Stereoselective Total Synthesis of the Natural (+)-Lasonolide A

Abstract

The natural (+)-lasonolide A (1), an anti-tumor agent, has been synthesized via thermodynamic benzylidene formation at the C 22 quaternary chiral center, use of a disulfone equivalent for elongation of the C 15 -C 17 three-carbon chain as well as introduction of the two trans olefins at C 15 and C 17 , iodocyclization for the upper THP, Michael addition for the bottom THP, and intramolecular Horner-Emmons olefination for the 20-membered macrolactone.In 1994, McConnel et al. identified lasonolide A from the shallow water Caribbean marine sponge, Forcepia sp., during the search for new anti-tumor agents from marine resources. 1 Lasonolide A exhibits anti-neoplastic activity by antagonizing the in vitro proliferation of A-549 human lung carcinoma cells as well as cell adhesion in a cell assay for the detection of signal-transduction agents. 2 Its relative stereochemistry was originally proposed incorrectly by extensive spectroscopic studies, and later revised as shown in 1, with the stereochemistry of the C 28 hydroxyl group and the absolute configuration, based on synthetic studies. 3,4 Lasonolide A is a novel 20-membered macrolactone, which comprises two cis-2,6-disubstituted tetrahydorpyrans, nine chiral centers including a quaternary center, and seven olefinic double bonds composed of one terminal, two cis and four trans olefins. The intriguing structural and biological features of the natural product attracted us to its total synthesis. In this paper, we present an efficient asymmetric total synthesis of the natural product (+)-lasonolide A (1).Following the retrosynthetic analysis of 1, introduction of the double bonds at C 2 and C 25 was planned by an intramolecular Horner-Emmons olefination and a Wittig reaction, respectively (Scheme 1). The appositely functionalized intermediate 2 could be prepared by the JuliaKocieński sulfone-coupling protocol 5 of sulfone 3 and aldehyde 4. Formation of the two tetrahydropyranyl rings was envisaged as iodocyclization of d-hydroxyalkene 5 for 3 and by intramolecular Michael addition of 7 for 4. While the quaternary center in 5 was proposed to be installed by thermodynamic differentiation of the two alkoxymethyl groups of 6, the homoallylic alkoxy group of 7 was conceived to be derived from an asymmetric allylation of the known alkene 8.The synthesis commenced with Swern oxidation 6 of the known alcohol 9 7 followed by the asymmetric allylation with allylboronate 10r 8 to afford the homoallylic alcohol 6 in 86% yield and 78% ee (Scheme 2). It was necessary to differentiate between the two alkoxymethyl groups of 6 in the next stage. It was hoped that thermodynamic formation of benzylidene from 6 would favor 11 rather than 12, due to the hydrogen-bonding between the axial primary hydroxyl group and the two ring oxygens. To determine the optimal procedure benzaldehyde was reacted with 6 Scheme 1 Retrosynthetic analysis O O HO O O O OH O HO 35 28 25 22 21 17 15 14 2 4 O O O OTBS TBSO TBSO OTBS (EtO) 2 OP O 2 O OH TBSO TBSO 3 + O OHC OTBS 4 OH O O Ph 5 O O OH 6 O OTIPS 7 EtOOC O...

Total Syntheses of the Histone Deacetylase Inhibitors Largazole and 2-epi-Largazole: Application of N-Heterocyclic Carbene Mediated Acylations in Complex Molecule Synthesis

“…Alternatively, 4 was accessed from known sulfone-alcohol 23 containing a tetrazole-sulfone moiety via thioester 24 generated under Mitsunobu conditions (Scheme 4). 18 Julia-Kocienski olefination 19 exploiting 24 and the sensitive α, β -epoxy-aldehyde 25 20 gave a 3.3: 1.0 mixture of alkenes ( E , Z )- 26 , which were separated at the stage of primary alcohols 22 (45% yield, two steps). Oxidation then provided the unstable epoxy-aldehyde 4 (87%).…”

“…After the mixture stirred for 5 min, a solution of alcohol 23 37 (562 mg, 2.09 mmol) in THF (3 mL) was added. After 5 min, a solution of thiooctanoic S -acid (380 mg, 2.37 mmol) in THF (3 mL) was added.…”

The Laulimalide Family: Total Synthesis and Biological Evaluation of Neolaulimalide, Isolaulimalide, Laulimalide and a Nonnatural Analogue

“…17:1). The newly generated OH group at C 20 was protected as TBS-, TES-and MOM-ethers 34 a-c which were oxidized to the sulfones 6 a, 6 b and 6 c. This worked well for 6 a and 6 c. In the case of the very labile allylic OTES ether in 6 b we had to use buffered heptamolybdate [17] and carefully monitor the reaction progress to avoid desilylation and subsequent epoxidation of the allylic alcohol.…”

Stereoselective Synthesis of Both Tetrahydropyran Rings of the Antitumor Macrolide, (−)-Lasonolide A

“…Parikh-Doering oxidation 11 of 15 gave the precursor aldehyde which, was subjected to a Julia-Kocienski reaction. 9 The requisite sulfone 17 was readily prepared by a Mitsunobu reaction with known alcohol 16 , 14 triphenyl phosphine, diisopropylazodicarboxylate (DIAD) and phenyl tetrazole thiol. Reaction of the sulfone 17 with KHMDS in a mixture (5:1) of DME and HMPA followed by addition of an aldehyde provided the corresponding trans- olefin as a major isomer ( trans/cis = 10:1 by 1 H NMR analysis) in 90% yield.…”