First Total Synthesis of (+)-Podophyllic Aldehydes

Abstract

The first total synthesis of three (+)-podophyllic aldehydes was achieved in a highly enantiocontrolled manner. Key steps include the organocatalyzed highly enantioselective cyclopropanation and Lewis acid-mediated chiral transfer ring expansion with excellent level of stereoinduction. This method can alternatively provide (+)-and (¹)-podophyllic aldehydes by switching the organocatalyst in the asymmetric cyclopropanation.Dihydronaphthalene-type lignans are attracting considerable attention because of their widespread distribution in nature and multiple, significant biological activities.1,2 Among them, (¹)-podophyllic aldehydes A, B, and C exhibit notable antineoplastic cytotoxicity and apoptosis-inducing activities (Scheme 1). 3 The first reported synthesis of (¹)-podophyllic aldehydes A, B, and C was started from natural (¹)-podophyllotoxin.3c,3d Although the asymmetric synthesis of both enantiomers is necessary for investigating their structure and activity relationship, the (+)-podophyllic aldehydes have not been synthesized. Here, we disclose the first total synthesis of (+)-podophyllic aldehydes A, B, and C utilizing organocatalyzed asymmetric cyclopropanation and Lewis acid-mediated chiral transfer ring expansion as key reactions.During the course of our synthetic studies on the transformation of dichlorocyclopropanes. 46 Recently, we reported the diastereoselective total synthesis of («)-cyclogalgravin and its dicarboxy analog utilizing the SmI 2 -promoted Reformatskytype addition of ester 2 to aldehyde and the Sc(OTf) 3 -mediated ring expansion of key intermediate 3 (Scheme 2).6b However, the enantioselectivity of the ring expansion of alcohol 3 to afford dihydronaphthalene has not been investigated. In addition, highly enantioselective dichlorocyclopropanation has not yet been achieved. Therefore, we attempted to synthesize 7a using the asymmetric cyclopropanation of aldehyde 5 with dimethyl α-bromomalonate (4) under the presence of organocatalyst 6. Fortunately, the cyclopropanation proceeded to afford the desired optically active diester 7a in 91% yield with 95% ee (Scheme 3). 8 The same cyclopropanation using organocatalyst D-6 provided the enantiomer 7b in 88% yield with 95% ee. We used diester 7a for the total synthesis of (+)-podophyllic aldehydes.Scheme 4 outlines the asymmetric synthesis of dihydronaphthalene 12 from diester 7a. After the reduction of the aldehyde group in diester 7a using NaBH 4 , the lactonization of the resulting alcohol with a catalytic amount of p-toluenesulfonic acid (PTS) in CHCl 3 gave γ-lactone 8 in 86% yield (2 steps) with 95% ee.8 Optical purity of lactone 8 was observed by HPLC analysis using a chiral column. The ee of the aforementioned asymmetric cyclopropanation was estimated based on the HPLC analysis of lactone 8. Treatment of γ-lactone 8 with 3,4-methylenedioxyphenylmagnesium bromide in THF resulted in a highly regioselective Grignard reaction on a slightly strained lactone ring to give β-ketoester 9 in 94% yield. After benzoyl protection of the hydroxy gro...

From Enantioenriched Donor‐Acceptor Cyclopropylcarbinols to Axially Chiral Arylnaphthalenes through Aryldihydronaphthalenes: Central‐to‐Axial Chirality Exchange

“…Following our previous report on the total synthesis of podophyllic aldehydes, we attempted to synthesize enantioenriched D‐A cyclopropylcarbinols 7 that bear ortho ‐substituents on pendant aryl groups as shown in Scheme 4 [13a] . Initially, the cyclopropanation of ortho ‐substituted cinnam‐aldehyde 1 with dimethyl α‐bromomalonate 2 using the Hayashi‐Jørgensen catalyst afforded the desired optically active diester 3 in moderate to high yield with high ee [12,14] .…”

Copper‐Catalyzed 1,5‐Addition of Grignard reagents to Enantioenriched Donor–Acceptor Cyclopropanes with Inversion

“…In addition, few mechanisms have been proposed for a similar reaction using a Grignard reagent with Cu(OTf) 2 , which are still ambiguous . Recently, we have reported intramolecular cyclization after ring opening of cyclopropanes with retention of configuration, and the oxy‐homo‐Michael addition of alcohols or carboxylic acids to cyclopropanes with inversion (Figure , D and E ) . Therefore, our interest focused on the stereoselectivity (retention or inversion) of the 1,5‐alkylation of an activated cyclopropane using a Grignard reagent with a copper catalyst (Figure , C ).…”

“…Note that a fluorophenyl moiety sometimes enhances biological activity in a structure–activity relationship study . In combination with our synthetic study of biologically active compounds, the fluorophenyl analogue 4 b was also employed to investigate the reaction. As expected, the reactions of 4 a and 4 b using primary alkyl Grignard reagents with Cu(OTf) 2 proceeded successfully to afford the trans ‐α,β‐disubstituted γ‐butyrolactones 5 aa , 5 ab , 5 ba and 5 bb with high diastereo‐ and enantioselectivities (Table , entries 1, 2, 4 and 5).…”

Recent strategies and tactics for the enantioselective total syntheses of cyclolignan natural products

“…[111][112][113][114] Podophyllic aldehydes A, B, and C, as prepared and analyzed by the Castro lab, have been found to possess antineoplastic cytotoxicity and apoptosis-inducing capabilities; thus, Nishii and coworkers were very interested in developing new methods to synthesize these compounds. 115 The Nishii group's strategy for the synthesis of (+)-podophyllic aldehydes in 2015 involved the unique use of a chiral transfer ring expansion from a 1,4-diarylbutane synthon to form the C2-C7 0 bond via pathway D (Fig. 3A) in the cyclolignan skeleton of the podophyllic aldehydes (Scheme 56).…”