Aldol discodermolide synthesis

Our final highlight in the discodermolide synthesis is the use of reagent control to get what we want and not what the molecules want. The combination of enol borinate 276 and an aldehyde 277 featuring a cis double bond, led to the formation of aldols anti- and syn-278. A model study had shown that the inherent selectivity with these enals could be improved by the use of ( )-Ipc groups on boron instead of cyclohexyl but it is not the selectivity that was wanted. (+)-Ipc groups were able to turn around the selectivity and improve the yield of the reaction while they were at it.50... 

Paterson, I., Delgado, O., Florence, G.J., Lyothier, I., Scott, J.P., Sereinig, N. (2003) 1,6-Asymmetric Induction in Boron-Mediated Aldol Condensations Application to a Practical Total Synthesis of (-F)-Discodermolide. Organic Letters, 5, 35-38. 

Scheme 13.71 shows the most recent version of a synthesis of (-l-)-discodermolide developed by Ian Paterson s group at Cambridge University. The synthesis was based on three major subunits and used boron enolate aldol addition reactions to establish the stereochemistry. 

In 2003, Paterson and co-workers reported a second-generation strategy for the synthesis of discodermolide, which aimed to eliminate the use of all chiral reagents and auxiliaries, and reduce the total number of synthetic steps (Scheme 24) [58, 59], These specific aims were achieved by employing an unprecedented aldol coupling at C5-C6 between C1-C5 aldehyde 118 and the advanced C6-C24 methyl ketone 119 and utilising diol 120 as a common precursor for the synthesis of the three subunits 118, 121 (C9-C16) and 98 (C17-C24). 

Panek and co-workers reported their synthesis of discodermolide in 2005 [62, 63], relying on the application of their crotylsilane methodology for the synthesis of polypropionate motifs [155,156] (see [157] forareview) [158,159,182], Their strategy involved key bond disconnections at C6-C7 and C14-05, based on an aldol coupling and the established Suzuki cross-coupling respectively, employing the key subunits 137 (C1-C6), 138 (C7-C14) and 81 (C15-C24) (Scheme 29). 

We have already collected some powerful tools for use in stereocontrolled aldol reactions, but we have not finished. We shall see now in Paterson s synthesis of (+)-discodermolide, how reagent control is used not to enhance the intrinsic substrate selectivity, but to overturn it. The aldol reaction is undoubtedly one of the most powerful ways of making carbon-carbon bonds and nature thinks so too. There are numerous natural products that are replete with 1,3 related oxygen functionality. Many of these are acetate or propionate-derived in nature. The methods detailed above developed from studies into the syntheses of these natural products. The manipulations of chiral ethyl ketones of this kind are of particular interest when it comes to natural products that are polypropionate-derived. 

As one might expect, there are very many aldol reactions to be found in Paterson s synthesis46 of dis-codermolide 261. The synthesis involves 23 steps (in the longest linear sequence) and the overall yield is 10.3%. If we naively equate the yield with those 23 steps then we have an average yield in every step of around 90%. Several other groups are interested in the synthesis of discodermolide 47,48... 

The Cilag resolution of the pyridyl amino acid is described in Org. Process Res. Dev. 2001, 5, 23. For an informative comparison of different auxiliary and catalytic methods for the synthesis of a simple chiral carboxylic acid, see Org. Process Res. Dev. 2003, 7, 370. For a leading reference to the use of enzymes to reduce ketones, see the account of the Codexis work on montelukast in Org. Process Res. Dev. 2010, 14, 193. The spectacular synthesis of discodermolide by Novartis using a series of aldol reactions is described in Org. Process Res. Dev. 2004, 8, 92, 101 and 107. 

Paterson developed asymmetric enolboration-aldolization involving diisopinocampheylboron triflate (57, 32), He has shown the utility of enolboration for the synthesis of various macrolide molecules. His recently completed target molecules include Concanamycin F (33) and the potential anticancer agent, Discodermolide (34) (Figure 6). 

The chiral boron enolates 7-14 add to aldehydes with high levels of stereocontrol in a predictable sense. These enolates are designed specifically for the aldol-based construction of the highly oxygenated and stereochemically challenging structures found in polyketide natural products, as illustrated here by their application to the total synthesis of concanamycin F and discodermolide. 

Altogether, our total synthesis of (+)-discodermolide uses four asymmetric boron aldol reactions and proceeds in 27 steps and 7.7% overall yield (for the longest linear sequence starting from commercial methyl (S)-3-hydroxy-2-methylpropionate). 

Paterson et al. achieved the convergent synthesis of the immunosuppressive agent discodermolide 205 by using a lithium-mediated aldol reaction with a chiral aldehyde (Scheme 8.31). The 2,6-dimethylphenyl ester 200 was derived to -enolate 201 by employing lithium 2,2,6,6-... 

Paterson 1, Florence GJ, Gerlach K, Scott IP, Sereinig N. A practical synthesis of (-l-)-discodermolide and analogues Fragment union by complex aldol reactions. J. Am. Chem. Soc. 2001 123(39) 9535-9544. 

Paterson I, Florence GJ, Gerlach K, Scott J. Total synthesis of the antimicrotubule agent (+)-Discodermolide using boron-mediated aldol reactions of chiral ketones. Angew. Chem. Int. Ed. 2000 39 377-380. 

Paterson, I. and Florence, G.J. (2000) Synthesis of (+)-discodermolide and analogues by control of asymmetric induction in aldol reactions of y-chiral (Z)-enals. Tetrahedron Lett., 41, 6935-6939. 

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