Organocatalysis in Total Synthesis

Ξ October 4th, 2008 | → 0 Comments | ∇ Organocatalytic aldol reaction, Total Synthesis |


The synthesis and the structural revision of Callipeltoside C

 

Joseph Carpenter, Alan B. Northrup, deMichael Chung, John J. M. Wiener, Sung-Gon Kim, and David W. C. MacMillan

Angew. Chem. Int. Ed. 2008, 47, 3568 - 3572


 

In this communication MacMillan and coworkers report the total synthesis of Callipeltoside C (1) ; this synthetic sequence, which is found upon the use of organocatalytic and organometallic tecnologies, provides acces of Callipeltoside C in 18 chemical steps and 12% overall yield.

 

The disconnection approac of Callipeltoside C into four components of 2 - 5 of similar complexity revealed the possibility of a convergent synthesis with broad latitude in the sequence of fragment coupling.

They proposed the use of a direct aldehyde–aldehyde aldol coupling in combination with a Semmelhackalk oxycarbonylation for the rapid construction of tetrahydropyran 2; they envisioned that the stereogenicity of the protected iodoalcohol 4 could be furnished by means of an enantioselective formyl a-oxyamination. Last, they recognized the opportunity to further evaluate the versatility of  MacMillan enamine-catalyzed two-step carbohydrate synthesis to rapidly assemble the desired deoxy sugar 3 from simple achiral starting materials. Moreover, the amino acid proline function as a suitable organocatalyst for all of these asymmetric processes.

 

 

The first step towards the construction of callipeltoside C involved an enamine-catalyzed double diastereo-differentiating aldol reaction between propionaldehyde and the Roche ester-derived aldehyde 6; Felkin-selective chelation-controlled addition of propargyl zinc to aldehyde 7 afforded alkynyl diol 8. The subsequent Semmelhack reaction  builds the central heterocyclic ring of callipeltoside C by a palladium-catalyzed alkoxycarbonylation; with other few passages, they can obtain the target 2.


 

Synthesis of fragment 3 began with Negishi carbometalation– iodination of 4-pentynol[14] followed by Swern oxidation to provide the trisubstituted vinyl iodide 11; the iodoaldehyde 11 was subjected to an organocatalytic oxoamination to afford 12. Borohydride reduction, O-N bond cleavage and selective protection of the diol give 3 in good yield, whic was trasnformed in the corrispective Grignard.

 

 

The Grignard 13 react with 2 to give the Anti-Felkin product 14; subsequent HWE reaction permits to link the chain with the chloro-cyclopropane system. With the Yamaguchi lactonization and other few steps they obtin 17 in good yield.

 

The D-proline-catalyzed aldol dimerization of 2-triisopropylsilanoxyacetaldehyde and other few steps afford 18 which was coupled with 17 by means of a Tietze glycosylation; subsequent desilylation affords the final target 1.

 

 

I think with this paper anyone can well understand the power of organocatalysis!