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...
Highly stereoselective Reformatsky reaction and Pd-catalyzed arylation using 1-(alkoxycarbonyl)cyclopropylzinc bromide proceeded to give the trans-adduct as the major product in good to high yields with good to excellent stereoselectivities.
The total synthesis of («)-cyclogalgravin and its dicarboxyl analog was achieved by using the SmI 2 -promoted Reformatsky type reaction and Sc(OTf) 3 -mediated diastereoselective ring expansion as key steps.
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