Laulimalide

This methodology has been used for the synthesis of the C3-C14 segment 24 of the antitumor agent laulimalide 23 (Scheme 4.22) [35]. The constrained chiral BOX ligand 21c in combination with Cu(OTf)2 afforded dihydropyrane 6f by a cycloaddition reaction in good yield and ee this was converted to the C3-C14 segment 24 via a Ferrier-type rearrangement in several steps. 

The novel marine natural product laulimalide (65), a metabolite of various sponges, has received attention as a potential antitumor agent due to its taxol-like ability to stabilize microtubules. There has been considerable synthetic effort toward 65, culminating within not more than 2 years in as many as ten... 

Fig. 7 Advanced dihydropyran fragments used in total syntheses of laulimalide (65)...

The complete laulimalide-directed work has been reviewed Mulzer J, Ohler E (2003) Chem Rev 103 3753... 

An interesting variant involves the use of an allylic alcohol as the alkene component. In this process, re-oxidation of the catalyst is unnecessary since the cyclization occurs with /Uoxygen elimination of the incipient cr-Pd species to effect an SN2 type of ring closure. Both five- and six-membered oxacycles have been prepared in this fashion using enol, hemiacetal, and aliphatic alcohol nucleophiles.439,440 With a chiral allylic alcohol substrate, the initial 7r-complexation may be directed by the hydroxyl group,441 as demonstrated by the diastereoselective cyclization used in the synthesis of (—)-laulimalide (Equation (120)).442 Note that the oxypalladation takes place with syn-selectivity, in analogy with the cyclization of phenol nucleophiles (1vide supra). 

The oxypalladation method mentioned above was introduced as a crucial step in the synthesis of several natural products. As shown in Scheme 8.51, Metz and coworkers used this strategy in an enantioselective synthesis of ricciocarpin A [122], Other impressive applications including the acetalization-RCM sequence have been employed in the synthesis of the AB ring of ciguatoxin [123] and of the Q-C fragment of laulimalide [124] (Scheme 8.52). 

In a total synthesis of (-)-laulimalide (288), Nelson et al. were able to assemble rapidly the bottom synthon of the target by adding carboalkoxyallenylstannane 286 to glycal 285 [60]. The Lewis acid activator Bu3SnOTf gave the best results, affording the anti SN2 addition product in 80% yield (Scheme 19.51). 

Bis(oxazoline)-mediated hetero-Diels-Alder reactions have also been utilized in total synthesis. For example, Ghosh and co-workers used inda-box 9a in the construction of a key intermediate for the synthesis of laulimalide 123, a potent... 

An intermediate in the synthesis of laulimalide by Davidson8 illustrates the differential protection of alcohols. The starting materials 56 and 57 already have an alcohol protected as a TBDMS silyl ether and a diol protected as an acetal. The alcohol in 58 is protected as a p-methoxybenzyl ether and the acetal hydrolysed by acetal exchange to give the free diol 60. Selective protection of the primary alcohol by a bulky acyl group (pivaloyl, i-BuCO ) 61 allows silylation of the secondary alcohol with a TIPS group 62. Finally the pivaloyl group is selectively removed by DIBAL reduction to release just one free alcohol 63. 

MS As with different chemical structures have been discovered in different natural sources. Taxanes come from plants, epothilones and cyclostreptin are of microbial origin, whereas discodermolide, dictyostatin, eleutherobin, laulimalide and peloruside were discovered in sea organisms (for a classification and MSA structures see [20]). We do not know of MSAs from a purely synthetic chemistry not related to natural products. 

One of these methods is NAMFIS (NMR Analysis of Molecular Flexibility in Solution) [62], which considers all candidate conformations that are theoretically accessible to the molecule and optimizes their mole fractions until their computed variables match the experimental NMR data (usually NOEs and J couplings, in the future potentially also residual dipolar couplings). NAMFIS has been used to analyze the solution structures of several tubulin-binding drugs, such as PTX [63], epothilones [26], discodermolide [60] or laulimalide [64],... 

The conformation of laulimalide in the free state has been studied by X-ray crystallography [129, 130] and solution NMR spectroscopy [64, 134],... 

In contrast, NAMFTS deconvolution of the NMR data in DMSO-t followed by post-NAMFIS energy evaluation (see below) identified 15 laulimalide conformations belonging to five classes with populations in the range 1-21% [64], NMR... 

Fig. 22 Top and side views of laulimalide X-ray structure [129]. The molecule adopts a flattened conformation...

Fig. 23 Overlay of selected conformers of laulimalide within 2 kcal mol-1 of the global minimum determined from molecular modeling and NMR data in CD3OD solution. These low-energy conformations closely resemble the X-ray conformation. (Reprinted with permission from [134]. Copyright 2005 Elsevier)...

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