Of discodermolide

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

Hung, D.T., Nerenberg, J.B., Schreiber, S.L. (1996) Syntheses of Discodermolides Useful for Investigating Microtubule Binding and Stabilization. Journal of the American Chemical Society, 118, 11054-11080. 

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. 

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. 

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

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... 

Schreiber and co-workers reported the first total synthesis of (-)-discodermolide (ent-1) in 1993, confirming the relative stereochemistry and establishing the absolute configuration [43, 44], In 1996, they reported the first synthesis of the natural... 

Further alkylation of the lithium (Z)-enolate of 25 with methyl iodide gave 26, introducing the C16 stereocentre (3 1 dr) and completing the carbon backbone. Oxidation at Cl and carbamate formation gave 27 which underwent a chelation-controlled reduction at C17 (30 1 dr). Finally, global deprotection completed the synthesis of discodermolide (1), with an overall yield of 4.3% achieved over 24 steps in the longest linear sequence. 

The Schreiber synthesis is particularly noteworthy in that the absolute configuration of discodermolide was assigned unambiguously, and through the preparation of numerous analogues the first structure-activity relationship study was possible [35,44], Their synthesis of the unnatural antipode (ent-1) also led to the unexpected discovery that it causes cell cycle arrest in the S-phase [107],... 

Scheme 3 Schreiber s subunit assembly and completion of discodermolide...

Z E = 49 1). At this stage, the (Z)-diene unit was introduced utilizing the Yamamoto olefmation protocol to give 43 [115]. A further five steps were then required to complete Smith s first-generation synthesis of (-)-discodermolide (ent-1), in 2.2% overall yield over 28 steps in the longest linear sequence based on the C1-C8 aldehyde 28. 

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