Stereodefined alkenes with a fluoro-chloro terminus as a uniquely enabling compound class

Abstract

Trisubstituted alkenyl fluorides are needed for research in biological chemistry, drug discovery, agrochemical development, and materials science. Among other applications, these entities are secondary amide bond mimics in one stereoisomeric form and induce a peptide turn in the other. Despite notable progress, however, many stereochemically defined trisubstituted fluoro-alkenes either cannot be prepared efficiently, or can be accessed in only one isomeric form. Here, we outline a general solution to this problem by first unveiling a practical, widely applicable, and catalytic strategy for stereodivergent synthesis of olefins bearing a fluoro and chloro terminus. This has been accomplished by cross-metathesis between two trisubstituted olefins, one of which is a purchasable but scarcely utilized trihalo alkene. Subsequent cross-coupling then be used to generate an assortment of trisubstituted alkenyl fluorides. The importance of the advance is highlighted by syntheses of, among others, a fluoro-nematic liquid crystal component, peptide analogs bearing an E- or a Z-amide bond mimic, and all four stereoisomers of difluoro-rumenic ester (anti-cancer).

That fluorine-containing organic molecules^1,2,3,4,5 are highly valuable is indisputable, and among such entities, trisubstituted alkenyl fluorides are a noteworthy sub-class. As one stereoisomer, trisubstituted alkenyl fluorides mimic a secondary amide bond^6,7,8,9, the primordial link between amino acids in a peptide chain, one that impacts a peptide’s stability and folding tendencies, among other functions. The alternative stereoisomer is a peptide turn inducer^10,11, a metabolically stable surrogate for the higher energy secondary amide stereoisomer, providing a rare opportunity for probing its impact on a polypeptide’s binding ability and/or other biological attributes¹². For example, when an amide bond of Leu-enkephalin (Fig. 1a) is replaced with a trisubstituted alkenyl fluoride, metabolic stability and physiochemical properties are improved, resulting in better oral bioavailability and distribution in the central nervous system¹³. Substitution of a C–H bond with a C–F unit can also enhance metabolic stability, binding affinity, and/or bioavailability of a drug candidate^14,15. The fluorine atom in 5-fluoro-resorcynolide, a member of a kinase-targeting family of compounds (Fig. 1a), stabilizes the stereoisomeric identity of the enoate, enhancing its inhibitor activity¹⁶.

Fig. 1 |. The importance of trisubstituted alkenyl fluorides and the state-of-the-art.

a, Trisubstituted alkenyl fluorides are key to advances in medicine and materials research. One example is fluoro-substituted Leu-enkephalin has superior physiochemical properties, is more metabolically stable, more orally bioavailable, and more effectively distributed in the central nervous system compared its non-fluoro variant. Another case is 5-fluoro-enone resorcynolide, where the alkenyl fluoride undergoes cysteine conjugate addition slower, resulting in improved kinase inhibitor activity. The importance of trisubstituted alkenyl fluorides extends to materials research, as exemplified by fluoro-nematic liquid crystal components. b, The state-of-the-art in olefin metathesis methods for preparation of trisubstituted alkenyl halides is limited in scope: only Z-n-alkyl-substituted products can be generated. c, Cross-metathesis processes that involves a 1,2-bromo,fluoro-ethene generate trisubstituted alkenyl bromides preferentially. X = chiral auxiliary; HMPA, hexamethylphosphoramide; TBS, t-butyldimethylsilyl; R, substituent.

The only way to access a fluorine-containing organic molecule is by chemical synthesis, and there have been considerable contributions in this area^{17,18,19,20,21}. Still, a good many trisubstituted alkenyl fluorides remain inaccessible because a broadly applicable and stereoselective strategy for generating trisubstituted alkenyl fluorides remains lacking⁷. This is a major shortcoming that hampers progress and not just in drug development. Researchers in material science have had to be content with investigating isomeric mixtures in the area of nematic liquid crystal development (Fig. 1a)²². The available methods^6–9,23 can be limiting. For instance, aryl-substituted products are generated in most cases, and/or stereoselectivity can be low. If selective, nearly always just the Z isomer is obtained (that is, the lower energy secondary amide bond analog).

Cross-metathesis between two olefins represents an attractive approach to stereoselective synthesis of trisubstituted alkenyl fluorides. Along these lines, one report details the preparation of products that contain a geminal difluoro moiety²⁴, where stereoselectivity is not a concern. In a later disclosure, it was shown that reactions promoted by a Ru complex and between methyl-2-fluoroacrylate and aliphatic monosubstituted olefins may be used to prepare Z-trisubstituted alkenyl fluorides (Fig. 1b)²⁵. Many alkenyl fluorides were obtained in useful efficiency levels (turnover number (TON), up to 175) and high stereochemical purity. Nonetheless, aside from being confined to generating α,β-unsaturated esters in only one regio- and stereoisomeric form, the method is limited to unhindered n-alkyl-substituted olefins; it was found that a number of useful polar groups were not tolerated (such as a primary alkyl bromide).

Results and Discussion

Trisubstituted alkenes with a fluoro-chloro terminus.

One way to synthesize trisubstituted alkenyl fluorides would be by selective preparation of an alkene that contains a fluorine atom and another, easily modifiable, substituent. Apropos, there is a small number of methods for preparation of trisubstituted alkenyl fluorides that contain a boryl unit^26,27 or iodo atom ^28,29. The need for multistep substrate synthesis notwithstanding, these strategies are confined to a few aryl-substituted products and one isomeric form.

An enticing possibility would be to synthesize, by catalytic stereoretentive³⁰ cross-metathesis, alkenyl fluorides that can then be modified easily. However, among the less than a handful of kinetically controlled methods for synthesis of trisubstituted olefins in high stereoisomeric purity^31,32,33, only one has been used to generate chloro- or bromo-substituted olefins, and none delivers a fluoro-substituted alkene preferentially. This is unlike the reactions with 1,2-disubstituted alkenes, which can readily furnish alkenyl fluorides³⁴. Instead, reaction between a trisubstituted alkene and Z-1-bromo-2-fluoro-ethene, via a bromo-substituted Mo alkylidene, gives a trisubstituted alkenyl bromide (97:3 Br:F; Fig. 1c). Generating a fluoro-substituted alkylidene would require the use of a significantly less practical 1,2-difluoroethene, a compound that is costly and explosive with the challenging boiling point of –72 °C.

We therefore contemplated the possibility of developing a catalytic strategy for diastereodivergent synthesis of trisubstituted olefins bearing a fluoro,chloro-substituted terminus (Fig. 2a). To the best of our knowledge, there are no methods reported for stereoselective synthesis of a 1,1-chloro,fluoro-, or 1,1-bromo,fluoro-trisubstituted olefin (catalytic or otherwise). We reasoned that such entities could become accessible by reactions involving E- or Z-1,2-dichloro-1-fluoroethene (i.e., Z-1 or E-1), which are commercially available in high stereoisomeric purity (96:4 Z:E or E:Z) and possess fitting physical properties (e.g., boiling point at 32 and 38 °C, respectively). Still, surprisingly, these latter poly-halogenated alkenes have rarely been utilized in reaction development. We further argued that the chloro,fluoro-substituted alkenes could be chemoselectively modified at the C–Cl site by dependable catalytic cross-coupling processes, allowing conversion to sundry other stereochemically defined trisubstituted alkenyl fluorides. In regard to the projected site-selective carbon–halogen bond functionalization, while reactions involving C–F bonds are known²⁶, there is precedent for chemoselective transformation at the C–Cl bond within the same entity^28,35. If successful, we would have identified a reasonably general strategy for stereocontrolled preparation of these valuable entities, which include peptide chains with an E-alkenyl fluoride serving as a turn inducer (Fig. 2b), or stereoisomeric fluoro-substituted analogs of bioactive entities such as rumenic acid, a compound that reduces metastatic regrowth in breast cancer³⁶, or oleoyl coenzyme A, regulator of Raas (renin-angiotensin system) interaction with DNA in mycobacteria³⁷.

Fig. 2 |. The adopted strategy and its mechanistic basis.

a, A fully catalytic approach for direct formation of trisubstituted alkenyl fluorides in either stereoisomeric form would entail stereoretentive cross-metathesis between commercially available, stereochemicaly defined trihalo alkene and an appropriate, readily accessible olefin. Subsequent site-selective and stereoretentive cross-coupling, may then be used to convert the C–Cl bond to a variety of other substituents. b, If successful, a number of highly desirable but difficult-to-access compounds would become readily available. This would include peptide chains that contain an E-trisubstituted alkenyl fluoride, which serves as the mimic of the higher energy isomer of an amide linkage, various stereoisomeric forms difluoro analogues of rumenic acid, a compound that is important to the fight against breast cancer, or analogues of oleoyl coenzyme A, a Raas inhibitor, in which there is a fluoro tag at one or the other alkenyl site. Pin, pinacolato; AA, amino acid residue.

Preliminary studies.

We had two concerns in regard to the above plan. One was that, as noted, stereoretentive olefin metathesis reactions that generate trisubstituted alkenes are uncommon (one example shown in Fig. 1b). This is largely because substrates that are considerably less reactive than disubstituted olefins must be used. Additionally, olefin metathesis with trisubstituted electron-deficient alkenes, such as E-1 or Z-1, is unprecedented, casting an even longer shadow on whether a catalytic cycle, in which a Mo alkylidene must undergo consecutive reactions with trisubstituted olefins, is viable. Nonetheless, we decided to investigate a model process with a 1,2-disubstituted alkene (e.g., ia (R = H), Fig. 3a). This way, an unstable methylidene generated from homocoupling of a monosubstituted olefin would be avoided^31,38, and the less hindered alkene (compared to the trihalo-alkene) would react first with a Mo neophylidene complex (e.g., ii). To maximize efficiency, the faster initiating Z isomer would be used. Our hope was that catalytically active iii would react with Z-1 to give mcb-i (mcb, metallacyclobutane), wherein the larger chlorine atoms would probably be oriented towards the smaller arylimido ligand. This would allow the fully substituted carbon to be at the less congested Cβ³⁴. Productive collapse of mcb-i would afford the fluoro-chloro-substituted olefin (Z-prod) and chloro-substituted alkylidene iv, which might react with the 1,2-disubstituted alkene³⁹.

Fig. 3 |. Mechanism-based development of the cross-metathesis approach.

a, Based on previous studies, it was expected that a Z-disubstituted alkene (ia) might be a suitable substrate, and the reaction would proceed via iii, mcb-i, iv, and mcb-ii to afford the desired trisubstituted alkenyl fluoride (outer catalytic cycle). b, Reaction between Z-1 and 3, while highly stereoretentive, was inefficient (41% conv.), however, affording significant amounts of byproducts 5 and 2. Mechanistic re-evaluation (inner cycle, panel a) indicated that cross-metathesis involving two trisubstituted alkenes would likely be more efficient because reaction via mcb-iii to generate v and vi would be less favored (red reaction arrow). c, Nonetheless, cross-metathesis between Z-1 and trisubstituted alkene 6a hardly proceeds. d, To address this, we envisioned facile initiation of the initial complex (ii) by an appropriate alkene additive (vii), affording viii, which would more readily react with a trisubstituted olefin (ib) to give mcb-iv, ix, and the desired intermediate ent-iii. e, In the event, with 10 mol % of a Z-1,2-disubstituted olefin, the reaction takes place readily and with exceptional stereochemical control. TBS, t-butyldimethylsilyl; Ar, aryl group; mcb, metallacyclobutane; ent, enantiomeric.

Another issue was that the transformation could either proceed via mcb-ii (desirable) or mcb-iii, depending on the regioselectivity with which a trisubstituted olefin adds to a chloro-alkylidene. Reaction via mcb-ii would re-generate Mo alkylidene iii and release Z-1-chloro-1-propene, a volatile byproduct. Alternatively, transformation via mcb-iii would afford a Z-1,2-disubstituted alkenyl chloride (v) and methyl-substituted alkylidene vi (R = H), which can react with Z-1 to give 2, a less valuable methyl-containing fluoro-chloro-substituted alkene. It was unclear how high the mcb-ii:mcb-iii (R = H) selectivity would be, especially with a bulky alkenyl moiety (blue circle), in which case it would be preferentially positioned at the central and less congested Cβ in mcb-iii (R = H). In short order, experimental data (Fig. 3b) indicated that our reservations were justified: reaction between Z-1 (94:6 Z:E) and Z-1,2-disubstituted alkene 3 in the presence of 5.0 mol % Mo-1a afforded a mixture of 4a (41% conv.) along with significant quantities of byproducts 5 (20% conv.) and 2a (24% conv.), likely formed via mcb-iii (R = H). The lesson was clear: to enhance efficiency, formation of mcb-iii (R = H) must be avoided. One solution would be to use a trisubstituted alkene instead (i.e., ib instead of ia, Fig. 2b) because then the positioning of a gem-dimethyl group at the more congested Cα would become less favorable (compare mcb-ii and mcb-iii, R = Me).

Cross-metathesis of two trisubstituted alkenes.

The one option left – cross-metathesis between two trisubstituted olefins with one being an electronically depleted trihalo alkene – was unorthodox. The major issue was efficiency, since trisubstituted alkenes are not known to re-enter a catalytic cycle easily^31,32,40,41. In regard to stereocontrol, we were reasonably confident, based on previous studies^31,33, that stereoretentivity would probably be high. The small number of kinetically controlled cross-metathesis processes, which may be used to convert one trisubstituted alkene to another, either involve exceptionally reactive Mo alkylidenes bearing an activating and diminutive substituent (e.g., a chlorine, a bromine³¹, or a nitrile group³³), or are confined to an allylic hydroxy or ether moiety³². Here, the same benefit would apply to one of the two steps in the proposed pathway (see iv → mcb-ii, Fig. 3a), but only if an alkyl-substituted alkylidene were to survive the demanding early stages of the process (see iii + Z-1 → mcb-i). Another worry was whether the Mo alkylidene system would be able to react with two different trisubstituted alkenes, and at the same time be long-lived enough to promote a process efficiently, but not so reactive that it would also react with the final product, causing erosion of kinetic selectivity.

For want of a more secure alternative, we set out to find out whether a hindered and more electron-rich all-carbon substituted alkenyl substrate or the halogenated trisubstituted olefin can preferentially react with a Mo neophylidene (e.g., Mo-1a) to afford alkylidene iii (Fig. 3a). Treatment of Z-1 (5.0 equivalents) and trisubstituted alkene 6a (Fig. 3c), under otherwise identical conditions, led to minimal transformation and most of Mo-1a remained intact (¹H NMR spectroscopy).

To facilitate catalyst initiation, we chose to add a small amount a Z-1,2-disubstituted alkene additive to the mixture (vii, Fig. 3d). This was based on the hope that the resulting alkylidene (viii) would react with a substrate molecule (ib), affording mcb-iv and then ent-iii, it remained to be seen if this would jump-start the transformation. Another question was whether coordination of a second trisubstituted olefin, leading to the formation of a more substituted mcb, would be too demanding. When the reaction involving trisubstituted alkene 6a was carried out with 10 mol % Z-hex-3-ene (Fig. 3e), there was 76% conversion to Z-trisubstituted alkenyl fluoride (4a), which was isolated in 70% yield after purification (95:5 Z:E). (For details regarding the choice of butene or hex-3-ene as an additive, see the supplementary information.) There was minimal (2%) conversion to 5, and 7 could not be detected (<2%), indicating that there was no longer any competitive formation of mcb-iii (R = Me). The presence of excess Z-1 ensured maximum efficiency.

Broadly applicable and stereodivergent.

Many n-alkyl-Z-trisubstituted chloro,fluoro-alkenes were synthesized under the conditions described above in up to 86% yield >98:2 Z:E ratio (Table 1). These include products bearing a bromide (4b), a tertiary amine (4c), a B(pin) group (pin, pinacolato 4d), an acetal (4e), an unprotected indole (4f), a benzofuran (4g), or a benzothiophene (4h), a lactone (from natural product auraptene; 4i), or a highly functionalized and electronically activated cyclopropane (4j). In situ protection/deprotection with commercially available HB(pin)⁴² allows for one-pot catalytic cross-metathesis with an alcohol (directly from natural product bisabolol; 4k). Synthesis of 4l, involving reaction of a diene bearing a disubstituted enoate, was highly chemoselective, favoring reaction at the more electron-rich, but hindered, trisubstituted olefin (4l).

Table 1 |.

Synthesis of E- or Z-trisubstituted alkenyl fluorides through catalytic stereoretentive cross-metathesis.

Reactions were carried out under N₂. Conversion to the desired product as measured by analysis of 400 MHz ¹H NMR spectra of unpurified mixtures with DMF serving as the internal standard; the variance of values is ±2%. Yield of isolated product after purification., average over at least three runs; the variance of values is estimated to be <5%. ⁺(pin)BH used for traceless protection.

^*10 mol % catalyst used. See the Supplementary Information Part 1, section 3, for details.

Bn, benzyl; pin, pinacolato; Boc, t-butylcarbonate; Mes, 2,4,6-trimethylphenyl.

Products bearing an α-branched alkene, ubiquitous in bioactive compounds and especially challenging to access by olefin metathesis, were obtained with similar efficiency and stereochemical purity (4m-n, Fig. 3b). Monosubstituted alkenes were used in these instances, on account of slow homocoupling and minimal likelihood of a short-lived Mo methylidene being formed. Synthesis of trisubstituted olefin 4o shows that β-branched olefins can be accessed. Another substrate class, challenging because of their tendency to undergo facile homocoupling, are aryl alkenes. In such instances, Z-β-methyl alkenes, available in a single step from commercially available materials, are more effective starting materials, and alkylidenes derived from the more electronically activated and less sterically demanding monoaryloxide chloride complex Mo-2⁴³ (see Fig. 4a) are optimal, as indicated by the synthesis of 4p (see Fig. 4a for additional cases).

Fig. 4 |. The catalytic method is broadly applicable, practical, and cost-effective.

a, When the product of a cross-metathesis reaction is too volatile for it to be isolated in high yield, the unpurified product may be used directly. For example, enoates 10a-c were obtained by direct catalytic cross-metathesis of the cross-metathesis products without purification. b, Not only may the catalytic approach be used to generate fluoro,chloro-substituted aryl olefins, sterically demanding aliphatic olefins are suitable substrates as well. The catalytic cross-metathesis/cross-coupling sequence may be used to access a variety of valuable products, such as fluoro-substituted enynes. c, Inexpensive monosubstituted olefins can be also be used as starting materials. This involves a one-pot process that generates the requisite trisubstituted alkene, followed by another cross-metathesis with E-1 or Z-1. d, The catalytic process can be performed on multi-gram scale, and excess trihalo alkene can be easily recycled without any diminution in efficiency or stereocontrol. See the Supplementary Information Part 1, section 3, for details. NMP, N-methyl-2-pyrrolidone.

The E-trisubstituted alkene isomers were accessed in similarly high stereoisomeric purity from E-1 (8a-i, Table 1). These transformations are somewhat less efficient than those furnishing the corresponding Z-alkenes, a difference that may be attributed to increased steric pressure in the intervening metallacyclobutanes (Cβ chlorine oriented towards the larger aryloxide ligand; see mcb-i, Fig. 2b).

Practical, scalable and economical.

Several additional points that highlight the broad scope and practicality of the approach are noteworthy. One is that, at times, the dihalo olefins can be too volatile to be isolated in high yield. In such instances, the cross-metathesis product may be converted to a more readily isolable and similarly desirable compound. One example is formation of fluoro-substituted enones 10a–c (Fig. 4a) by catalytic cross-coupling with alkenylzinc halide 9 (prepared in one step and >98% yield from the commercially available alkenyl bromide). It should be mentioned that Horner-Emmons reactions afford E-enoates preferentially¹⁶. Another key attribute of the approach is that, other than aryl-substituted olefins, hindered alkyl olefins can also be used as substrates. Cross-metathesis with sterically demanding silyl ether 11 (Fig. 4b) and subsequent catalytic cross-coupling, concomitant with silyl ether removal, afforded 12a in 41% overall yield as a single olefin isomer (>98:2 Z:E). Allylsilane 12b, which may be used for additions to different carbonyl compounds, was synthesized in a similar manner (40% overall yield, >98:2 Z:E).

As noted earlier, a trisubstituted alkene is needed for optimal efficiency, so that an unstable methylidene complex is avoided.³¹ Nevertheless, monosubstituted olefins can be used as starting materials. For instance, treatment of terminal olefins 13a or 13b (Fig. 4c) with inexpensive 2-methyl-2-butene (20 equiv.) and 1.0 mol % Mo-1a, removal of excess butene under mild vacuum, followed by addition of Z-1 (10 equiv.), Z-hex-3-ene (10 mol %), and 5.0 mol % Mo-1a afforded 4o and 4q 57% and 83% yield, and 92:8 and 95:5 Z:E selectivity, respectively. Analogously, 10h and 10k were synthesized by a one-pot procedure in 44% and 52% yield and in 98:2 and 97:3 E:Z ratio, respectively. It is worth noting that there are naturally occurring bioactive 1,1-dimethyl-trisubstituted alkenes [for example, indomethacin (anti-inflammatory⁴⁴), auraptene (anti-cancer⁴⁵), or imperatonin (anti-convulsant⁴⁶)] that can be used as substrates, and some are renewable feedstock (such as geraniol, farnesol, or linalool). The catalytic protocol is scalable: 1.27 grams of 13c was transformed to 1.1 grams of 4m (72% yield). Furthermore, 1.2 grams of 14 was converted to 0.82 gram of 4r (62% yield, 95:5 Z:E; Fig. 3e) by a reaction involving commercially available Mo-1c (used as received). Excess Z-1 was recovered in 80% yield (4.29 g, after distillation) and was re-used to generate 4q in 60% yield and 95:5 Z:E ratio.

Readily diversifiable products.

A host of compounds were prepared with minimal loss of stereoisomeric purity and in either stereoisomeric form by chemoselective transformation at the C–Cl bond of the trisubstituted alkenyl products (Table 2). The importance of deuterium-labeled organic molecules in drug discovery research⁴⁷ renders regio- and stereoselective synthesis of isotopically labeled fluoro- alkenes, such as 15, noteworthy. The corresponding alkenyl boronates (e.g., 16) and bromo- and iodo-substituted derivatives (e.g., 17 and 18) are effective cross-coupling substrates⁴⁸. Because the latter sets of compounds are more reactive than alkenyl chlorides, they may be conveniently converted to a variety of trisubstituted fluoro-alkenes. As will be demonstrated (see below), the ability to generated E- or Z-trisubstituted olefins containing a fluorine and a chlorine substituent and those that bear a fluorine substituent and a boryl unit makes it possible to synthesize every 1,3-diene stereoisomer in which the C2 and/or the C3 site(s) are fluoro-labeled. Aside from being limited to aryl olefins, only Z-boryl-containing trisubstituted alkenyl fluorides can be accessed through the extant methods^26,27,49. The chlorine substituent may be exchanged with other heteroatoms, exemplified by the preparation of enamine 19 (Table 2), enol ether 20, and alkenyl phosphonate 21. Equally noteworthy are trifluoromethyl-substituted 22, allylic alcohol 24, 1,4-diene 25, oxazole 26, alkenyl nitrile 28, and carboxylic ester 29. Although there are alternative strategies⁷ for preparation of some of the same types of trisubstituted alkenyl fluorides (e.g., aryloxy-substituted⁵⁰, phosphonate-substituted⁵¹, heterocycle-substituted⁵², or cyano-substituted⁵³), the present approach is more direct, is not confined to aryl alkene substrate and products, and can be used to obtain Z or E isomers.

Table 2 |.

Diversification of Trisubstituted alkenyl fluorides.

Reactions were carried out under N₂. Conversion to the desired product as measured by analysis of 400 MHz ¹H NMR spectra of unpurified mixtures with DMF serving as the internal standard; the variance of values is ±2%. Yield of isolated product after purification., average over at least three runs; the variance of values is estimated to be <5%. See the Supplementary Information Part 1, section 3, for details.

G, carbon-based moiety; R, carbon- or heteroatom-based moiety; pin, pinacolato; XPhos, 2-dicyclohexylphosphino-2’,4’,6’-triisopropylbiphenyl; dppf, 1,1’-bis(diphenylphosphino)ferrocene; SPhos, 2-dicyclohexylphosphino-2’,6’-dimethoxybiphenyl; DMF, dimethylformamide; DME, dimethoxyethane; CyJohnPhos, (2-biphenyl)dicyclohexylphosphine.

Site-selective cross-coupling.

The availability of E-trisubstituted alkene 10l (65% yield, 97:3 E:Z), containing a dichloro-olefin terminus, afforded us the opportunity to establish whether chemoselective cross-coupling at one of the dihalo-substituted alkenes is feasible. Under the Sonogashira conditions (Fig. 5a), the C–Cl bond proximal to the C–F underwent transformation, and fluoro-substituted enyne 30a was isolated in 53% yield along with 8% of the chloro-substituted enyne (87:13 regioisomeric ratio (r.r.)). In contrast, and unexpectedly, the cross-coupling performed under Negishi conditions with alkenylzinc chloride 9 proceeded with the opposite selectivity, furnishing chloro-substituted enone 31 in 80% yield as the only regioisomer (>98:2 r.r.). Outcomes were the same when the Z-alkene was used (see 4j, Table 1). (The origin of the selectivity profile is under investigation.) It merits mention that attempts at using E-1 or Z-1 directly as the starting materials for cross-coupling led to low regioselectivity and/or low conversion in most cases. On occasion, when cross-coupling was comparatively efficient, the preferential isomer within the inseparable mixture of products was the one derived from reaction at the C–Cl bond of the dihalo-substituted carbon (that is, the alkene with a fluoro-chloro terminus was not generated).

Fig. 5 |. Site-selective cross-coupling, and site-selective and regiodivergent fluoro-labeling.

a, Chemoselective cross-coupling reactions with a substrate containing two dihalo alkenes further expands the utility of the approach. b, Fluoro-substituted derivatives of hachijodine G (anti-leukemic) obtained through sequential catalytic cross-metathesis and cross-coupling with a readily available terminal alkyne. c, The approach is applicable to preparation of fluoro-containing analogs of macrocyclic bioactive entities, such as coriolide (pheromone). d, A convenient approach to regiodivergent preparation of monofluoro analogs of oleoyl coenzyme A (regulates Raas interaction with DNA). See the Supplementary Information Part 1, sections 6–8 for details. NMP, N-methyl-2-pyrrolidone; r.r., regioisomeric ratio; SPhos, 2-dicyclohexylphosphino-2’,6’-dimethoxybiphenyl; pin, pinacolato; DMF, dimethylformamide; THF, tetrahydrofuran; DMAP, dimethylaminopyridine; C-Phos, 2’(dicyclohexylphosphanyl)-N²,N²,N⁶,N⁶-tetramethyl[1,1’-biphenyl]-2,6-diamine.

Site-specific fluoro-labeling.

A fluorine atom may be incorporated site specifically within an unsaturated bioactive compound. For instance, in situ protection/catalytic cross-metathesis of primary alcohol 32 (Fig. 5b) with Z-1, followed by cross-coupling with alkynyl pyridine 33 (prepared in one step) afforded E-fluoro-substituted 1,3-enyne 34 in 81% yield and >98:2 E:Z ratio. After two more steps, a site specifically fluorine-tagged analogue of hachijodine G, a naturally occurring anti-leukemic alkaloid⁵⁴, was isolated in 64% overall yield (for 2 steps).

Fluoro-substituted 1,3-dienes were prepared with similar ease and efficiency. For example, 4-fluoro analogue of coriolide (Fig. 5c), a macrocyclic pheromone⁵⁵, was synthesized via 35 and enantiomerically pure 36, each obtained in a single step from commercially available materials, and 37. After five steps, the final product was secured in 55% overall yield, and in high diastereo- and enantiomeric purity (>98% E,E and >99:1 enantiomeric ratio (e.r.)).

Regiodivergent fluoro-labeling.

The approach can be used to generate either regioisomeic form of a trisubstituted alkenyl fluoride. For example, cross-metathesis between alkene 35 and Z-1 (Fig. 5d) followed by cross-coupling with commercially available n-octylzinc bromide gave E-trisubstituted alkenyl fluoride 38 in 81% yield and as a single stereoisomer. The same sequence but with a purchasable trisubstituted olefin and alkylzinc halide 39, prepared in one step and 82% yield, delivered stereoisomerically pure E-trisubstituted alkenyl fluoride 40 in 77% yield. If synthesis of oleyl coenzyme A⁵⁶ were to involve trisubstituted alkenyl fluorides 38 or 40, either of the fluoro-organic analogs would be obtained site-specifically (Fig. 5d).

Stereodivergent fluoro-labeling.

Diastereodivergent synthesis of trisubstituted alkenyl fluorides may be implemented in several ways. Cross-metathesis of sterically hindered α-branched monosubstituted alkene 41, prepared in one step and 81% yield, with E- and Z-1 (Fig. 6a), followed by cross-coupling with commercially available boronic acid 42, afforded the Z and E isomers of the fluoro-nematic liquid component in 65% and 74% overall yield (2 steps) and >98:2 Z:E and 95:5 E:Z ratio, respectively.

Fig. 6 |. Diastereodivergent synthesis of monofluoro- and difluoro-labeled bioactive compounds.

a, A fluoro-nematic liquid crystal component can be prepared in either stereoisomeric form. b, Stereoselective synthesis of peptide-like structures with E- and Z-amide bond mimics. c, Site-specific and diastereodivergent synthesis of difluoro analogs of rumenic acid methyl ester (anti-cancer). See the Supplementary Information Part 1, sections 9–11 for details. SPhos, 2-dicyclohexylphosphino-2’,6’-dimethoxybiphenyl; DIBAL–H, diisobutylaluminum hydride; Cbz, carboxylbenzyl; THF, tetrahydrofuran; pin, pinacolato; dba, dibenzylideneacetone; XPhos, 2-dicyclohexylphosphino-2’,4’,6’-triisopropylbiphenyl; G4, fourth-generation.

E- or Z-Amide bond mimics E- and Z-46 were also prepared (Fig. 6b). Transformation of homoallylic silyl ether 43 (obtained enantiomerically enriched in one step), a challenging α-branched substrate that also contains a sizeable homoallylic silyl ether (see Fig. 3b), furnished stereoisomerically pure trisubstituted alkenyl fluoride 44 in 54% overall yield (two steps). Compound 44 is an uncommon case; it is a product that has been previously prepared, and a comparison in efficiency is thus warranted. The three-step protocol described here (48% overall yield) is more efficient compared to the former five-step process, which afforded 44 in 24% overall yield⁵⁷. The ensuing sequence, involving enol amide 45⁵⁸, delivered E-46, mimic of the higher energy amide conformer, in 51% yield (27% overall yield, 6 steps) and in diastereoisomerically pure form (>98:2 E:Z and diastereomeric ratio (d.r.)). Similarly, Z-46, was isolated in 20% overall yield (six steps; >98:2 Z:E and d.r.).

As noted earlier, one of the noteworthy features of the approach is the possibility of convergent and stereodivergent synthesis by cross-coupling between two stereochemically defined trisubstituted alkenyl fluorides. One illustrative example involves the initial conversion of alkene 35 (prepared in one step and 97% yield) to fluoro-substituted alkenyl boronates E-47 and Z-47 by a cross-metathesis/cross-coupling sequence (73% and 55% overall yield and 95:5 E:Z and >98:2 Z:E, respectively). Alkenyl boronates 47 cannot be prepared by the existing methods in either stereoisomeric form^31,32, which are limited to aryl olefin compounds and can only provide a Z isomer. Next, chloro-substituted alkenyl fluorides E-49 and Z-49 (57% and 92% yield, >98:2 E:Z and 94:6 Z:E, respectively) were synthesized by cross-metathesis involving 48 (obtained in one step and 94% yield). All four possible stereoisomers of difluoro analogs of rumenic acid methyl ester³⁶ were then synthesized by catalytic cross-coupling of the appropriate fluoro-containing trisubstituted alkenyl boronate and alkenyl chloride. The latter 2,3-difluoro-substituted 1,3-dienes were isolated in 54–65% yield and >98:2 stereoisomeric purity. In a similar manner, monofluoro rumenic methyl esters might be prepared by the union of a disubstituted (non-fluoro) alkenyl boronate and E- or Z-49 or through cross-coupling between a disubstituted alkenyl chloride and E- or Z-47.

Conclusions

We have developed a broadly applicable and practical approach to laboratory synthesis of trisubstituted alkenyl fluorides, one that provides a direct route to formerly inaccessible compounds while offering several advantages. The strategy may be used to generate a variety of fluorine-tagged organic molecules in a scalable, efficient, site specific, diastereodivergent, and/or regiodivergent fashion. Substrates and reagents are readily available; excess tri-haloethylene compound may be recycled and reused. In most cases, a commercially available Mo complex may be used. Performing a cross-metathesis with a Mo complexes imbedded within air-stable paraffin pellets is another option³⁴. Molybdenum is a relatively abundant metal, and applications involving its use are more likely to be cost-effective and have long-term impact (vs. ruthenium). There is room for improvement, however. More efficient catalytic processes that proceed with higher TON values would be desirable (up to ~17 for the transformations described above).

Considering the central position of organofluorine compounds, the prevalence of alkenes in medicine, agrochemistry, and materials science, and the dearth of methods for stereocontrolled synthesis of trisubstituted alkenyl fluorides, the present approach will have a notable impact on several fronts and, in particular, on preparation of fluorine-tagged bioactive molecules and drug discovery. Access to either trisubstituted alkenyl fluoride isomers introduces a distinct way of incorporating a peptide turn. Equally important, in contrast to much of the state-of-the-art, the approach is not confined to aryl- or heteroaryl-substituted products. The importance of this attribute is manifested by the fact that nearly all the fluoro-containing bioactive compounds discussed above contain an alkyl-substituted alkenyl fluoride. Stereoselective functionalization of the fluoro-chloro-substituted alkenes could lead to a range of fluoro-substituted stereogenic carbon^59,60, or, perhaps more uniquely, a fluoro,chloro-substituted center, which may be viewed as a new organofluorine bio-isostere.

The findings described here debunk the generally held view that cross-metathesis between two trisubstituted alkenes is unlikely to be efficient. This presumption is understandable, as it has been shown on several occasions that, irrespective of catalyst activity, trisubstituted olefins usually resist entering a catalytic olefin metathesis cycle (little or no post-metathesis isomerization). We demonstrate that if a catalyst possesses the proper reactivity/longevity balance and under the appropriate conditions, reactions involving two trisubstituted olefins can be promoted efficiently and stereoretentively. The results described here foreshadow olefin metathesis processes that generate other highly substituted and otherwise difficult-to-access alkenes in high stereoisomeric purity.

Data availability

All data in support of the findings of this study are available within the Article and its Supplementary Information.