P-chiral phosphorus heterocycles: a straightforward synthesis

Abstract

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.

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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

One of the main reasons why P-chiral phosphanes have been less applied in asymmetric catalysis than phosphanes having a chiral backbone is their challenging synthesis. Due to the immense interest in these compounds and the efforts made to expand their structural scope, this problem is about to be overcome.^2d–f,3 Thus, established synthetic strategies involve kinetic resolution and dynamic kinetic resolution of racemates, stereotopic face differentiation and desymmetrisation.^2d–f,3 Nevertheless, there is a major lack of stereoselective approaches to P-chiral phosphanes, in contrast to their C-stereogenic counterparts. In this regard, we have shown in a preliminary study that it is possible to apply the principle of stereotopic face differentiation to a P=C double-bond motif by using an asymmetric phospha-Diels–Alder reaction.³ After establishing this stereoselective route to 1-phosphanorbornenes, it was apparent that this approach should also facilitate access to P-chiral 7-phosphanorbornenes with the phosphorus atom in the bridge position. To date, only two synthetic strategies have been reported which give access to this class of compounds.⁴ The advantage of the approach presented here is the use of very cheap and easily accessible starting materials, which also offer the possibility for facile functionalisation and therefore a broad substrate scope.

An important aspect of this approach is the flexible synthesis of P-heterocyclic dienes (Scheme 1). Reaction of 1 with sulfur gives 2a. Thiophospholes 2b–e can be easily obtained from 1via reductive P–C(Ph) bond cleavage, followed by addition of tert-butyl chloride to remove phenyllithium.⁵ Then the phospholide is treated with an electrophile and sulfur to give 2b–e. Compounds 2a–e were fully characterised, and compounds 2d,e were additionally characterised using X-ray crystallography (see ESI†).

Scheme 1 Facile synthesis of P-heterocyclic dienes.

Trivalent phospholes with exocyclic carbon substituents act as poor dienes, and often react only with very strong dienophiles or after rearrangement at higher temperatures⁶ due to the conjugation of the lone pair of electrons at phosphorus and the hyperconjugation of the exocyclic σ-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 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).

Scheme 2 Asymmetric phospha-Diels–Alder reaction yielding P-chiral 7-phosphanorbornenes.

Table 1 Reaction conditions, selectivities and yields

	Conditions	syn : anti^a	d.r. (of all syn)	Yield of 3 (%)
a R^1 to C=C. b Not assignable.
a	PhMe, 110 °C, 3 d	—^b	68 : 21 : 7 : 4	49
b	PhCl, 130 °C, 5 d	96 : 4	85 :7 : 5 : 3	52
c	PhCl, 130 °C, 5 d	98 : 2	93 : 5 : 2 : 0	70
d	PhCl, 130 °C, 5 d	—^b	—^b	50
e	PhCl, 130 °C, 5 d	—^b	—^b	51

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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 °C 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; furthermore, 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. Nevertheless, 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.

The stated configuration of the main stereoisomers was supported by selective NOE NMR experiments (Scheme 3). Moreover, evidence for the syn orientation of R¹ and the C=C 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 C=C double bond, which is suspected to undergo σ–π interactions in such strained cage systems.^12f,13 Additionally, if R¹ in 3 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 C=C 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)°).¹⁴

Scheme 3 Transition state (blue = attractive, red = repulsive) and absolute configuration of 3a–e including the supporting NOEs.

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.‡

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 interactions (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.

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 phosphorus heterocycles. In this respect, the scope of products is very variable due to the facile route and cheap and easily accessible substrates. Moreover, the introduced chiral auxiliary enables further functionalisation, such as substitution reactions or reductive cleavage of the auxiliary, which are of interest for subsequent ligand design and applications in asymmetric catalysis.

For this purpose, 3a–e must be deprotected. Desulfurisation of the stable compounds 3b–e was attempted with RANEY® nickel or triethylphosphane but only resulted in elimination of “P(S)R¹” to give the cyclohexadiene–MOxF fragment. This behaviour was observed for 7-phosphanorbornenes before and shows their tendency towards elimination reactions.¹⁶ With trichlorosilane, no reaction was observed. The method of choice for 3b,d,e was treatment with nickelocene/allyl iodide and subsequently 1-methylimidazole, which was also previously used for the desulfurisation of 7-phosphanorbornenes.^10a The trivalent compounds 4b,d,e, (Scheme 4) were obtained in situ. After two days at room temperature in solution, transformation of the syn to the anti isomer had occurred (singlet at 84–86 ppm in the ³¹P{¹H} NMR spectra).^10a

Scheme 4 Desulfurisation of 3b,d,e and isomerisation of 4b,d,e; ³¹P{¹H} NMR chemical shifts without lock.

These phosphanes could become valuable tools in asymmetric catalysis; the corresponding applications of the in situ generated phosphanes 4b,d,e are now underway and will be reported elsewhere.

This work was supported by the Saxon State Ministry of Science and the Arts (doctoral fellowship for T.M. (Landesgraduiertenstipendium)). Support from the Graduate School “Building with Molecules and Nano-objects (BuildMoNa)” is gratefully acknowledged. We thank Dr P. Lönnecke and MSc F. Windisch (X-ray crystallography) for their support.

Notes and references

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Footnotes

† 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

‡ wR₂ = 0.0662. Absolute structure parameter = −0.01(4). Selected bonds lengths [pm] and angles [°]: 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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