Desymmetrization of enone-diones via rhodium-catalyzed diastereo- and enantioselective tandem conjugate addition-aldol cyclization

Abstract

Catalytic tandem conjugate addition-enolate trapping represents an effective strategy for the design of catalytic transformations that enable formation of multiple C—C bonds. Recently, using enantioselective rhodium-catalyzed conjugate addition methodology, we developed a catalytic tandem conjugate addition-aldol cyclization of keto-enones. Here, we report related desymmetrizations and parallel kinetic resolutions involving the use of diones as terminal electrophiles. The Rh-enolate generated on enone carbometallation effectively discriminates among four diastereotopic π-faces of the appendant dione, ultimately providing products that embody four contiguous stereocenters, including two adjacent quaternary centers, with quantitative diastereoselection and high levels of enantiomeric excess. This methodology allows concise entry to optically enriched seco-B ring steroids possessing a 14-hydroxy cis-fused C-D ring junction, as found in naturally occurring cardiotonic steroids derived from digitalis.

A principal goal of modern organic chemistry relates to the development of chemical transformations that enable rapid increases in molecular complexity. Tandem or “domino” processes (1–3), including catalytic tandem conjugate addition-electrophilic trapping (4–8) and tandem conjugate reduction-electrophilic trapping (9–21), are of inherent interest, because such transformations may result in the formation of multiple covalent bonds. Stereochemical complexity may be increased through the desymmetrization of molecules possessing enantiotopic functional groups (22, 23). Enantioselective catalytic transformations that combine both tandem bond formation and desymmetrization potentially enable the concomitant generation of multiple C—C bonds and multiple stereogenic centers. Here, we report a diastereo- and enantioselective tandem conjugate addition-aldol cyclization of enone-diones, whereby two C—C bonds and four contiguous stereogenic centers are created in a single manipulation with control of relative and absolute stereochemistry (Scheme 1). Through the use of chiral racemic enone-dione substrates, the first examples of parallel kinetic resolutions (24) by enantioselective conjugate addition are achieved (25–33). This new catalytic methodology enables concise entry to seco-B ring steroids possessing a cis-fused C-D ring junction with a bridgehead hydroxyl residue, as found in naturally occurring cardiotonic steroids derived from digitalis.

Scheme 1.

Materials and Methods

General Experimental Methods. All reactions were performed under an atmosphere of argon, unless otherwise indicated. Anhydrous solvents were transferred by an oven-dried syringe. Flasks were flame-dried and cooled under a stream of nitrogen. 1,4-Dioxane was distilled from sodium and degassed with Ar before use. Deuterated solvents were used as received from Cambridge Isotope Laboratories (Cambridge, MA). Chemical reagents were purchased from Strem Chemicals (Newburyport, MA) or Aldrich and used without further purification, unless otherwise noted. Substrates 1 and 2 have been characterized (21). [Spectral data for all previously unreported compounds (¹H NMR, ¹³C NMR, IR, and high-resolution mass spectra) and single crystal x-ray crystallographic data for compounds 3c and 7a are provided in Supporting Text, which is published as supporting information on the PNAS web site.]

Analytical TLC was carried out by using 0.2-mm commercial silica gel plates (DC-Fertigplatten Kieselgel 60 F₂₅₄, EMD Chemicals, Gibbstown, NJ). Preparative column chromatography using silica gel was performed according to the method of Still et al. (34). Solvents for chromatography are listed as volume/volume ratios. Infrared spectra were recorded on a Perkin–Elmer 1420 spectrometer. Samples were neat (evaporated from dichloromethane or chloroform onto NaCl plates). High-resolution mass spectra were obtained on a Karatos MS9 by using chemical ionization, positive ionization mode. Accurate masses are reported for the molecular ion (M + 1) or a suitable fragment ion. Melting points were determined by using a Thomas Hoover Uni-melt apparatus (Arthur H. Thomas Co., Philadelphia) and are uncorrected. Enantiomeric purity was determined by chiral stationary phase HPLC analysis. Specific conditions for the analysis of each chiral product are provided in Supporting Text.

Proton NMR (¹H NMR) spectra were recorded with a Varian Gemini (300 MHz) or Varian Gemini (400 MHz) spectrometer, as indicated. Chemical shifts are reported in delta (δ) units, ppm downfield from trimethylsilane. Coupling constants are reported in Hz. Carbon-13 NMR (¹³C NMR) spectra were recorded on a Varian Gemini 300 (75 MHz) or Varian Gemini 400 (100 MHz) spectrometer, as indicated. Chemical shifts are reported in δ units, ppm relative to the center of the triplet at 77.0 ppm for deuteriochloroform. ¹³C NMR analyses were run routinely with broadband decoupling.

Representative Procedure for the Preparation of Substrates 1, 2, and 5–7: Preparation of Substrate 2. A solution of 2-allyl-2-methylcyclohexane-1,3-dione (35) (4.02 g, 24.2 mmol, 100 mol%) in dichloromethane (240 ml) was treated with ozone at –60°C for 90 min and then stirred with triphenylphosphine (6.37 g, 24.3 mmol, 100 mol%) for 2 h at ambient temperature. The reaction mixture was evaporated, and the residue was passed through a short plug of silica to give the crude aldehyde. The aldehyde was dissolved in chloroform (240 ml) and the Wittig reagent derived from α-chloroacetone (36) (9.25 g, 29.2 mmol, 120 mol%) was added. The reaction mixture was allowed to stir at ambient temperature for ≈20 h, at which point the solvent was removed in vacuo and the crude product of olefination was purified by flash chromatography (SiO₂; 60:40 hexanes/ethyl acetate). Substrate 2 was isolated as a viscous yellow oil in 37% yield over the two-step sequence (1.86 g, 8.95 mmol).

Representative Procedure for the Substrates 3, 4, and 8: Preparation of Substrate 3. To a vigorously stirred suspension of 2-methyl-1,3-cyclopentanedione (4.35 g, 38.8 mmol, 100 mol%) in H₂O (65 ml) at ambient temperature was added acrolein (3.36 g, 59.9 mmol, 154 mol%). The mixture was allowed to stir at ambient temperature for ≈18 h, at which point the now homogeneous reaction mixture was concentrated in vacuo to give a wet solid. To the solid was added dichloromethane (80 ml), and the resulting suspension was stirred for 15 min, at which point insoluble materials were removed by filtration. The filtrate was concentrated in vacuo to provide crude 2-methyl-2-propionaldehyde-1,3-cyclopentanedione in 70% yield as an orange oil (4.58 g, 27.2 mmol). The aldehyde was dissolved in chloroform (270 ml), and the Wittig reagent derived from α-chloroacetone (36) (10.42 g, 32.7 mmol, 120 mol%) was added. The reaction mixture was allowed to stir at ambient temperature for ≈20 h. After removal of the solvent, the crude product was purified by flash chromatography (SiO₂; 80:20 hexanes/ethyl acetate). Substrate 3 was obtained as a viscous yellow oil in 47% yield (2.69 g, 12.9 mmol).

Representative Procedure for Enantioselective Catalytic Tandem Conjugate Addition-Aldol Cyclization: Preparation of Product 2a. To a flame-dried Schlenk tube charged with phenyl boronic acid (122.0 mg, 1.0 mmol, 200 mol%), (S)-2,2′-bis(diphenylphosphino)-1,1′-binapthyl (23.3 mg, 37.5 μmol, 7.5 mol%), and [Rh(COD)(OCH₃)]₂ (6.1 mg, 12.5 μmol, 2.5 mol%) under an atmosphere of Ar(g) was added anhydrous dioxane (5.0 ml, 0.1 M). The mixture was allowed to stir at ambient temperature for 5 min, at which point aqueous KOH [KOH (2.8 mg, 50 μmol, 10 mol%)/H₂O (45 μl, 2.5 mmol, 500 mol%)] was added, and the mixture was allowed to stir for 10 min at ambient temperature. Finally, substrate 2 (104.2 mg, 0.50 mmol, 100 mol%) was added, and the reaction vessel was placed in an oil bath preheated to 95°C. The reaction mixture was allowed to stir at 95°C, until complete consumption of starting material was observed by TLC, at which point the reaction mixture was evaporated on to silica gel. Purification by flash chromatography (SiO₂; 80:20 hexanes/ethyl acetate) provides 2b as a white solid in 87% yield (124.6 mg, 0.435 mmol).

Results and Discussion

Recently, we developed a catalytic diastereo- and enantioselective tandem conjugate addition-aldol cyclization of ketoenones (37). This transformation, which takes advantage of Rh-catalyzed enone conjugate addition methodology (38–50), provides five- and six-membered cycloaldol products with high levels of relative and absolute stereochemical control. Given these results, it was of interest to assess the applicability of this methodology to the desymmetrization of appendant diones. Initial studies focused on the tandem conjugate addition-aldol cyclization of enone-dione 1 with phenyl boronic acid as carbometallating agent. Gratifyingly, by using [Rh(COD)Cl]₂ as precatalyst, the desired conjugate addition-aldol cyclization product was obtained with excellent levels of diastereo- and enantioselectivity. However, chemical yields were highly variable, presumably because of sensitivity of the catalyst with respect to oxidation. The corresponding methoxy-bridged dimer [Rh(COD)(OCH₃)]₂ is more resistant to oxidation (51). Accordingly, transformations performed in conjunction with [Rh(COD)(OCH₃)]₂ proved to be both more reproducible and higher yielding, providing the tandem conjugate addition-aldol cyclization product 1b in 87% yield, >99:1 diastereoselectivity, and 90% enantiomeric excess.

By using [Rh(COD)(OCH₃)]₂ as precatalyst, the tandem conjugate addition-aldol cyclization of diverse substrates was investigated. For aromatic and aliphatic enone-containing systems, five- and six-membered ring formation occurs smoothly to afford the corresponding diquinane and hydrindane products with quantitative levels of diastereoselection and high levels of enantiomeric excess. Thus, although a total of 16 stereoisomers are potentially generated in this transformation, a single stereoisomer predominates in each case. As demonstrated by the catalytic tandem 1,4-addition-aldol cyclization of substrates 1–3, phenyl boronic acid, para-bromophenyl boronic acid, and para-methoxyphenyl boronic acid serve equally well as carbometallating agents. As demonstrated by the reaction of enone-dione 4, strained cis-decalone ring systems possessing aryl substitution on the concave face of bicycle may be generated in moderate yield and with excellent levels of stereocontrol. Finally, as illustrated by the reaction of substrates 5 and 6, both indane-diones and acyclic diones serve well as terminal electrophiles. One limitation of this methodology resides in the use of substrates that incorporate α,β-unsaturated esters. For such substrates, conjugate addition proceeds readily, but subsequent aldolization is not observed. These results are summarized in Table 1.

Table 1. Dione desymmetrization by diastereo- and enantioselective catalytic tandem conjugate addition-aldol cyclization.

Entry	Substrate	Product	Yield,* %
			1a, R = CH3, 83% yield >99:1 de, 90% ee
			1b, R = CH3, 87% yield >99:1 de, 90% ee
					1c, R = Ph, 94% yield >99:1 de, 87% ee
			1d, 88% yield >99:1 de, 94% ee
			2a, 97% yield >99:1 de, 90% ee
			2b, R = CH3, 87% yield >99:1 de, 91% ee
					2c, R = Ph, 86% yield >99:1 de, 85% ee
			2d, 77% yield >99:1 de, 92% ee
			3a, 80% yield >99:1 de, 86% ee
			3b, 82% yield >99:1 de, 85% ee
			3c, 85% yield >99:1 de, 86% ee
			4a, 65% yield† >99:1 de, 88% ee
			5a, 93% yield >99:1 de, 88% ee
			6a, 95% yield† >99:1 de, 87% ee

Reactions were performed in accordance with the representative experimental procedure.

^*Isolated yields after purification by silica gel chromatography. Diastereomeric excess (de) and enantiomeric excess (ee) were determined by chiral stationary-phase HPLC analysis.

^†Yield based on recovered starting material.

The diastereoselectivity observed in these transformations may be accounted for on the basis of a stereochemical model that invokes intermediacy of a Z-enolate and a Zimmerman–Traxler type transition state (Scheme 2) (53). Although Z-enolate formation is not surprising in the phenyl-substituted enolates, such high levels of selectivity are noteworthy for methyl-substituted enones and likely arise from the fact that the Rh-enolates derived on conjugate addition are known to exist predominantly as the η³-haptomer (45). The relative and absolute stereochemical assignment of the reaction products is supported by single crystal x-ray diffraction analysis of 3c.

Scheme 2.

Products 3a–3c are of interest because they represent seco-B ring steroids. The unusual 14-hydroxy cis-fused C-D ring junction is consistent with the structure of the cardiotonic steroid digitoxin, which is an active constituent of digitalis, one the most broadly prescribed treatments for congestive heart failure, irregular heart-beat, and atrial fibrillation (53). Application of this enantioselective catalytic tandem conjugate addition-aldol cyclization methodology toward the synthesis of digitoxin and related cardiac steroids requires further investigation (Scheme 3).

Scheme 3.

The highly enantioselective desymmetrization of dione-based terminal electrophiles suggests the feasibility of performing the parallel kinetic resolution of chiral racemic enonediones (24–33). Here, the absolute stereochemistry of the substrate should dictate which of the two nonequivalent carbonyl moieties of the appendant dione participates in aldolization. To assess the efficiency of parallel kinetic resolutions by catalytic enantioselective tandem 1,4-addition-aldol cyclization, racemic enone-dione 7 was exposed to standard reactions conditions. The regioisomeric products 7a and 7b were obtained as single diastereomers in 43% and 41% chemical yield and >99% and 87% enantiomeric excess, respectively. The structural assignment of 7a is supported by single crystal x-ray diffraction analysis. The differential degree of asymmetric induction observed for compounds 7a and 7b suggests that substrate stereochemistry plays only a modest role in directing the π-facial selectivity of the enantiodetermining enone carbometallation event. For the related substrate 8, an appendant β-keto-amide moiety serves as the terminal electrophile. As anticipated, exposure of 8 to standard conditions for conjugate addition-aldolization affords both cyclized and noncyclized products 8a and 8b, respectively. This result underscores the fact that substrate stereochemistry strictly guides the regiochemistry of dione addition and, in cases where the “targeted” carbonyl moiety of the dione is recalcitrant with respect to addition, aldolization onto the “nontargeted” carbonyl to form epimeric aldol products does not occur (Table 2).

Table 2. Parallel kinetic resolution by diastereo- and enantioselective catalytic tandem conjugate addition-aldol cyclization.

Reactions were performed in accordance with the representative experimental procedure. Isolated yields after purification by silica gel chromatography are listed. Diastereomeric excess (de) and enantiomeric excess (ee) were determined by chiral stationary-phase HPLC analysis.

In summation, an effective catalytic protocol for the desymmetrization and parallel kinetic resolution of enone-diones by tandem conjugate addition-aldol cyclization has been developed. This transformation, which results in the formation of two C—C bonds and four contiguous stereogenic centers, enables the rapid assembly of complex polycyclic ring systems from simple precursors with high levels and diastereo- and enantiocontrol. Future studies will focus on the application of this methodology toward the synthesis of naturally occurring cardiotonic steroids, including digitoxin.