Discodermolide

The utility of RCM methodology for the synthesis of open-chain building blocks from a,fi-unsaturated d-lactones is exemplified by the partial syntheses of Cossy aimed for (+)-methynolide (the aglycon of the methymicin family of macrolide antibiotics) [45], and the anticancer agent discodermolide [46], as well as during a recent total synthesis of the highly cytotoxic marine natural depsipeptide apratoxin A by Forsyth and Chen [47]. 

In a recent synthesis of (-i-)-discodermolide, Nozaki-Hiyama reaction of the aldehyde 1617 with the unsaturated Peterson reagent 1618 then treatment with KH in THE gave the diene 1619 in 74% yield [19] (Scheme 10.8). 

Figure 4.38 Synthesis map showing starting materials used for the synthesis of discodermolide.

Smith, A.B. Ill, Freeze, B.S., Xian, M., Hirose, T. (2005) Total Synthesis of (-l-)-Discodermolide A Highly Convergent Fourth-Generation Approach. Organic Letters, 7, 1825-1828. 

Mickel, S.J., Sedelmeier, G.H., Niederer, D. etal. (2004) Large-Scale Synthesis of the Anti-Cancer Marine Natural Product (-l-)-Discodermolide. Part 2 Synthesis of Fragments Ci 5 and Cg-H. Organic Process Research Development, 8, 101-106. 

Smith, A.B. Ill, Beauchamp, T.J., LaMarche, M.J. etal. (2000) Evolution ofa Gram-Scale Synthesis of (-F)-Discodermolide. Journal of the American Chemical Society, 122, 8654-8664. 

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. 

Nerenberg, I.B., Hung, D.T., Somers, P.K., Scheiber, S.L. (1993) Total Synthesis ofthe Immunosuppressive Agent (—)-Discodermolide. Journal of the American Chemical Society, 115, 12621-12622. 

For enolates with additional functional groups, chelation may influence stereoselectivity. Chelation-controlled alkylation has been examined in the context of the synthesis of a polyol lactone (-)-discodermolide. The lithium enolate 4 reacts with the allylic iodide 5 in a hexane THF solvent mixture to give a 6 1 ratio favoring the desired stereoisomer. Use of the sodium enolate gives the opposite stereoselectivity, presumably because of the loss of chelation.61 The solvent seems to be quite important in promoting chelation control. 

Entry 2 shows an E-enolate of a hindered ester reacting with an aldehyde having both an a-methyl and (3-methoxy group. The reaction shows a 13 1 preference for the Felkin approach product (3,4-syn) and is controlled by the steric effect of the a-methyl substituent. Another example of steric control with an ester enolate is found in a step in the synthesis of (-t-)-discodermolide.99 The E-enolate of a hindered aryl ester was generated using LiTMP and LiBr. Reaction through a Felkin TS resulted in syn diastereoselectivity for the hydroxy and ester groups at the new bond. 

Entry 5, where the same stereochemical issues are involved was used in the synthesis of (+)-discodermolide. (See Section 13.5.6 for a more detailed discussion of this synthesis.) There is a suggestion that this entry involves a chelated lithium enolate and there are two stereogenic centers in the aldehyde. In the next section, we discuss how the presence of stereogenic centers in both reactants affects stereoselectivity. 

Scheme 2.6 shows some examples of the use of chiral auxiliaries in the aldol and Mukaiyama reactions. The reaction in Entry 1 involves an achiral aldehyde and the chiral auxiliary is the only influence on the reaction diastereoselectivity, which is very high. The Z-boron enolate results in syn diastereoselectivity. Entry 2 has both an a-methyl and a (3-benzyloxy substituent in the aldehyde reactant. The 2,3-syn relationship arises from the Z-configuration of the enolate, and the 3,4-anti stereochemistry is determined by the stereocenters in the aldehyde. The product was isolated as an ester after methanolysis. Entry 3, which is very similar to Entry 2, was done on a 60-kg scale in a process development investigation for the potential antitumor agent (+)-discodermolide (see page 1244). 

These conditions were also employed for a late stage of the synthesis of (+)-discodermolide (see Entry 17, Scheme 2.17). 

The combination of reagents and methods can provide for stereochemical control of addition to a-substituted aldehydes.195 An application of the methodology can be found in the synthesis of (+)-discodermolide that was carried out by J. A. Marshall and co-workers and is described in Scheme 13.69. 

The first (+)-discodermolide synthesis was completed by Stuart Schreiber s group at Harvard University and is outlined in Scheme 13.68. This synthesis was carried through for both enantiomers and established the absolute configuration of the natural material. The retrosynthetic plan outlined in Scheme 13.67 emphasizes the stereochemical triads found at C(2)-C(4), C(10)-C(12) and C(18)-C(20) and was designed to use a common chiral starting material. Each of the segments contains one of the stereochemical triads. 

Scheme 13.67. Retrosynthetic Analysis of (+)-Discodermolide to Fragments containing Stereotriads3... 

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. 

The synthesis of (+)-discodermolide shown in Scheme 13.74 was developed in the laboratories of the Novartis Pharmaceutical Company and was designed to provide sufficient material for initial clinical trials. The synthesis is largely based on the one... 

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