P-chiral phosphorus heterocycles: A straightforward synthesis

Article abstract of DOI:10.1039/c4cc00318g

A straightforward synthesis of P-chiral polycyclic 7-phospha-norbornenes via an asymmetric Diels-Alder reaction is presented. The employed starting materials are cheap, easily accessible and of structural diversity facilitating a new flexible route towards differently functionalised P-chiral phosphanes. This journal is the Partner Organisations 2014.

Full text of DOI:10.1039/c4cc00318g

Volume 50 Number 44 4 June 2014 Pages 5799–5928
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Evamarie Hey-Hawkins et al.
P-chiral phosphorus heterocycles: a straightforward synthesis

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P-chiral phosphorus heterocycles:
a straightforward synthesis†
Cite this: Chem. Commun., 2014,
50, 5826
Tobias Moller, Peter Wonneberger, Nadja Kretzschmar and Evamarie Hey-Hawkins*
¨
Received 14th January 2014,
Accepted 16th March 2014
DOI: 10.1039/c4cc00318g
www.rsc.org/chemcomm
A
straightforward synthesis of P-chiral polycyclic 7-phospha-
norbornenes via an asymmetric Diels–Alder reaction is presented.
The employed starting materials are cheap, easily accessible and of
structural diversity facilitating a new flexible route towards differently
functionalised P-chiral phosphanes.
Chiral compounds are of great importance today and affect almost
everybody’s life. They are mainly applied in life sciences and drug
development, but also in the food and fragrance industries, and
their efficient and targeted syntheses are no longer solely of
academic interest.1 As a result, the fields of asymmetric synthesis
and enantioselective catalysis, in particular, are still growing. For
such an expanding field, new tools and reagents are permanently
desired. Surprisingly, a class of such tools that was used in the very
beginning of enantioselective catalysis has experienced a comeback
recently: the class of P-chiral phosphanes.2
Scheme 1 Facile synthesis of P-heterocyclic dienes.
the phosphorus atom in the bridge position. To date, only two
One of the main reasons why P-chiral phosphanes have been less synthetic strategies have been reported which give access to this class
applied in asymmetric catalysis than phosphanes having a chiral of compounds.4 The advantage of the approach presented here is the
backbone is their challenging synthesis. Due to the immense interest use of very cheap and easily accessible starting materials, which also
in these compounds and the efforts made to expand their structural offer the possibility for facile functionalisation and therefore a broad
scope, this problem is about to be overcome.2d–f,3 Thus, established substrate scope.
synthetic strategies involve kinetic resolution and dynamic kinetic
An important aspect of this approach is the flexible synthesis of
resolution of racemates, stereotopic face differentiation and desym- P-heterocyclic dienes (Scheme 1). Reaction of 1 with sulfur gives 2a.
metrisation.2d–f,3 Nevertheless, there is a major lack of stereoselective Thiophospholes 2b–e can be easily obtained from 1 via reductive
approaches to P-chiral phosphanes, in contrast to their C-stereogenic P–C(Ph) bond cleavage, followed by addition of tert-butyl chloride to
counterparts. In this regard, we have shown in a preliminary study remove phenyllithium.5 Then the phospholide is treated with an
that it is possible to apply the principle of stereotopic face differ- electrophile and sulfur to give 2b–e. Compounds 2a–e were fully
entiation to a PQC double-bond motif by using an asymmetric characterised, and compounds 2d,e were additionally characterised
phospha-Diels–Alder reaction.3 After establishing this stereoselective using X-ray crystallography (see ESI†).
route to 1-phosphanorbornenes, it was apparent that this approach
Trivalent phospholes with exocyclic carbon substituents act as
should also facilitate access to P-chiral 7-phosphanorbornenes with poor dienes, and often react only with very strong dienophiles or
after rearrangement at higher temperatures6 due to the conjugation
¨
¨ ¨
Universitat Leipzig, Fakultat fur Chemie und Mineralogie, Johannisallee 29, 04103,
Leipzig, Germany. E-mail: tobias.moeller@uni-leipzig.de, hey@uni-leipzig.de;
Tel: +49 341 9736151
of the lone pair of electrons at phosphorus and the hyperconjugation
of the exocyclic s-P–C bond with the dienic system.6,7 Substitution of
the exocyclic carbon substituent at the phosphorus atom by a
heteroatom decreases the hyperconjugation effect and activates the
phosphole towards cycloaddition reactions.4f,8 However, if organyl-
substituted derivatives are required, blocking the lone pair of
† Electronic supplementary information (ESI) available. CCDC 981039 (2d), 981040
(2e), 981041 (3a), 981042 (3b) and 981043 (3c), synthesis and full characterisation of
2a–e and 3a–e, and in situ synthesis of 4b,d,e. For ESI and crystallographic data in
CIF or other electronic format see DOI: 10.1039/c4cc00318g
5826 | Chem. Commun., 2014, 50, 5826--5828
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Scheme 3 Transition state (blue = attractive, red = repulsive) and abso-
lute configuration of 3a–e including the supporting NOEs.
Scheme 2 Asymmetric phospha-Diels–Alder reaction yielding P-chiral
7-phosphanorbornenes.
electrons is the only choice. One possibility is coordination to a
metal, which activates the phosphole, but makes it synthetically less
available as a substrate.4a,9 Another possibility is sulfurisation, which
leaves the substrate synthetically more accessible, but does not
activate the diene further.10
In the key step, the Diels–Alder reaction, (5R)-(L-menthyloxy)-
2(5H)-furanone (MOxF) was used as dienophile, since it had
previously shown very good selectivities in stereoselective reactions
(Scheme 2).3,11 The cycloaddition reaction provides chiral C1- (3a–c)
and C2-symmetric (3d,e) P-chiral 7-phosphanorbornenes (Table 1).
The applied conditions show that high activation energies are
needed. Even at elevated temperatures, full conversion of the
substrates occurred only after 5 d. However, in the case of 3a,
decomposition took place slowly even at room temperature; optimal
conditions were found to be 110 1C for 3 d. The methylene group at
the phosphorus atom in 2b–e and 3b–e seems to be important for
full conversion and the stability of the formed product.
The stereoselectivities for the C1-symmetric derivatives 3b,c
are good. For 3a, the moderate d.r. could be attributed to the
less flexible phenyl group at the phosphorus atom; further-
more, the syn/anti ratio for 3a could not be determined, because
numerous signals of decomposition products were present in
the 31P{1H} NMR spectrum of the reaction mixture. In the case
of C2-symmetric products (3d,e), the minor stereoisomers and
hence their ratios could not be assigned because of the more
complex mixture of possible cycloaddition products. Neverthe-
less, for both compounds the main stereoisomer could be
assigned as the C2-symmetric isomer. The main diastereomers
of 3c–e could be readily obtained in pure form.
Fig. 1 Molecular structure of 3b in the solid state showing the absolute
configuration of the main stereoisomer; thermal ellipsoids are drawn at
50% probability. Hydrogen atoms are omitted for clarity.‡
were in a syn relationship with respect to the chiral auxiliary, the lone
pair of electrons at phosphorus (blocked or free) would be above the
CQC double bond and therefore in its shielding cone due to the
anisotropic effect. Consequently, the 31P NMR resonance would be
more upfield shifted, as was observed before.10a,12e,g Single crystals
could be obtained for 3a–c and were analysed using X-ray diffraction
measurements (see ESI†). As a representative example, the molecular
structure of 3b is shown in Fig. 1. The structure confirms the
absolute configuration proposed and shows structural properties
known for 7-phosphanorbornenes and -norbornadienes such as the
small bond angle at the phosphorus bridge (C3–P1–C6 81.67(5)1).14
An explanation for the occurrence of mainly one out of eight
stereoisomers (per phosphanorbornene system) can be drawn from
the transition state showing one attractive and two repulsive inter-
actions (Scheme 3): (1) the attractive endo mode of transition states
in Diels–Alder reactions is well known and attributed to secondary
orbital interactions of the HOMO (diene) and LUMO (dienophile).15
(2) Furthermore, steric shielding of the re side of MOxF by the bulky
menthyloxy substituent causes approach of the thiophosphole from
the si side. (3) In this approach, the sulfur atom, which is sterically
less demanding than R1, points towards the dienophile resulting in a
syn orientation of the substituent R1 at the phosphorus atom and the
double bond in 7-phosphanorbornenes 3a–e.
The stated configuration of the main stereoisomers was sup-
ported by selective NOE NMR experiments (Scheme 3). Moreover,
evidence for the syn orientation of R1 and the CQC double bond can
be taken from the 31P NMR studies showing a strong downfield shift
to 108–113 ppm for 3a–e. This deshielding effect has been known for
norbornenes and -norbornadienes for a long time, and was also
observed for other elements in the bridge position.12 It is caused by
the CQC double bond, which is suspected to undergo s–p inter-
actions in such strained cage systems.12f,13 Additionally, if R1 in 3
Table 1 Reaction conditions, selectivities and yields
Conditions
syn : antia
d.r. (of all syn)
Yield of 3 (%)
b
a
b
c
d
e
PhMe, 110 1C, 3 d
PhCl, 130 1C, 5 d
PhCl, 130 1C, 5 d
PhCl, 130 1C, 5 d
PhCl, 130 1C, 5 d
—
68 : 21 : 7 : 4
85 :7 : 5 : 3
93 : 5 : 2 : 0
49
52
70
50
51
96 : 4
98 : 2
It is remarkable that these three interactions cause very good
selectivities in a single concerted step and yield such complex
structures of high rigidity. This feature is what makes the Diels–
Alder reaction so unique and facilitates access to P-chiral
b
b
—
—
—
b
b
—
a
b
R1 to CQC. Not assignable.
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This work was supported by the Saxon State Ministry of
Science and the Arts (doctoral fellowship for T.M. (Landesgra-
duiertenstipendium)). Support from the Graduate School
‘‘Building with Molecules and Nano-objects (BuildMoNa)’’ is
¨
gratefully acknowledged. We thank Dr P. Lonnecke and MSc
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Notes and references
‡ wR2 = 0.0662. Absolute structure parameter = À0.01(4). Selected
bonds lengths [pm] and angles [1]: S1–P1 194.00(7), P1–C21 182.8(1),
P1–C3 185.0(1), P1–C6 185.5(1), C1–C2 154.3(2), C1–C6 155.4(2), C1–C8
153.4(1), C2–C3 155.8(2), C2–C7 151.8(2), C3–C4 150.7(2), C4–C5
134.4(2), C5–C6 151.7(2); C21–P1–C3 109.44(5), C21–P1–C6 110.10(6),
C3–P1–C6 81.67(5), C21–P1–S1 113.21(4), C5–C6–P1 99.38(7), C1–C6–P1
98.78(7), C4–C3–P1 99.54(7), C2–C3–P1 98.78(7).
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5828 | Chem. Commun., 2014, 50, 5826--5828
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