Catalytic Enantioselective Cyclization and C3-Fluorination of Polyenes

Abstract

(xylyl-phanephos)Pt²⁺ in combination with XeF₂ mediates the consecutive diastereoselective cation-olefin cyclization/fluorination of polyene substrates. Isolated yields were typically in the 60s while enantioselectivies reached as high as 87%. The data are consistent with a stereoretentive fluorination of a P₂Pt-alkyl cation intermediate.

The fluorination of pharmaceutical drug candidates is an important strategy for masking metabolic hot spots.¹ Despite recent progress with electrophilic fluorinating reagents,² the synthesis of such compounds is still challenging and many deficiencies remain, especially in the asymmetric fluorination of non-enolate-based carbon nucleophiles.^3,4,5 Fluorinated steroids (Scheme 1), in particular, are important bioactive compounds with a deficiency of methods for their synthesis.^6,7,8

Scheme 1.

Common fluorinated steroids.

De novo syntheses of carbocycles with the flexibility for F-incorporation are rare, though such methods would considerably expand the accessibility of such privileged structures.¹ Transition metal catalyzed cyclizations, if suitably coupled to M-C fluorination reactions,⁴ could provide a route to complex fluorinated carbo- and hetero-cycles with control of absolute and relative stereochemistry.

Electrophilic Pt(II) complexes are effective initiators of C-C bond forming cation-olefin cascades.^9,10,11 The fate of the organometallic intermediate of these cascades can be controlled through ligand choice, and when the supporting ligand is a diphosphine, this intermediate is susceptible to β-H elimination and leads to net dehydrogenated products. If this complex could instead be intercepted by a Pt-C fluorination reaction, a catalytic cyclization/fluorination protocol would result with concomitant access to C3-fluorinated compounds.^6d The rapidity and stereospecificity with which [(triphos)Pt-R][BF₄] reacts with XeF₂ to yield C-F products (Eq. 1) suggested that the desired interception might be capable of competing with β-H elimination.¹²

(1)

In the diphosphine catalyst series that we have examined, (S)-xylyl-phanephos ((S)-(–)-4,12-bis[di(3,5-xylyl)phosphine]-[2,2]-paracyclophane) has consistently provided the highest enantioselectivity for various cyclization chemistries. As a starting point for our catalytic cyclization/fluorination goal, we adapted conditions previously optimized for cyclization/β-H elimination reactions.^10b The modified conditions included use of AgBF₄ and NCC₆F₅ to generate the “active” [(S)-(xylyl-phanephos)Pt(NCC₆F₅)₂][(BF₄)₂] catalyst. Subsequent addition of a base (to facilitate cyclization), substrate and an electrophilic fluorine source generated the desired product (1) as a single (stereoretentive) isomer, along with variable quantities of β-H eliminated product (3) and the Brønsted product (5) (Table 1); several additional phosphines are included for comparison.

Table 1.

Selected optimizing conditions.

Entry	P2	Base	% 1a (%ee)b	%3a	%4a	%5a
1	(R)-DTBM-SEGPHOS	None	20	14	0	57
2	(R)-DTBM-SEGPHOS	Ph2NH	34	28	trace	14
3	(R)-DTBM-SEGPHOS		63(13)	8	11	0
4	(R)-xylyl-MeO-BIPHEP		85(5)	10	3	0
5	(S)-xylyl-phanephos		72(75)	7	3	trace

^aUncorrected GC percentages

^bDetermined by chiral GC.

In screening a variety of electrophilic fluorine sources, it was discovered that only XeF₂ effectively competed with β-H elimination. Other less reactive F⁺ sources showed predominant to exclusive β-H elimination to 3.¹³ In addition to the desired 1, over fluorination to 4 was also observed. Since controls showed that 1 does not react with XeF₂ and acid is known to enhance the F⁺ potential of XeF₂,¹⁴ we surmised that the HF byproduct of cyclization was activating the XeF₂. This problem was easily solved by the addition of TMSOMe as an HF sponge, which additionally obviates the need for a base.¹⁵

Optimization studies included testing multiple bisphosphines, solvents, and other TMS-X derivatives.¹⁵ Once again (S)-xylyl-phanephos was uniquely enantioselective (~75%) for controlling the % ee of the cation-olefin cascades. Of the tested HF scavengers, TMSOMe was the most effective inhibitor of double fluorination and like previous ionic cascades, nitro-methane was the optimum solvent. A catalyst formulation comprised of 10 mol% (S)-(xylyl-phanephos)PtI₂, 25 mol% AgBF₄, 30 mol% NCC₆F₅ and stoichiometric quantities of XeF₂ and TMSOMe at 0 °C provided 1 in 67% yield and with 75% enantiomeric excess.¹⁶

These optimized conditions were subsequently applied to a variety of alcohol and phenol terminated dienes and trienes (Table 2). In most cases, high conversion of substrate occurred within three hours, however, the reactions were allowed to proceed for 24 h at 0 °C to ensure complete consumption of the XeF₂. For the substrate classes in Table 2, no Brønsted acid derived products like 5 were observed, and a single diastereomer consistent with stereoretentive fluorination of the intermediate P₂Pt-alkyl cation, was observed.

Table 2.

Catalytic electrophilic fluorination.^a

Entry	Polyene	Product	Yield 1 (%ee)b	Yield 3c
1			67% (75)	14%
2			67% (73)	15%
3d			49% (86)	15%e
4			56% (81)	16%
5			60% (87)	13%
6			68% (83)	24%
7			80% (81)	trace
8f			63%g	22%
9f			69% (10)	10%e
10h			56% (78)	0%

^aCondtions: 10 mol% (S)-(xylyl-phanephos)Ptl₂, 25 mol% AgBF₄, 30 mol% NCC₆F₅, 1.1 equiv TMS-OMe, 1.1 equiv XeF₂, 0.4 mL CD₃NO₂, 0 °C, 24 h. Starting material is mass balance of reaction.

^bIsolated yield, % ee determined by chiral GC.

^cGC yield.

^dReaction run using 1.6 equiv XeF₂.

^ePercentage is fluorinated elimination species only

^fReaction with 20 mol% polystyrene-bound piperidine base run, no TMS-OMe, see SI for details.

^gDue to the volatility of this compound, a GC yield is reported.

^hContains 23% unidenfied species, mass balance is unreacted starting material. Cannot separate the unidentified species from the product, therefore GC yield reported.

As shown in Table 2, variants on the phenol termini were well tolerated, except for α-naphthol (entry 3), wherein competitive fluorination of the aryl ether product occurs even with TMSOMe. In situ monitoring indicated that aryl fluorination occurred post cyclization / Pt-C fluorination. In this case, extra XeF₂ was used to compensate for the difluorination stoichiometry. Unexpectedly, para-substituents improved the ee’s (entries 4–7).

Dienyl- and trienyl alcohols and phenols were also viable substrates though they behaved peculiarly. In the case of entries 8 and 9, the yields were poor under standard conditions, but could be recovered by exchanging TMSOMe for a polystyrene-bound piperidine base (see Table 1). In contrast, the triene alcohol in entry 10 performed better under the standard conditions. These base effects are not yet understood.

In situ monitoring of a cyclization/fluorination of 2 indicated that the alkyl cation (as the nitrile adduct, 6) serves as the catalyst resting state (³¹P NMR). These data support our current view of the mechanism (Scheme 2), that has 6 competitively undergoing β-H elimination or F⁺ attack to generate a [Pt]^IVR(F) dication, which undergoes a stereoretentive reductive elimination to 1. Neither the [Pt]^IV nor the [Pt]-H species are observable by NMR, however, literature precedence suggests that both routes are viable.^{17,5d,5f,5i,5k}

Scheme 2.

Proposed catalytic cycle for electrophilic fluorination.

In summary, we illustrate that P₂Pt-dicationic catalysts can mediate the enantioselective cation-olefin cyclization/fluorination reactions of polyprenoids to yield C3-fluorinated carbocycles. The key feature of the putative catalytic cycle is the selective reaction of XeF₂ with P₂Pt-alkyl cations over P₂Pt-dications, which enables the sequential cyclization/fluorination.