A Synthesis of Mycalamide B

Abstract

Mycalamide B, a potent antitumour agent, was synthesised from cheap, readily available starting materials: ethyl lactate, ethyl isobutyrate, 4-chlorobutanal, and 4-chlorobutanoyl chloride. The trioxabicyclo[4.4.0]decane ring system was created by reaction of a methoxymethyl ether with a silyloxyoxirane induced by phosphorus pentoxide.Mycalamides A 1 and B 2 were isolated from a sponge of the genus Mycale and shown to be potent inhibitors of tumour proliferation in a number of human tumour cell lines. 1,2 Total syntheses of mycalamides A and B have been reported by Hong and Kishi and elegant approaches to the various advanced fragments have been described by Nakata 3,4 , Roush 5,6 and Hoffmann 7,8 . We now report a synthesis of mycalamide B which shares the same fragment linkage strategy as our synthesis of 18-O-methylmycalamide B (Scheme 1). 9 However, the synthetic routes to the fragments 5 and 6 have been completely redesigned to offer greater flexibility, efficiency, and economy. Scheme 1The preparation of the 6-lithio-3,4-dihydro-2H-pyran 6 (Scheme 2) began by a diastereoselective conjugate addition of lithium dimethylcuprate to the ester 7 (Note 1) in the presence of TMSCl. The adduct 8, obtained in 95% yield, revealed a dr of >15:1. 10,11 The final C-C bond forming reaction in the sequence was also highly diastereoselective. Alkylation of the potassium enolate of the ester 8 with allyl bromide gave the third contiguous stereogenic centre in 9 in 99% yield (dr > 20 :1). Routine transformations accomplished the conversion of 9 to the alcohol 12 in preparation for the next critical step in the sequence, the inversion of configuration at C-2 (mycalamide numbering), which was plagued by competing elimination. However, the combination of trityl as the protecting group and p-chlorobenzoic acid as the nucleophile returned the nicely crystalline inverted ester 13 in 79% yield. Oxidative cleavage of the alkene followed by acid treatment achieved simultaneous trityl deprotection and lactonisation to give the second crystalline compound of the series, the lactone 15. The phenylselenide group in 16 was introduced by nucleophilic substitution of the butyrolactone. 12 Reductive cleavage of the p-chlorobenzoate in 16 (Note 2) returned a hydroxy acid which lactonised to 17 in 72% yield. Conversion of lactone 17 to the stannane 18 was accomplished by a 3-step sequence previously described in our synthesis of Pederin. 13 Dihydropyranone 25, a critical intermediate in the synthesis of the trioxabicyclo[4.4.0]decane ring system (Scheme 3), harbours a single stereogenic centre at C-15 which was constructed efficiently by two different routes. In the first route, the lithium enolate prepared from ethyl isobutyrate was condensed with 4-chlorobutanoyl chloride to give the β-keto ester 18 in 93% yield. Catalytic asymmetric hydrogenation 14-16 of the β-keto ester using [(R)-(+)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl] chloro (p-cymene) ruthenium chloride installed the requisite (R)-configured stereogenic centre in good yield a...

A starlike amphiphilic graft copolymer with hydrophilic poly(acrylic acid) backbones and hydrophobic polystyrene side chains

“…To retain ester groups so that they can be hydrolyzed to carboxylic groups, another method was used to connect ATRP initiation groups to the α‐carbon of the ester groups of polyacrylate backbone using lithium diisopropylamide (LDA) and α‐bromoisobutyryl bromide as shown in Scheme . Ester groups of polyacrylate backbone and C‐Br groups of ATRP initiation groups were supposed to be not affected during the reaction, as evidenced from the previous similar reaction shown below 49 …”

Progress toward the Total Synthesis of Psymberin/Irciniastatin A

“…To this end, we relied heavily on the pioneering work of Kocienski and coworkers to synthesize the pyran core. Kocienski's synthesis of pederin, theopederin and the mycalamides all share the common pyran intermediate 8 7. We envisioned that the analogous protected alcohol 9 (and later 10 ) would dovetail nicely into our synthesis of 1 .…”

A Synthesis of Theopederin D and a Formal Synthesis of Pederin

“…We have already described a synthesis of pederin from the metallated dihydropyran 2 and the amide 7. 11 We now report the conversion of dihydropyranone 3 to amide 7 which, together with our much improved synthesis of metallated dihydropyran 2 15 represents a new formal total synthesis of pederin.…”

“…[3][4][5][6][7] The potent antitumour and antiviral activities of the marine compounds has stimulated interest in their synthesis because they are only available in minute amounts from natural sources. Total syntheses have been reported for pederin itself, [8][9][10][11] mycalamides A [12][13][14] and B 14,15 , and onnamide A. 16 Progress towards theopederin derivatives has been recorded 17,18 but no total syntheses have yet appeared.…”