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!

 

Total Synthesis of (+)-Citotrienin A

Ξ July 30th, 2008 | → 0 Comments | ∇ Total Synthesis |

Angew. Chem. Int. Ed. 2008, 47, 1-5


 

Today I will steal a little of work to the famous Totally Synthetic Blog and I talk about the total synthesis of the (+)-cytotrienin A, reported by Hayashi et al. in the Angewandte. This molecule is a microbial antitumor secondary metabolite.

I talk about this paper because in this synthesis (quite complex and long but fascinating in the same time) there are two organocatalytic passages. 

 

The synthesis started with an organocatalytic aldol reaction between furfural and propionaldehyde. The reaction was modified from the original procedure which was not useful for large-scale synthesis. The diol was obtained in good yield and d.e. without solvent and using surfactant-proline catalyst show below. The development of reaction without solvent is an important goal in organic green chemistry.  

The diol was treated with p-anisaldheyde dimethyl acetal to provide the protected diol; the reduction with DIBALH ( to give primary alcohol) and the oxidation to aldehyde gave the product A.

 

The reaction of A with vinyl zincate prepared from vinyl iodide, BuLi and Me2Zn gave the relative product F in hight yield and dr. Now a seqeunce of reactions affords G 

  1. Protection of secondary hydroxy group with TIPS
  2. Cleavage of the furan ring with O2 under irradation conditions 
  3. Cis/Trans isomerization using DABCO, followed by Luche reduction
  4. Protection of the primary hydroxy group wiyh trythyl ether
  5. The secondary free hydroxy group was converted into formate esther, which was removed by Tsuji’s protocol (Palladium-PBu3). 
  6. Remotion of the PMB

Reaction of G with acyl cloride show below, and subsequent selective removal of the TIPS group gave primary alcoho,l, which was transformed into iodide. (B)

 

Lithiation of the sulfone show below with LHMDS for coupling with B gave H in good yield, after protection of the phenol as its Boc derivate, and the reduction of the azide into amine. The condensation of the amine with cycloexenyl carboxylic acid gave to amide formation. The desulfinylation (difficult for the presence of a nitro-group in the aromatic ring) was carried out with the remotion of the Boc protection and the treatment of the phenol with NaBH4 (retro Micheal plus reduction). The phenol was protectd in its Alloc derivate and removal of the Tr group gave alcohol, which was oxidated and subsequent Wittig reaction to provide C. 

 

TIPS group was replaced by TES group (for difficult to removal TIPS after the construction of the triene moiety); reduction of the nitro group and removal of the Alloc protecting group gave I in good yield; the amine I was treated with carboxylic acid D in the presence of BOB-Cl as condensation agent. The syntesis finished with a RCM reaction catalyzed by first generation Grubbs catalyst. 

 

 In the end we have only to discuss the syntesis of D, which was synthesized by a proline-mediated α-aminoxylation of aldehyde show below with notrosobenzene. Horner-Emmons reaction, Williamson etherification (after treatment with copper solfate in methanol), reduction with DIBAL-H of the esthers and subsequent oxidation and Wiitig reaction gave the final diene. 

 

 

Organocatalysis in Total Synthesis

Ξ July 26th, 2008 | → 0 Comments | ∇ Total Synthesis |

 J.  Org. Chem. 2008, 73, 5198-5201      

 

In this report, Kumaraswamy and Kumaraswamy reported the enantioselective total synthesis of Eicosanoid using three catalytic steps, among which an organocatalytic cyclopropanation. 

 

 

 

 The trans-cyclopropane motif is a prevalent structural unit in a number of marine oxylipin family members.The starting material is the monoprotected pentadiol as its banzyl ether, followed by oxidation to yield aldehyde. Addition of vinylmagnesium bromide at 0 °C for 12 h afforded an allyl alcohol, which on further oxidation furnished vinyl ketone. tertButyl bromoacetate reacted with enone  in the presence of 10 mol % of cat 1 (DHQD)2Pyr and Cs2CO3 as base upon heating furnished cyclopropane A in 85% isolated yield.


 

 The use of dimeric ligand cat 1 (DHQ)2Pyr would generate the enantiomer B. Nevertheless, subjecting tert-butyl bromoacetate and enone  in the presence of 10 mol % of cat 1 (DHQ)2Pyr under identical conditions led to the product B with decreased enantioselectivity. After considerable experimentation,  it was found that the benzyl ether of quinine ligand B gave approximately equal magnitude of rotation as B but opposite in sign.