Asymmetric approach to the pentacyclic skeleton of Aspidosperma alkaloids via enantioselective intramolecular 1,3-dipolar cycloaddition of carbonyl ylides catalyzed by chiral dirhodium(II) carboxylates

Abstract

This paper describes asymmetric tandem carbonyl ylide formation-intramolecular 1,3-dipolar cycloaddition reaction of diazo imides containing a tethered indole catalyzed by chiral dirhodium(II) carboxylates as an approach to the pentacyclic skeleton of Aspidosperma alkaloids. The cycloaddition of carbonyl ylides derived from indolyl-substituted 2-diazo-5-imido-3-ketoesters under the influence of dirhodium(II) tetrakis[N-tetrachlorophthaloyl-(S)-tert-leucinate], Rh 2 (S-TCPTTL) 4 , provides cycloadducts in moderate yields and enantioselectivities of up to 66% ee as well as with perfect endo diastereoselectivity. This is the first example of asymmetric induction in an intramolecular cycloaddition of a carbonyl ylide across an indolyl -bond. --------------------------------Over the past four decades, Aspidosperma alkaloids have been a source of structurally intriguing target molecules that continue to challenge the capabilities of contemporary organic synthesis. Efficient and elegant strategies for the total synthesis of various members of this alkaloid family have been reported. 1,2Padwa and co-workers demonstrated that the tandem cyclic carbonyl ylide formation-1,3-dipolar cycloaddition reaction 3 of diazo imides catalyzed by Rh 2 (OAc) 4 is one of the most powerful methods for the rapid construction of the pentacyclic ABCDE framework of (−)-vindoline (1) 4,5 and (−)-vindorosine (2) 6,7 (eq. 1). 8The same group has Corresponding author. Tel.: +81 11 706 3236; fax: +81 11 706 4981. E-mail address: hsmt@pharm.hokudai.ac.jp (S. Hashimoto).2 accomplished the total synthesis of (±)-aspidophytine 9 employing an intramolecular 1,3-dipolar cycloaddition of carbonyl ylide across the indole -bond. 10((Please Insert Eq. 1 here:))The synthetic utility of the carbonyl ylide cycloaddition strategy has also been demonstrated in its application to the synthesis of a variety of natural products. 11Over the past decade, considerable effort has been directed to the development of an enantioselective version of carbonyl ylide formation-1,3-dipolar cycloaddition catalyzed by chiral dirhodium(II) complexes. [12][13][14][15] In this process, the chiral dirhodium(II) catalyst must be capable of associating with carbonyl ylide intermediates in the cycloaddition step, because catalyst-free carbonyl ylides are achiral. Hodgson and co-workers were the first to demonstrate high levels of asymmetric induction (up to 90% ee) in intramolecular cycloadditions of carbonyl ylides derived from unsaturated -diazo--ketoesters using binaphtholphosphate catalyst Rh 2 (R-DDBNP) 4 (4) ( Figure 1).Recently, we reported catalytic enantioselective intermolecular cycloadditions of 2-diazo-3,6-diketoesters-derived carbonyl ylides with arylacetylene, alkoxyacetylene, and styrene dipolarophiles using Rh 2 (S-TCPTTL) 4 (3a), Gratifyingly, the use of benzyl ester 7c greatly improved the enantioselectivity to provide cycloadduct 6c in 50% yield with 63% ee (entry 3), whereas a low level of asymmetric induction was obtained in the reaction of 2-pheny...

Ruthenium‐Catalyzed Asymmetric Hydrogenation of 3‐Oxoglutaric Acid Derivatives: A Study of Unconventional Solvent and Substituent Effects

“…Filtration and evaporation in vacuo provided the crude amide as a light-yellow oil (11.9 g, 65.7 %), which was used without further purification. 1 This crude amide was hydrolyzed [44] with KOH (3.7 g, 66.4 mmol) in EtOH/H 2 O (3:1) to give the 1-(tert-butylcarbamoyl)cyclopropanecarboxylic acid (8.9 g, 87 %) as a white solid. 1 The last step was similar to that used for the synthesis of 5 j following the procedure of Masamune and co-workers.…”

“…The solvent was evaporated under vacuum to give the crude acid 5-ethoxy-2,2-dimethyl-3,5-dioxopentanoic acid (5 s; 7.2 g, 92 %), which was used directly in the synthesis of the amide. [44] An aqueous solution (40 mL) of KOH (6.0 g, 107 mmol) was added dropwise to diethyl cyclopropane-1,1-dicarboxylate (20 g, 107 mmol) in EtOH (120 mL) and the mixture was stirred at room temperature for 5 h. EtOH was evaporated and the aqueous phase was washed with Et 2 O (2 30 mL). Then tBuNH 2 (1.3 g, 18 mmol) in CH 2 Cl 2 (5 mL) was added dropwise.…”

“…Acid 5 s (3 0 g, 14.8 mmol) was dissolved in CH 2 Cl 2 (30 mL) and then EDC·HCl (3.5 g, 18 mmol) and DMAP (180 mg, 1.5 mmol) were added in portions at 0 8C. 1 This crude amide was hydrolyzed [44] with KOH (3.7 g, 66.4 mmol) in EtOH/H 2 O (3:1) to give the 1-(tert-butylcarbamoyl)cyclopropanecarboxylic acid (8.9 g, 87 %) as a white solid. After the addition, the mixture was stirred at room temperature for 6 h, washed with 10 % aqueous HCl, and extracted with CH 2 Cl 2 (3 10 mL).…”

Recent Developments in Enantioselective Metal‐Catalyzed Domino Reactions

“…In the same context, these authors have described the first example of asymmetric induction (up to 66% ee) in an intramolecular 1,3-dipolar cycloaddition of carbonyl ylides in situ generated from the diazo decomposition of indolyl-substituted 2-diazo-5-imido-3-ketoesters under the influence of Rh 2 (S-TCPTTL) 4 This reaction constituted an elegant approach to the pentacyclic skeleton of Aspidosperma alkaloids. [74] In addition, Hodgson et al investigated the enantioselective intramolecular domino carbonyl ylide formation−1,3-dipolar cycloaddition reaction employing sulfonyl functionality as a different type of electron-withdrawing group at the ylidic carbon, specifically using unsaturated -diazo-,-diketo sulfones. [75] Among a series of chiral catalysts tested, chiral dirhodium(II) tetrakis[N-benzene-fused-phthaloyl-(S)-valinate], Rh 2 (S-BPTV) 4 , provided the best albeit moderate enantioselectivity of 43% ee for the cycloadduct derived from phenyl sulfone along with 75% yield.…”

Metal complexes versus organocatalysts in asymmetric 1,3-dipolar cycloadditions

“…The reversal diastereoselection observed in this example was attributable to steric hindrance of part of the functional groups present in the precursor material. 77 The intramolecular version of this reaction was evaluated with analogous starting compounds bearing the alkene moiety (dipolarophile) placed at the R 1 substituent in molecules 149 at the appropriate distance. The rhodium complex 138 ( Figure 10) (10 mol%) was the best catalyst but the enantioselection of the process was very disappointing (up to 44% ee).…”