Methyl discodermolide

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. 

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). 

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. 

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). 

A similar strategy was employed for synthesizing (-)-discodermolide starting from (i )-(3)-hydroxy-2-methyl propionate 1 [3b], synthetic variant of the natural product were also prepared such as 16-e/ /-discodermolide, truncated versions of discodermolide were also synthesized such as the C1-C15, C16-C24 and C8-C24 fragments. 

The synthesis of (+)-discodermolide was achieved from 34 , which was prepared from (S)-(+)-methyl 3-hydroxy-2-methylpropionate 1 (Scheme 10). A slight modification has been made for practical reasons, the dibutylboron enolate C was used instead of the dibutylboron enolate A (Scheme 10). Compound 34 was transformed to 36 and 38 by using the same pathway as for the synthesis of 36 and 38 (Scheme 11). 

Compounds 72-74 are presumably formed by hydration of the double bond. In 74, the C16 methyl group apparently has the opposite configuration to that observed in discodermolide. This stereocenter is... 

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). 

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