Hypervalent Iodine(III)-Promoted Intermolecular C–C Coupling of Vindoline with β-Ketoesters and Related Substrates

Abstract

The regioselective intermolecular coupling reaction of vindoline with a wide range of substrates including β-ketoesters, β-diketones, β-ketoaldehydes, β-ketonitriles, malononitriles, and β-cyanoesters provides an opportunity for the synthesis of vinblastine analogues containing deep-seated changes in the upper velbanamine subunit. The transition-metal free hypervalent iodine(III)-promoted intermolecular sp³/sp² coupling, representing a special class of selective C–H activation with direct carbon–carbon bond formation, proceeds with generation of a quaternary center capable of incorporation of the vinblastine C16′ methyl ester and functionalized for subsequent divergent heterocycle introduction.

A central component in the current synthesis of the bisindole alkaloids including vinblastine¹ has been the development of methods that permit the generation of the key C15–C16′ bond that links the upper velbanamine subunit with vindoline by conducting a challenging sp³/sp² coupling reaction with generation of a quaternary center. To date and because of their structural complexity, this has largely focused on approaches that permit the synthesis of the natural products^2–12 with little consideration for the extension of the efforts to key analogues containing deep-seated changes in the upper velbanamine subunit.^13–17 In efforts focused on the potential replacement of the velbanamine indole, we became interested in the development of a coupling reaction with vindoline that would permit the late stage, divergent¹⁸ introduction of a range of alternative heterocycles. Herein, we report the development of a powerful and effective intermolecular coupling reaction of vindoline with substituted acidic methylene compounds typified by β-ketoesters, enlisting hypervalent iodine(III) reagents. Central to the design of the studies, the coupling substrates permit the incorporation of the C16′ methyl ester as well as functionality (a ketone) that should permit the late-stage, divergent heterocycle introduction.

With 2-carbomethoxycyclopentanone (2a) and 2-carbomethoxycyclohexanone (2b) as model substrates, a range of oxidants were examined for their ability to promote their coupling with vindoline (1) including ceric ammonium nitrate (Ce(NH₄)₂(NO₃)₆), Mn(OAc)₃, VOF₃, FeCl₃ or Fe(phen)₃(PF₆)₃ and a full set of alternative Fe(III) complexes,^9,11–13 CuCl₂ and Cu(acac)₂, and DDQ in a range of solvents with a variety of recommended additives, as well as Koser’s reagent (PhI(OTs)OH). Although small amounts of coupling were occasionally observed with the Fe(III)-based reagents,¹³ only the iodine(III)-based reagents consistently provided the coupling product in modest conversions (2a, 33–29%; 2b, 0%, in 0.05 M in HFIP,¹⁹ 25 °C, 5–10 min). In a survey of readily available iodine(III)-based reagents including Koser’s reagent (PhI(OTs)OH), phenyliodine(III) diacetate (PIDA), and phenyliodine(III) bis(trifluoroacetate) (PIFA) and several aryl substituted variants, PIFA¹⁹ emerged as the most effective reagent for further optimization studies. With the more challenging of the two model substrates (2b), the choice of solvent (1:1 HIPA–H₂O, 0.05 M) with the inclusion of H₂O and addition of a tertiary amine additive (Et₃N, 10 equiv) resulted in effective room temperature coupling to provide 3b in good yields (Figure 2). Clear from the representative optimization efforts summarized in Figure 2 are the key roles played by the combined elements of the mixed aqueous solvent system (1:1 HFIP–H₂O vs HFIP, HFIP with H₂O (5 equiv), or 1:1 HFIP–MeOH; entry 5 vs entries 2, 8 or 9), the use of hexafluoroisopropanol (HFIP) relative to other potential related co-solvents (TFE, entry 5 vs entry 7), the importance of the added base (entry 5 vs entry 4), and the nature of the base (entry 5 vs entry 6).

Figure 2.

Representative initial optimization studies.

In instances where the reaction failed to produce the coupling product or provided it in more modest conversions, the PIFA electrophilic substitution of vindoline was observed and provided 4. Efforts to convert 4 to the product 3b under a variety of conditions were not successful, resulting in no reaction with 2b or, on occasion, expectedly transferring instead the less electron rich phenyl group to the substrate 2b. Mechanistically and in line with the proposals of Kita,¹⁹ this suggests the reaction may proceed by an initial single electron oxidation of vindoline to generate the corresponding radical cation that either reacts with the deprotonated β-ketoester nucleophile 2b to provide 3b after subsequent oxidation of the addition product radical or competitively recombines with the reagent-derived radical anion to non-productively provide 4 (eq 1).

(1)

With these parameters defined, the reexamination of the oxidant (PIFA vs PIDA or Koser’s reagent) and the amount of reagent employed revealed the superior behavior of PIFA (3 equiv) under these reaction conditions (Figure 3). Aside from defining a productive stoichiometry range for the use of PIFA (2–3 equiv), the studies further revealed that use of excess PIFA (6 equiv) can result in the subsequent consumption of the desired product 3b.

Figure 3.

Final optimization studies.

With these conditions defined, the scope of the reaction was examined with a range of substituted acidic methylene compounds (Figure 4).

Figure 4.

Scope of the PIFA-promoted coupling reaction.

A range of substituted β-ketoesters (2a–2d, 2j, and 2m, but not 2e and 2f), β-diketones (2h, 2i and 2l), β-ketonitriles (2g, 2k, and 2n), the malononitrile 2p, and the β-cyanoester 2o participated effectively in the coupling reaction to provide the corresponding products 3 as a mixture of diastereomers (ca. 1:1), whereas the less acidic dimethyl methylmalonate 2q did not. It is likely that in HFIP (pKa = 9.3), insufficient amounts of the less acidic substrates such as 2q are deprotonated (vs solvent) under the reaction conditions to permit coupling with the vindoline-derived intermediate radical cation competitive with generation of 4. Even the initially unexpected behavior of 2a–f appears to be related to the relative acidity of the β-ketoesters, which display a trend correlating precisely with the coupling capabilities (2a > 2b > 2d > 2c > 2e > 2f),²⁰ with the pKa cutoff for observation of the coupling reaction lying between 2c (not 2d) and 2e (Supporting Information Figure S1). By simply converting the β-ketoester 2f to the more acidic β-ketonitrile 2g, the substrate now participates effectively in the coupling reaction. Finally, the coupling reaction failed to provide identifiable coupling products if the substrates were unsubstituted (secondary vs tertiary centers), potentially producing a non-quaternary center.

An additional and special case of coupling substrates proved to be β-ketoaldehydes (Figure 5). Here, the reaction could be conducted best without the addition of Et₃N, but using the sodium enolates directly with PIFA (2–3 equiv) in HFIP–H₂O (25 °C, 0.05 M, 30 min).

Figure 5.

β-Ketoaldehyde coupling reaction.

In addition to providing access to velbanamine-derived analogues of vinblastine incorporating alternatives to the key indole, the approach also offers the opportunity to access those containing the indole as well. Representative of such opportunities and without optimization, the PIFA-promoted coupling of 2u or 2v with (−)-vindoline provided the coupling products 3u (39%) and 3v (47%) that, upon reduction to the saturated aniline (Zn, aq NH₄Cl–acetone, 25 °C, 24 h), undergo condensation with the proximal ketone to provide the indole 5¹³ as a 1:1 mixture of diastereomers (Scheme 1).

Scheme 1.

The intermolecular coupling of a wide range of substrates with vindoline provides an opportunity for the synthesis of vinblastine analogues with deep-seated changes in the upper velbanamine subunit, including those possessing heterocyclic substitutions for the indole. Notably, the transition-metal free hypervalent iodine(III)-promoted intermolecular sp³/sp² coupling, representing a special class of selective C–H activation with carbon–carbon bond formation, proceeds with generation of a quaternary center capable of direct incorporation of the vinblastine C16′ methyl ester and functionalized for subsequent divergent heterocycle introduction.

Figure 1.

Structure of vinblastine and vindoline.