The world of organocatalysis

Organocascade Catalysis

Ξ August 1st, 2009 | → 0 Comments | ∇ Cascade reactions |

          Cycle-Specific Organocascade Catalysis: Application to Olefin Hydroamination, Hydro oxidation, and Amino-oxidation, and to Natural Product Synthesis

 Bryon Simmons, Abbas M. Walji, and David W. C. MacMillan

Angew. Chem. Int. Ed. 2009, 48, 1 – 6

 

Recently MacMillan’s group disclosed the concept of organocascade catalysis, a strategy that combines two modes of catalyst activation into one mechanism, allowing the rapid conversion of simple achiral starting materials into stereochemically complex, single-enantiomer products. This strategy can also render a variety of transformations that are not yet possible using  monocyclic catalysis pathways (e.g. enantioselective HCl, HF, and aryl–Cl addition across olefins). 

In this paper they describe the use of imidazolidinone 1 and proline 2 as a dual-catalyst system that allows access to a lot of valuable transformations, such as olefin hydroamination, hydro-oxidation, and amino-oxidation. They also report the first use of this organocascade catalysis as a strategy for natural product synthesis by the enantioselective construction of the sesquiterpene (-)-aromadendranediol.

 

Imidazolidinones such as 1 have been estabilished as LUMO-lowering iminium catalyst; while they can also serve as enamine catalyst, they do not contain the necessary structural features to partecipare in bifunctional enamine catalysis. In contrast, proline 2 has been shown to be an enamine catalyst,  but this amino acid is generally ineffective as an iminiumm catalst with enals or enone. The combination of imidazolidinone 1 and proline should provide a dual-catalyst system that satisfies the chemoselectivity requirements fos cycle-specific catalysis.

 

 

The initial studies were directed on cycle-specific catalysis towards the enantioselective olefin hydroamination, olefin hydro-oxidation and reductive Mannich reaction. The experiments were performed using methylcinnamaldehyde, Hantzsch ester, two separate combinations of proline and imidazolidinone and one of the three electrophiles that are known to be susceptible to bifunctional enamine activation.  

 

 

Reaction	Catalys Combination	Yield	ee	Syn/Anti
Olefin Hydroamination	A	75%	99%	1 : 6
Olefin Hydroamination	B	82%	99%	8 : 1
Olefin hydro-oxidation	A	73%	99%	1 : 11
Olefin hydro-oxidation	B	62%	99%	10 : 1
Reductive Mannich	A	86%	99%	14 : 1 (dr)
Reductive Mannich	B	80%	99%	12 : 1 (dr)

 

The synthetic methodologies has been applied to the synthesis of (-)-aromadendranediol, a widely distributed sesquiterpene, by means of a triple-cascade catalysis (metathesis, iminium catalysis and enamine catalysis).

 

 

Cascade Organocatalysis

Ξ December 27th, 2008 | → 2 Comments | ∇ Cascade reactions, Thiourea catalysis |

A New entry to Cascade Organocatalysis: Reaction of Stable Sulfur Ylides and Nitroolefines Sequentially Catalyzed by Thiourea and DMAP

Liang-Qiu Lu, Yi-Ju Cao, Xiao-Peng Liu, Jing An, Chang-Jiang Yao, Zhi-Hui Ming, and Wen-Jing Xiao

J. AM. CHEM. SOC. 2008, 130, 6946–6948

 

The development of new synthetic methods that would rapidly transform readily accessible starting materials into complex molecules is of considerable current interest. Recently, significant efforts have been made to develop organocatalytic cascade reactions with the objective to mimicking the biosynthetic strategy.

Sulfur ylides and nitroolefines have proven to be extremely useful reagents in organic synthesis; their reactivities and synthetic diversities provide an important platform for the development of novel cascade strategies. In this paper, the authors describe a new cascade protocol: an unprecedent reaction of stable sulfor ylides and nitroolefines sequentially catalyzed by thiourea and DMAP to afford diverse structurally complex oxazoldin-2-ones

They initially studied the reaction of sulfori ylide 1 with trans-nitrostyrene 2 in the presence of 10% mol of Takemoto’s catalyst  3: the reaction afforded anti-5-benzoyl-4-pheyloxazolidin-2-one 4 as a major isolable product (35%) with great diastereoselectivity (> 95:5) and low enantioselectivity (ee 6%). Encouraged by this result, we wxaminedthe reaction in detail under a variety of conditions. Below are shown the general reaction and catalysts used to find the best reaction conditions.

 

Among the catalyst examinated in dichloromethane, the combination of catalyst 6 and DMAP showed the highest activity for this cascade organocatalysis, while the reaction gave a complicated mixture in the absence of catalysis; with the use of 6 or DMAP alone, the reaction gave 3 in poor yields. Other catalyst combinations such as 7/DMAP, 4-5/DMAP, 6/DBU, 6/DABCO, 6/NEt ₃, were less effective.

The reaction is really general and a lot of different nitroolefines and sufur ylides can be used; in any case the oxazolidin-2-one can be obtained in high yields and dr. 

What about the mechanism? Below is shown the catalytic cycle of the reaction.

 

The cascade sequence is initiated by the addition of sulfur ylide A to nitroolefin D in the presence of thiourea catalyst C, which results in the formation of diuble H-bonding nitronate E.  Subsequent oxygen alkylation affords isoxazoline N-oxide F and regenerates the thiourea catalyst. F can be converted into oxaziridine intermediate G under the reaction condition, which then generates intermediate H, upon deprotonation of the deuterium by DMAP. The ring opening is driven by a release in ring strain that would yield nitrene L via intermediate I. Finally Hofmann rearrangement of nitrene L to form isocyanate M: this would allow for intramolecular ring closing to provide N, which then reacts with DMAP-D^₊ to afford oxazolidin-2-one and regenerates DMAP. 

A demonstration of the synthetic manipulation of the products is presented in the scheme below: the oxazolidin-2-ones can be readly converted into 1,2-aminoalcohols and hydroxyl-aminoacid.

 

 

 

 

 

 

 

 

 

Organocatalytic Mukaiyama Aldol Reaction

Ξ October 28th, 2008 | → 0 Comments | ∇ Aldol Reaction, Mukayama reaction |

 

Asymmetric Mukaiyama Aldol Reaction of Nonactivated Ketones Catalyzed by allo-Threonine-Derived Oxazaborolidinone

Shinya Adachi and Toshiro Harada

Org Lett (ASAP)

 

Chiral tertiary alcohols are important frameworks frequently found in biologically active compounds and catalytic asymmetric aldol addition to ketone acceptors has received growing attention since the resulting tertiary aldols are valuable building blocks for these subunits.

They have recently reported that allo-threonine-derived oxazaborolidinone (OXB) 1 is an efficient catalyst for the asymmetric Michael reaction and Diels-Alder reaction, of acyclic unsaturated ketones. The characteristic feature of the OXB catalyst for the enantioselective activation of the less reactive ketone carbonyl groups prompted us to employ it in the ketone aldol reaction. Herein, they wish to report the first example of the asymmetric Mukaiyama aldol reaction of nonactivated ketones by employing a dimethylsilyl ketene S,O-acetal as a nucleophile with OXB 1.

 

The potential of OXB catalyst 1 in ketone aldol reaction was first evaluated in the reaction of p-bromoacetophenone with silyl ketene S,O-acetals 3. The reaction with 20% of 1 gave the alcohol 4 in 20% yield and 84% ee. When they use dimethylsilyl derivative rather than trimethylsilyl, they obtain 4 in 90% ee toghether with reduction product 5. 

The scope of the OXB-catalyzed ketone aldol reaction was examined in toluene at -10 °C. A variety of acetophenone derivatives bearing substituents at the para-, meta-, or ortho-position underwent reaction with 3b to give the corresponding aldol products 4 in high enantioselectivity (91-98% ee) and in satisfactory yield.

 

The scope of the OXB-catalyzed ketone aldol reaction was examined in toluene at -10 °C . A variety of acetophenone derivatives bearing substituents at the para-, meta-, or ortho-position underwent reaction with silyl ketene S,O-acetal to give the corresponding aldol products 4 in high enantioselectivity (91-98% ee) and in satisfactory yield.

The absolute stereochemical course of the present reaction  is rationalized in terms of an activated complex model, in which nucleophile 3 attacks selectively from the open re face of a ketone.

 

The attack of ketene silyl acetal 3 to activated enone 6 first generates unstable intermediate 7. A pathway involving direct silyl-group migration of 7 to give 4 is less likely. However, prolonged reaction time and higher temperature were required for the reaction to proceed in a catalytic manner, leading to the formation of the silyl derivatives 4.

The result can be rationalized by assuming a stepwise silyl-group migration via silyl ester 8; initial rapid migration to form 8 followed by slow formation of 4  with regeneration of OXB 1. According to this pathway, at the low temperature, the reaction stopped at 8 to give silylated species after hydrolysis as an exclusive aldol product. At higher temperature, transformation of 8 to 4 proceeded slowly to afford the observed mixture of products after workup.

 

 

Organocatalysis and Photoredox Catalysis

Ξ October 12th, 2008 | → 0 Comments | ∇ Photoredox catalysis, organocatalysis and redox catalysis |

 

Merging Photoredox Catalysis with Organocatalysis: The Direct Asymmetric Alkylation of Aldehydes

David A. Nicewicz and David W. C. MacMillan

Science 322, 77 (2008)

 

Here I report a MacMillan’s paper recently published in Science: the paper regards the asymmetric alkylation of aldehydes by means of both organocatalysis and photoredox catalysis.

Nature’s ability to convert solar energy to chemical energy in photosynthesis has inspired the development of a host of photoredox systems in efforts to mimic this process. The most studied one-electron photoredox catalyst has been Ru(bpy)₃²⁺ : an inorganic complex that has facilitated important advances in the areas of energy storage, hydrogen and oxygen evolution from water, and methane production from carbon dioxide.

 

Over the last years, the organocatalytic methods are grown at a dramatic pace; now chemists are able to make 130 chemical reactions by means of organocatalysis. Recently, MacMillan’s research group introduced the concept of organo– singly occupied molecular orbital (SOMO) catalysis, a one-electron mode of activation that has enabled the development of several useful transformations.

Given the widespread success of both electron transfer catalysis and organocatalysis, MacMillan’s group recently questioned whether it might be possible to merge these two powerful areas, with the goal of solving long-standing, yet elusive problems in chemical synthesis.

They hypothesized that the enantioselective catalytic a-alkylation of aldehydes, could be carried out by the marriage of inorganic electron transfer and organic catalysis.

 

They proposed that two catalytic cycles might be engineered to simultaneously generate an electron-rich enamine (8) from the condensation of an aldehyde and an amine catalyst and an electron-deficient alkyl radical (5) via reduction of an alkyl bromide with a Ru photoredox catalyst. Given that electron-deficient radicals are known to rapidly combine with elettronrich olefins to forge even the most elusive C–C bonds, we hoped that this dual-catalysis mechanism would successfully converge to enable the direct coupling of aldehydes with alpha-bromo ketones or esters.

 

It has long been established that Ru(bpy)₃²⁺ (1) will readily accept a photon from a variety of light sources to populate the *Ru(bpy)₃²⁺(2) metal-to-ligand charge transfer (MLCT) excited state. This high-energy intermediate would efficiently remove a single electron from a sacrificial quantity of enamine, to initiate our first catalytic cycle and provide the electron-rich Ru(bpy)₃⁺ (3). Given that Ru(bpy)₃⁺ (3) has been shown to be a potent reductant, we anticipated that single-electron transfer (SET) to the alpha-bromocarbonyl substrate 4 would rapidly furnish the electron-deficient alkyl radical 5 while returning Ru(bpy)₃²⁺ (1) to the catalytic cycle.
Concurrent with this photoredox pathway, the organocatalytic cycle would begin with condensation of the imidazolidinone catalyst 6 and the aldehyde substrate 7 to form enamine 8. At this stage, we expected the two catalytic cycles to intersect via the addition of the SOMOphilic enamine 8 to the electron-deficient alkyl radical 5, thereby achieving the key alkylation step. This coupling event would concomitantly produce an electron-rich a-amino radical 9, a single-electron species that has a low barrier to oxidation. Once again, convergence of our catalytic cycles should ensure SET from alpha-amino radical 9 to the *Ru(bpy)₃²⁺ (2) excited state to produce the iminium ion 10 and regenerate the active reductant, Ru(bpy)₃⁺ (3), a step that would close the photoredox cycle (24).
Hydrolysis of the resulting iminium 10 would reconstitute the amine catalyst 6 while delivering the requisite enantioenriched alpha-alkyl aldehyde product.

With respect to operational convenience, it is important to consider that this alkylation protocol does not require any heating or cooling, all of the components employed in this study (substrates, catalysts, and solvents) are commercially available and inexpensive, and a simple household 15-W fluorescent light bulb can be employed as a suitable light source.

 

 

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!