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. 

 

 

3,3-Disubstituted Oxindoles by Organocatalytic Mannich Reaction

Ξ July 28th, 2008 | → 0 Comments | ∇ Mannich Reaction |

 Org. Lett.  ASAP, July 19, 2008

Quaternary 3,3-disubstituted oxindoles have become important taraget in organic chemistry as this structural frameworks form the core unit of many natural molecules. Morover, the construction of chiral quaternary centres represents one of the most challenging subjects in asymmetric synthesis. Ying-Chun Chen et al. report the highly stereoselective Mannich reaction of 3-substituted oxindoles and N-Boc imines catalyzed by enviromentally benign organocatalyst.

It could be investigated that nucleophilic oxindoles and electrophilic N-Boc imines should be concertedly activated by thiourea-tertiary amine compounds, which have recently demonstred great success as bifunctional Brønsted acid Brønsted base catalysts for an array of 1,2- and 1,4- addition reactions.

Based on these considerations, bifunctional thiourea-tertiary amines A - D with diversely structured scaffolds were screened in the Mannich reaction of 3-benzyloxindole and N-Boc-benzaldimine.

 


 

The starting materials were smoothly consumed after 10 h, and the diastereomers 4a and 5a could be well separated. Catalyst D possessing a chiral 1,2- diphenylethylene-diamine (DPEN) skeleton demonstrated to be the superior one in regard to both diastereo and enantioselectivity.

With the optimal reaction conditions in hand, they then examined a variety of oxindoles and imines to establish the general utility of this novel asymmetric transformation. Generally, with oxindoles and imines various substituted, the yield and de was very good.

Moreover, to determine the absolute configuration of the asymmetric Mannich products, single crystals suitable for X-ray crystallographic analysis were fortunately obtained from enantiopure  E (below) that bears a sulfur atom.

 

 

On the basis of X-ray analysis, the structure contains a (C2S,C16S) configuration.

 

 

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.