNG
(5H)-furanone[13]
(MOxF). The cycloaddition products were converted in situ
to their air-stable sulfur derivatives 3 and 4, of which 3
could be isolated and the endo and exo isomers separated
by column chromatography. Due to its cyclic structure and,
therefore, efficient chirality transfer, MOxF is highly suita-
ble for the hetero Diels–Alder reaction.[13] Commonly used
dienophiles that are applied in diastereoselective cycloaddi-
tion reactions act through a chelating “anchor” between the
dienophile and the chiral portion of the substrate.[3b,10] Since
these chelating “anchors” are always Lewis acids, they
would strongly interact with the phosphorus atom in a
phosphole, and make the desired hetero Diels–Alder reac-
tion unlikely to occur.
For hydrogen as a migrating group (R1 =H), the [1,5]-sig-
matropic shift takes place at very low temperatures and the
2H-phosphole 2a dimerizes rapidly on warming to room
temperature.[8b,9a] Attempts to trap the 2H-phosphole at low
temperatures with MOxF always resulted in an inseparable
mixture of products. However, when the corresponding
dimer 1a was heated in the presence of the dienophile, a
mixture of 3a and 4a was obtained after sulfurization, from
which endo isomer 3a could be isolated by column chroma-
tography in high yield. Consequently, we extended this ap-
proach to aryl-substituted 1H-phospholes 1b and c. In con-
trast to 2a, aryl substituents migrate only at high tempera-
tures (ca. 1408C).[9b] Heating 1H-phospholes 1b and c in the
absence of the dienophile gave a mixture of various 2H-
phosphole dimers and 1H-phospholes (as shown by 31P{1H}-
NMR spectroscopy), suggesting an equilibrium between the
two species at high temperatures.[8c] However, heating 1H-
phospholes 1b and c in the presence of MOxF at 1408C
gave a mixture of 3b and c and 4b and c that could be sepa-
rated by column chromatography to give endo- and exo-3b
and c in high yield and good selectivities (see the Supporting
Information).
On the other hand, 2H-phospholes appeared to be highly
versatile substrates as they are readily available and offer
many possibilities for modification.[7] Even though they are
mostly generated and trapped in situ, their chemistry is well
investigated and understood,[8] especially their use in cyclo-
b,9]
addition reactions.[8a,
Employing 2H-phospholes 2a–c in
asymmetric Diels–Alder reactions allows the generation of
multiple stereogenic centers in one step (Scheme 1,
Table 1).[3b,10] Related 1-phosphanorbornadienes have shown
excellent results in catalysis.[11]
[a] M. Sc. T. Mçller, Prof. Dr. E. Hey-Hawkins
Universitꢀt Leipzig, Faculty of Chemistry and Mineralogy
Institute of Inorganic Chemistry
Johannisallee 29, 04103 Leipzig (Germany)
E-mail: hey@uni-leipzig.de
[b] M. B. Sꢁrosi
Faculty of Chemistry and Chemical Engineering
Attempts to extend this successful method to bis(phosp-
holes)[12] resulted in an inseparable and complex mixture of
products due to the increased number of regio- and stereo-
isomers.
˘
Babes¸-Bolyai University, M. Kogalniceanu 1
400084, Cluj-Napoca (Romania)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201203671.
16604
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Chem. Eur. J. 2012, 18, 16604 – 16607

COMMUNICATION
Scheme 1. Asymmetric [4+2] cycloaddition through 2H-phospholes.
Table 1. Conditions, stereoselectivities,[a] and yields for compounds 3a–c
and 4a–c.
H) shows the largest atomic orbital coefficient at the phos-
phorus atom and the second largest at C3, while the LUMO
of MOxF shows the largest atomic orbital coefficient at C3’
and the second largest at C2’, suggesting the biggest orbital
overlap between P···C3’ and C3···C2’ (Figure 1). The endo
T
Solvent Regioisomers endo/exo Diastereomers: Yield[b]
[8C]
3/4
(3, siC
)
siC C/reC
[%]
=
C
=
=
C
a
b
c
60
THF
98:2
97:3
97:3
93:7
70:30
73:27
98:2
92:8
91:9
87
84
83
140 xylene
140 xylene
[a] Determined by 1H NMR spectroscopy. [b] Sum of yields of separated
diastereomers.
The observed selectivities can be explained by the transi-
tion states of the two main isomers exo-3a–c and endo-3a–c
(Scheme 2). Firstly, the two molecules approach mainly in
an endo fashion, which in consequence leads to the main di-
astereomer. Due to the attractive secondary orbital interac-
tions between the C=O functionality and the diene system,
the endo product is kinetically favored, as is known for such
systems with normal electron demand.[3b,10] As a conse-
quence, the endo/exo ratio accordingly decreases at higher
temperature (Table 1, 3b and c). Secondly, due to the steri-
cally demanding l-menthyloxy group (OR*), the 2H-phosp-
hole preferentially approaches from the si face of the dieno-
phile, and high diastereoselectivity results (Table 1). Thirdly,
the high regioselectivity can be explained by looking at the
frontier orbitals: The HOMO of the 2H-phosphole 2a (R1 =
Figure 1. Contour plots of the HOMO of 2H-phosphole (2a; left) and the
LUMO of MOxF (right). Isovalue: 0.06; the largest atomic orbital coeffi-
cients are shown in brackets; hydrogen atoms are omitted for clarity.
and exo isomers of 3a–c show inverse configuration at the
phosphorus atom and norbornene fragment, which could be
of special interest for applications in asymmetric catalysis.
Since the absolute configuration of the dienophile MOxF
is known, the stereochemistry including the absolute config-
Scheme 2. ACHTUNGTRENNUNG[1,5]-Sigmatropic shift and transition states of the 2H-phospholes and the dienophile MOxF.
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E. Hey-Hawkins et al.
uration of all products was determined by 2D and selective
NOE NMR experiments (see Supporting Information). Ad-
ditionally, endo-3a was deprotected with Raney nickel and
Acknowledgements
This work was supported by the Saxon State Ministry of Science and the
Arts (doctoral fellowship for T.M. (Landesgraduiertenstipendium)). The
theoretical investigations were supported by CNCSIS-UEFISCDI, proj-
ects PN II ID PCCE 129/2008, Romania (M.B.S.). Support from the
Graduate School “Building with Molecules and Nano-objects (BuildMo-
Na)” and the EU-COST Action CM0802 PhoSciNet is gratefully ac-
knowledged. We thank Dr. P. Lçnnecke (X-ray crystallography) and Dr.
M. Findeisen (NMR spectroscopy) for their support.
treated in situ with [W(CO)5ACTHNUGRTNEUNG(MeCN)] to give the corre-
sponding tungsten complex 5 in 60% yield after chromato-
graphic workup. Crystal structure analysis of 5 confirmed
the proposed absolute configuration (Scheme 3, Figure 2).[14]
Keywords: asymmetric synthesis
·
chiral phosphanes
·
diastereoselectivity
differentiation
·
Diels–Alder reaction
·
face
Scheme 3. Desulfurization and subsequent metal complexation of endo-
3a.
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Figure 2. ORTEP of 5 showing the absolute configuration of the main
stereoisomer. Ellipsoid level at 50%. Hydrogen atoms are omitted for
À
À
clarity. Selected bonds lengths [pm] and angles [8]: W1 P1 246.32(8), P1
À
À
À
À
C5 180.6(3), P1 C6 182.9(3), P1 C1 185.5(3), O3 C8 138.63, O2 C8
145.8(3) and C1-P1-W1 119.04(9), C5-P1-W1 126.02(10), C6-P1-W1
125.32(9), C8-C1-P1 117.65(18), C7-C2-C3 113.2 (2), O3-C8-C1 107.6(2).
In conclusion, although Diels–Alder reactions of 2H-
phospholes or MOxF have been well investigated, their
combination leads to an unexplored and very promising
area of face differentiation of phosphorus atoms in a planar
enviroment. Here, we have shown that the principle of face
differentiation for a P=C bond is a new synthetic tool for
highly selective and efficient synthesis of P-chiral phos-
phanes from cheap and readily available starting materials.
The sulfur-protected compounds 3a–c can be stored and
handled in air and can be readily deprotected prior to use.
This synthetic approach will now be extended to other 1H-
phospholes. Moreover, application of deprotected 3a–c in
asymmetric catalysis will be tested. Further modification of
3a–c, for example, reductive cleavage of the pseudo auxili-
ary group, should result in water-soluble chiral phosphanes
with potential applications in two-phase catalysis.[15]
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Phospha-Diels–Alder Reaction
COMMUNICATION
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[14] CCDC-896596 (5) contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Center via www.ccdc.cam.ac.uk/
data_request/cif.
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Received: October 15, 2012
Published online: November 30, 2012
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