Chemical Salsa

Taken from Ref. [1].

This week we will look at a ‘Nobel-Prize’ star – the olefin metathesis reaction. Metathesis is the process in which 2 olefinic fragments are redistributed to afford a new olefinic product, with ethylene (in most cases) as a side-product. Metathesis is an extremely useful reaction in natural product and polymer synthesis, and no doubt a number of its variations are developed. The catalysts involve either Ruthenium (Ru) or Molybdenum (Mo). While Ru-based catalysts are very general in natural product synthesis, Mo-based catalysts tend to be more selective for certain kinds of substrates.


Figure 1. Olefin Metathesis and Stereochemical Rationale. Taken from [2].

While strategies such as Ring-Closing Metatheses (RCM) are widely employed in synthesis, the prospect of the metathesis reaction has a long way to go. One of the most challenging types of metathesis is ‘the’ cross-metathesis (CM). It represents the reaction between 2 different olefins (e.g. A and B) to afford the required product, A-B. From the mechanism, it is inevitable that homocoupling can often take place to give statistical mixtures of A-A and B-B, which are undesirable products in the synthetic perspective (Figure 1) [1,2].

Furthermore, cross metathesis produces the thermodynamically-feasible E-olefin products, yet it rarely produces Z-olefins(Figure 1). The difficulty concerning the Z-isomer synthesis is originated from the reversibility of the metathesis process. Since a Z-alkene is more reactive than an E-alkene, it is more likely to engage in the reversible reaction and thus retard the metathesis process. While a certain class of cross metathesis, the ring-opening cross-metathesis (ROCM) shows some promise as the relief of ring strain of the substrates can provide a thermodynamic driving force, this privilege is not shared by the common olefinic substrates in a normal cross metathesis. Thus, it is clear that a Z-selective cross metathesis reaction should be a highly sought-after process.


Figure 2. Olefin Metathesis by Hoveyda, Schrock et. al. Taken from Ref. [1].

This week, we have an article in ‘Nature’ from Hoveyda and Schrock et. al., which features a chiral-at-metal Mo catalyst for Z-selective cross metathesis (Figure 2) [1]. By careful ligand design, they can encourage the formation of Z-isomer product through the formation of the corresponding metallocyclobutane intermediate, for which its formation is encouraged because the bulky, monodentate arylalkoxide ligand can rotate freely to enable that to take place (Figure 3) [1, 2].


Figure 3. The stereochemical rationale proposed by Hoveyda et. al. Taken from [1].

They have investigated Z-selective cross-metathesis in 2 groups of substrates – enol ethers and allylic amides. It is indeed a great choice to try the enol ether as it has the advantage that it is more electron-rich and therefore it can form a more stable alkylidene intermediate, which will lead to a longer catalyst lifetime and thus a better turnover. The group has also optimized the equivalents of enol ether used in the reaction, so that they can ensure the higher conversion possible along with the highest Z:E isomer ratio.

Another key issue they have looked into is the potential of formation of other side-products through the reaction of ethylene (CH2=CH2), which is inevitably generated through the metathesis mechanism. The group has devised a trick to exclude this ‘not-so-innocent party crasher’ in the metathesis reaction. By carrying out the reaction under reduced pressure, ethylene could be extruded from the reaction medium. This restored the conversion and stereoselectivity, and attenuated the effects enacted by intermediates associated with ethylene, such as unproductive cross-metatheses and further olefin isomerizations.

In order to demonstrate the strategy’s versatility, they have employed their metathesis reaction in 2 examples of natural product synthesis - a plasmologen phospholipid and the immunostimulant KRN7000.

The work was also covered in the article by Lee. [2]


References:

1. Catalytic Z-selective olefin cross-metathesis for natural product
synthesis.
Simon J. Meek, Robert V. O’Brien, Josep Llaveria, Richard R. Schrock, Amir H. Hoveyda
Nature 2011, 471, 461.

2. Overcoming catalytic bias
Daesung Lee
Nature 2001, 471, 452.

A Potential Textbook Addition

Figure 1. Catalytic asymmetric allylic alkylation. Taken from Ref. [1]

The article of the week concerns a type of reaction which may be familiar to students of Organic Chemistry – the reaction of a cuprate (R2CuLi).

It is beyond doubt that organolithiums and Grignard Reagents are very useful reagents in synthesis, as they enable the formation of carbon-carbon bonds. Yet these textbook reactions suffer from strong reactivitives of the organometallics – the stronger and more basic these reagents are, the less controllable and selective the reaction outcome will be. For course, this long-standing issue has stimulated the developments of better methods to generate C-C bonds.

One of the interesting effects of adding a Cu(I) salt to these reagents is that it changes the chemical behaviors of the resultant reagents. While Organolithiums and Grignards are seen as hard reagents, cuprates (R2CuLi) are soft reagents which undergo Michael and SN2’ reactions.

While Grignard reagents can be switched to a soft reagent by a catalytic amount of Cu (I), the hallmark of an organolithium-derived cuprate is that its generation is a stoichiometric process. The stoichiometry is of great importance here – 2 equivalents of RLi reacts with 1 equivalent of copper (I) salt to afford R2CuLi (Li: Cu = 2:1). If the ratio is 1:1, the reagent is called an ‘organocopper’ reagent (e.g. MeCu.LiI), which is selective for certain substrates. Because of this, a catalytic protocol of the generation of cuprates from organolithiums should be a fascinating one.


Figure 2. Ligand screening. L4, L5, and L6 prove to be advantageous ligands. Taken from Ref. [1]

Professor Ben Feringa and his group has got a nice publication on Nature Chemistry this week, which nicely demonstrated the catalytic version discussed above (Figure 2) [1]. The reaction they have investigated is designated as an allylic alkylation. Using the allylic halides, they carried out allylic alkylations with the cuprates generated under catalytic amount of Cu(I), from the organolithiums. By employing phosphoramidite or the TaniaPhos ligands, they could achieve the asymmetric allylic alkylation, with the major product being the SN2’ product (rather than the completing SN2 product) with impressive e.e.


Figure 3. The investigation of the mechanism. Probing the active copper species. Taken from Ref. [1].

They have also carried out NMR studies to probe the chemical species involved in the reaction (Figure 3). They found that the diphosphine copper monoalkyl species (e.g. TaniaPhos-CuMe , compound A in Figure 3) was the active species responsible for the allylic alkylation at -80ºC, and they have verified this proposal via additional control experiments. They have also shown that the use of ether as a solvent will lead to detrimental effects on the reaction (due to the formation of species B in Figure 3). The best solvent for the catalytic reaction is dichlorometahane.

A nice addition to the list of textbook reactions in the near future!

References:

1. Catalytic asymmetric carbon–carbon bond formation via allylic alkylations with organolithium compounds
Manuel Perez, Martın Fanana´s-Mastral, Pieter H. Bos, Alena Rudolph, Syuzanna R. Harutyunyan and Ben L. Feringa
Nature Chemistry
13th March, 2011
DOI: 10.1038/NCHEM.1009

The Radicalization of Photocatalysis

Figure 1. The Iridium catalyst used in the study. Taken from Ref. [1].

Some weeks ago I have shown you a brilliant article by Professor Corey Stephenson’s group, which involves catalysis with a photoredox catalyst. [2] Indeed, they have a number of contributions to this field recently. [1-3]


Figure 2. The atom-transfer radical addition. Taken from Ref. [1].

The radical nature of the catalytic cycle is exhibited nicely in an article on JACS this week. [1] The reaction is an atom-transfer radical addition. These types of reactions have proved to be very useful in natural product and polymer synthesis.


Figure 3. The Mechanism of the atom transfer reaction. Taken from Ref. [1].

The group has chosen a number of chemical entities who are ‘attached’ to the olefins. Other than their potential utilities, the rationale why these particular chemical functionalities are chosen can be explained by a consideration of the mechanism. In the presence of a visible light source, the Ir3+ salt enters an excited state. Upon the encounter with the halo-substituted substrate, it will lead to the generation of the single-electron organic intermediate, which is nicely stabilized by the electron-withdrawing group present in the substrate. These radical intermediate then adds to the olefin to generate the next reactive intermediate of the reaction pathway. The final addition of the departed halide leads to the ‘atom-transferred’ product.


Figure 4. The potential utilities of the reaction. Taken from Ref. [1].

The group has demonstrated the potential utilities of their approach. They succeed in the installation of a trifluoromethyl (CF3) to acyclic alkenes. As CF3 group has proved to be an important functionality in drug synthesis, a general development of this methodology will prove to be beneficial. Another use is the formation of stabilized cyclopropanes. While they are useful in their own rights, they also represent good precursors for useful chemical transformations such as [3+2] cycloadditions.

References:

1. Intermolecular Atom Transfer Radical Addition to Olefins Mediated by Oxidative Quenching of Photoredox Catalysts
John D. Nguyen, Joseph W. Tucker, Marlena D. Konieczynska, and Corey R. J. Stephenson
J. Am. Chem. Soc. 2011
dx.doi.org/10.1021/ja108560e

2.Visible-light-mediated conversion of alcohols to halides
Chunhui Dai,Jagan M. R. Narayanam& Corey R. J. Stephenson
Nature Chemistry 2011
doi:10.1038/nchem.949

Also see:

http://emockscience.blogspot.com/2011_01_01_archive.html

3. (a) Visible Light-Mediated Intermolecular C−H Functionalization of Electron-Rich Heterocycles with Malonates
Laura Furst, Bryan S. Matsuura, Jagan M. R. Narayanam, Joseph W. Tucker and Corey R. J. Stephenson
Org. Lett., 2010, 12 (13), P. 3104–3107

(b) Visible-Light Photoredox Catalysis: Aza-Henry Reactions via C−H Functionalization
Allison G. Condie, Jos C. Gonzlez-Gmez and Corey R. J. Stephenson
J. Am. Chem. Soc., 2010, 132 (5), pp 1464–1465

(c) Electron Transfer Photoredox Catalysis: Intramolecular Radical Addition to Indoles and Pyrroles
Joseph W. Tucker, Jagan M. R. Narayanam, Scott W. Krabbe and Corey R. J. Stephenson
Org. Lett., 2010, 12 (2), pp 368–371

(d) Electron-Transfer Photoredox Catalysis: Development of a Tin-Free Reductive Dehalogenation Reaction
Jagan M. R. Narayanam, Joseph W. Tucker and Corey R. J. Stephenson
J. Am. Chem. Soc., 2009, 131 (25), pp 8756–8757

Re-constructing Alcohols

Figure 1. The Iridium Catalyst used in the study. Taken from Ref. [1].

The impressive work of the week is from Professor M.J. Krische’s group, for which some of their works in Redox Coupling have been covered before in my article ‘Atom Economy’ [1]. Published in Nature Chemistry, they have succeeded in coupling methanol (CH3OH) to the structurally intriguing allene to afford a number of higher alcohols [2]. They have used similar iridium catalysts to carry out a number of carbon-carbon coupling reactions recently [3].


Figure 2. Ir-catalysed C-C coupling of methanol to allene. Taken from Ref. [1].

Methanol (CH3OH), the simplest alcohol (alkanol) of all, is indeed a very useful precursor in many industrial processes, and the best examples are the Monsanto process and the Cativa process. In most circumstances, the reactive portion of a methanol molecule is AT the oxygen end. Krische et.al. has demonstrated that the carbon end can indeed become reactive and carry out a carbon-carbon coupling with an allene under Iridium catalysis. The significance of this is two fold. The coupling reaction leads to the generation of a quaternary carbon center, and more importantly, the fact that methanol reacts at the carbon end represents a C-H activation process of an usually ‘inert’ methanol molecule. This latter significance is clearly something worth looking further into. Of course, this reaction is atom-economical.


Figure 3. The proposed mechanism. Taken from Ref. [1].

The catalytic cycle [1] commences when methanol enters and displaces the allyl ligand in the Iridium pre-catalyst. Through the formation of the O-Ir bond, a dehydrogenation occurs and the bound methanol is converted into formaldehyde. The formaldehyde is detached from the catalyst at this stage, and it will ‘come back’ in the later part of catalysis. The vacant site created by the departure of formaldehyde is taken up by the allene substrate, which forms an allylic iridium intermediate (via η-3 interaction). It is at this stage the formaldehyde comes back to the catalytic cycle, and the addition of the nucleophilic iridium intermediate to formaldehyde affords the precursor of the final product. The product is liberated from the catalytic cycle by methanol.

The coverage from the RSC Chemistry World Website gives further insights and perspectives from that of Professor Krische [4].

http://www.rsc.org/chemistryworld/News/2011/February/27021101.asp

Note Added: on 4th March 2011, a new publication from the same group appears on Angew. Chemie. Int. Ed., using a similar Iridium Catalyst.

Enantioselective Iridium-Catalyzed Vinylogous Reformatsky-Aldol
Reaction from the Alcohol Oxidation Level: Linear Regioselectivity by
Way of Carbon-Bound Enolates
Abbas Hassan, Jason R. Zbieg, and Michael J. Krische
Angew. Chemie Int. Ed. 2011
DOI : 10.1002/anie.201100646


References:

1. http://emockscience.blogspot.com/2010/06/c-6-carbons-12-carbons-18-carbons-waste.html

2. Iridium-catalysed direct C–C coupling of methanol and allenes
Joseph Moran, Angelika Preetz, Ryan A. Mesch and Michael J. Krische
Nature Chemistry
Published online 27 February 2011
DOI: 10.1038/NCHEM.1001

3. For recent examples of the use of similar Ir catalysts in C-C coupling reactions, see:

(a) Synthesis of the Cytotrienin A Core via Metal Catalyzed C-C Coupling
Michael Rössle, David J. Del Valle, and Michael J. Krische, Org. Lett. 2011, ASAP.
DOI: 10.1021/ol200160p

(b) Total Synthesis of (+)-Roxaticin via C-C Bond Forming Transfer
Hydrogenation: A Departure from Stoichiometric Chiral Reagents, Auxiliaries,
and Premetalated Nucleophiles in Polyketide Construction
Soo Bong Han, Abbas Hassan, In Su Kim, and Michael J. Krische
J. Am. Chem. Soc., 2010, 132 (44), 15559.

(c) Iridium-Catalyzed anti-Diastereo- and Enantioselective Carbonyl (Trimethylsilyl)allylation from the Alcohol or Aldehyde Oxidation Level
Soo Bong Han, Xin Gao, and Michael J. Krische
J. Am. Chem.Soc. 2010, 132, 9153.

(d) anti-Diastereo- and Enantioselective Carbonyl (Hydroxymethyl)allylation from the Alcohol or Aldehyde Oxidation Level: Allyl Carbonates as Allylmetal Surrogates
Yong Jian Zhang, Jin Haek Yang, Sang Hoon Kim, Michael J. Krische
J. Am. Chem. Soc. 2010, 132, 4562.

(e) Iridium-Catalyzed Hydrohydroxyalkylation of Butadiene: Carbonyl Crotylation
Jason R. Zbieg, Takeo Fukuzumi and Michael J. Krische
Advanced Synthesis and Catalysis 2010, 352, 13-15, 2416.

(f) 1,n-Glycols as Dialdehyde Equivalents in Iridium-Catalyzed Enantioselective Carbonyl Allylation and Iterative Two-Directional Assembly of 1,3-Polyols†
Yu Lu, In Su Kim, Abbas Hassan, David J. Del Valle and Michael J. Krische
Angew. Chem. Int. Ed. 2009, 48, 27, 5018.

4. http://www.rsc.org/chemistryworld/News/2011/February/27021101.asp

Without Losing It

Figure 1. The concept from Stoltz et. al. Taken from Ref. [1].

This week sees 2 nice publications for which the synthetic methods concerned have strong potentials as tools in diversity-oriented synthesis (DOS).

The first work, from Prof. Stoltz’s group, pivots on a ring contraction reaction from a 7-membered cycloheptenone to a 5-member acyl-cyclopentenone (Figure 1) [1]. The 7-membered ring precursor is made by a decarboxylative alkylation, catalyzed by Pd(0). An important aspect of the reaction is that a new quaternary, stereogenic carbon center is generated in the process. Asymmetric methods that enable the generations of quaternary carbon centers are highly sought after, and many efforts towards their catalytic versions are also investigated.


Figure 2. The ring contraction. Taken from Ref. [1].

The ring contraction is carried out by LiOH to generate the 5-membered ring (Figure 2). Albeit its simple chemical structure, the 5-membered ring is indeed heavily functionalized and it shows a diverse array of possible reactivities, which is described in Figure 3. A personal observation is that the ‘skipped’ diene should also enable some forms of metal-catalyzed (di)-functionalizations to generate new rings, and the diene also has strong potential to engage in metathesis reaction.


Figure 3. The versatility of the acylcyclopentenone. Taken from Ref.[1].

Stoltz’s results in Figure 3 should convince us that a number of structurally-diverse products can indeed be generated from this common precursor.



Figure 4. The concept of Müller's work. Taken from Ref. [2].

The second work is from Prof. Müller’s group (Figure 4) [2]. They generate a ynedione from a 2-step procedure. Starting with an aromatic heterocycle, they make the intermediate ‘glyoxylyl chloride’ with oxalyl chloride. Then they carry out a Castro- Stephens coupling with Cu(I) catalysis to afford the ynedione (Figure 5). Worthy of note is the contrasting result in a decarboxylative Sonogashira coupling ((which involves a Pd(0) / Cu(I) system), to yield a single-carbonyl ynone instead.


Figure 5. The synthesis of ynedione. Taken from Ref. [2].

The densely functionalized ynedione has the potential to generate a variety of diverse chemical structures, for which a number of them are heterocycles (Figure 6).


Figure 6. The versatility of the ynedione. Taken from Ref. [2].

References:

1. Ring-Contraction Strategy for the Practical, Scalable, Catalytic
Asymmetric Synthesis of Versatile g-Quaternary Acylcyclopentenes.
Allen Y. Hong, Michael R. Krout, Thomas Jensen, Nathan B. Bennett, Andrew M. Harned, and Brian M. Stoltz
Angew. Chemie. Int. Ed.
DOI: 10.1002/anie.201007814

2. Three-Component Synthesis of Ynediones by a Glyoxylation/
Stephens–Castro Coupling Sequence
Eugen Merkul, Janis Dohe, Charlotte Gers, Frank Rominger, and Thomas J. J. M üller
Angew. Chemie. Int. Ed.
DOI: 10.1002/anie.201007194

Acid Joke - Redux

Figure 1. Platinum-catalyzed hydroarylation - or is it? Taken from Ref. [1].


Figure 2 . Palladium-catalyzed dioxygenation. Taken from Ref. [2].

If you remember the ‘inside joke’* I told you last week, for which hydrochloric acid might have the potential to replace all the precious gold catalysts, then it has clearly hit the spot. The 2 articles I am showing you share exactly this concern. Both publications ask the same question: when we are talking about a metal catalyst (platinum and palladium salts in these cases) participating in alleged catalytic cycles, is it really something else acting as the catalyst instead?

That contender, in many circumstances, is a proton (H+) – which addresses the implication behind my joke. Researchers have long been concerned about the notion that it can be through the generation of a catalytic amount of acid, at some point in the catalytic cycle, that really acts as the true catalyst for the reaction.

Thus the first paper [1], for which a platinum catalyst is supposed to catalyze a hydroarylation reaction (Figure 1), is in fact catalyzed by the protic acid (H+) generated during the catalytic cycle. The second paper [2], which describes a dioxygenation using PhI(OAc)2 as oxidant and Palladium salt as a catalyst. The researchers discover that the generation of acid through the catalytic cycle are again the true ‘magic’ behind the catalysis itself. Upon careful mechanistic studies, that leads to their development of a triflic acid (a strong protic acid)- catalyzed dioxygenation.

For the take home message – it is best for me to quote directly from Professors Bergman and Tilley’s paper – ‘We recommend that thorough control experiments for
acid catalysis become standard protocol for all new reactions of
organometallic catalysts, even when no acid is present in the
starting materials.’ [1] This can indeed save research funding too!

References:

*The line I wrote on Facebook for the 'Acid Test' Article last week –’There is a joke that HCl can replace all the expensive gold catalysts in catalytic reactions, and then there are real Bronsted acid catalysts out there to set things right.’

1. Disambiguation of Metal and Brønsted Acid Catalyzed Pathways for
Hydroarylation with Platinum(II) Catalysts
Miriam A. Bowring, Robert G. Bergman, and T. Don Tilley
Organometallics
dx.doi.org/10.1021/om2000458

2. The Nature of the Catalytically Active Species in Olefin Dioxygenation with PhI(OAc)2: Metal or Proton?
Yan-Biao Kang and Lutz H. Gade
J. Am. Chem. Soc.
dx.doi.org/10.1021/ja110805b

A Very Long Engagement

Figure 1. Phosphorescence. (Taken from Ref. [1])

The topic of the week concerns a photolumiscent phenomenon known as ‘phosphorescence’ (Figure 1). While it is related to fluorescence, it has a major difference that it does not re-emit the radiation it absorbs immediately. The reason behind this delay is down to quantum mecahincs, and that is associated with the ‘forbidden’ energy state transitions. The key is through a process called ‘intersystem crossing’.*


Figure 2. The theories behind the work. (Taken from Ref. [1])

The diagram in the publication explains the phenomenon in a succinct manner (Figure 2) [1]. It is clear that there is a ‘competition’ between the emissions either as fluorescence or phosphorescence, and they correspond to 2 different energy pathways. The aromatic compound, Br6A, contains a bromo and an aldehyde functional group, which are both triplet-producing. In a disordered, solution state (Figure 2, part a), fluorescence is emitted due to a singlet (S) decay. While some triplets (T) can be generated, they will be lost as vibrations, and no phosphorescence can be emitted. The situation in a crystalline form is different (Figure 2, part b). The singlet decay can be suppressed (no fluorescence emission), and a singlet-to-triplet conversion can lead to the emission of phosphorescence. This can be rationalized by the O…Br interactions among the network of the aromatic molecules – electron density in the oxygen atom on the carbonyl group is delocalized to the outer orbitals of the bromine atom, and this promotes a spin-orbit coupling and leads to intersystem crossing. Unfortunately, while phosphorescence can be achieved, the quantum yield is only modest because of the fast excimer formation, vibrational loss is still prevalent (Figure 2, part c). It is only by dilution of the aromatic compounds for which we can suppress completely the vibrational loss, and leads to intense phosphorescence and achieves a promising quantum yield (Figure 2, part d).


Figure 3. Br6A. (Taken from Ref. [1])

Indeed , phosphorescence is an extremely rare phenomenon in organic compounds.
The research group has shown us that it is possible to incorporate the character of phosphorescence into pure organic compounds by adopting the reasoning describef above. Thus they have shown That Br6A is capable of the emission of phosphorescence with a modest quantum yield. (Figure 3) In order to enhance phosphorescence, they use the dilution strategy to achieve this aim. When the compound is diluted with a reasonably similar compound, dibromobenzene, the quantum yield is enhanced. The similarity of dibromobenzene means that it will not affect the overall crystal stacking of the compoundS. The best quantum yield achieved is close to 55%. [1]


Figure 4. Phosphorescence with different colours. (Taken from Ref. [1])

Another focus of the work is the generation of phosphorescence leading to the emission of different colours.** (Figure 4) This nicely illustrates the relationships between chemical structure and properties. The default Br6A leads to the emission of a green colour. They create 3 more model compounds, with gives rise to 3 different colours. This is rationalized through different electron densities present in the aromatic nuclei.

a. BrC6A (blue) – the original methoxy group is replaced by a less electron-donating alkyl group, which reduces the electron density of the aromatic nucleus.
b. BrS6A (yellow) - a thiol ether is included. This leads to a ‘red shift’.
c. Np6A (orange)– A Naphthyl nucleus is present of a single benzene nucleus, which obviously increases both the electron density and the conjugation length.

Thus by modifications of the chemical structures, one can significantly fine-tune the chemical properties of the compounds, and these changes undoubtly provide insights for useful applications.

Notes:

A good starting point is the Wikipedia page for 'phosphorescence'
http://en.wikipedia.org/wiki/Phosphorescence

*I have to admit that, even in a qualitative manner, this topic is a complex one. The rationale behind all these phenomena warrants a complete article. I do not want to divert the focus from the more intriguing aspects of the research work in this publication. Thus the rationalizations of all the theories behind this work will be based on the perspective of the research workers. Further discussions are welcome.

**Each colour corresponds to a particular wavelength on the electromagnetic spectrum. By figuring out the wavelength of a particular colour, and using the relation E = hf, this can eventually provide information about the electron density of a conjugated organic compound.

Reference:

1. Activating efficient phosphorescence from purely organic materials by crystal design.
Onas Bolton1, Kangwon Lee, Hyong-Jun Kim1, Kevin Y. Lin and Jinsang Kim
Nature Chemistry
Published Online 13 February 2011
DOI: 10.1038/NCHEM.984

The Acid Test

Figure 1.(a) The planar carbocation. (b) The concept of the asymmetric addition described in this work. (c)Asymmetric hydroamination. Taken from Ref. [1]

Bronsted acid catalysis is an interesting field and it is very important. Not only we can achieve useful reactions by the judicious choice of the right counterion, but also asymmetric reactions are possible if we have a chiral counterion as our comrade. On the other hand, the ‘textbook-ish’ planar carbocation intermediate, which is generated either from a SN1 reaction or the electrophilic addition of an acid to an alkene [1], is notorious (literally) because of its planar structure, and the inevitable consequence of generating enantiomeric products in subsequent reactions.

These 2 aspects have led to an impressive achievement of a chiral Bronsted acid calaysis by Professor Toste and his group (Figure 1, 2) [2]. The protagonist is an acid known as ‘dithiophosphoric acid’. The concept is to add a chiral Bronsted acid catalyst to an diene precursor. This results in the generation of a chiral intermediate. Upon the SN2’ reaction that follows, the result is a chiral cyclic product, with the re-generation of the acid catalyst [1,2].


Figure 2. The asymmetric hydroamination. Taken from Ref. [2].

A prime example for this approach is the extremely useful asymmetric hydroamination [1, 2], which are catalyzed by many transition metal salts. An analogous useful reaction, which I also want to draw your attention to, is an hydroarylation reaction involving an ‘indole-allene’ precursor by the acid catalyst (Figure 3) [2]. Allenes have proved to be useful building blocks and the work of the catalyst leads to the useful tricyclic structure, with the double bond intact for further manipulations. As always, the group has carried out further experiments to verify the mechanisms [2].


Figure 3. Useful indole analogue sythesis. Taken from Ref. [2].

The Toste group has also carried out innovative ‘chiral counterion’ catalysis with transition metal salts in their past research [3], and this publication is indeed relevant to their engagements in that field, too.

-Ed Law 11/02/2011


This work is covered in a NATURE article by Gaunt in the same issue [1].

References:

1. Organic chemistry: Metals are not the only catalysts
Matthew Gaunt
Nature, 470, 183–185

2. Asymmetric additions to dienes catalysed by a dithiophosphoric acid
Nathan D. Shapiro, Vivek Rauniyar, Gregory L. Hamilton, Jeffrey Wu & F. Dean Toste.
Nature, 470, 245–249.

3. (a) A Powerful Chiral Counterion Strategy for Asymmetric Transition Metal Catalysis.
Gregory L. Hamilton, Eun Joo Kang, Miriam Mba, and F. Dean Toste
Science 2007, 496-499

(b) Chiral Anion-Mediated Asymmetric Ring Opening of meso-Aziridinium and Episulfonium Ions
Gregory L. Hamilton, Toshio Kanai and F. Dean Toste
J. Am. Chem. Soc., 2008, 130 (45), 14984–14986.

Science's Ménage à trois

Figure 1. The allylcarbamate deprotection. The chemical product (green), the Pd microspheres (red) are present in the nucleus (blue). Taken from Ref. [1].

This piece of impressive work involves a grand Ménage à trois of chemistry, biology and materials. The workers carry out Pd(0)-catalyzed reactions in a cell, using an heterogeneous Pd(0) catalyst.

They use palladium nanoparticles, which are trapped with polystyrene microsphere. This approach can prevent the potential toxicity of palladium towards cells. They load the HeLa cells with fluorescently labeled Pd(0) microspheres. Then, they add in the relevant chemical substrates to test if Pd(0)-catalyzed reaction take place. The 2 reactions they elect to study are: an allylcarbamate deprotection and the Suzuki reaction.

First, for the allylcarbamate deprotection (Figure 2). The chemical substrates are lipophilic, which means they are capable of crossing the cell-membrane to the intracellular regions. They are also non-fluorescent. The curious aspect is that if the reactions do occur, they will be ‘unlocked’ and become fluorescent. As the fluorescent chemical products are retained within the cell, we will be able to observe these compounds using both Fluorescene and confocal microscopy.

For example, the allylcarbamate cleavage will lead to the liberation of the amino group in compound 2 – and the electron density of the amino group will set up the π-electron conjugation in the product structure. (Figure 2) We will observe the fluorescent emission at 521 nm. Indeed, a confocal microscopy image shows the presence of both the product 2 and the Pd(0) microsphere in the cell. (Figure 1)


Figure 2. The concept of the allylcarbamate deprotection. Taken from Ref. [1].

For the Suzuki scenario, it is a bit more intriguing. (Figure 3) The two coupling partners are both lipophilic and non-fluorescent. When they are both internalized into the HeLa cells, loaded with Pd(0) microsphere, the cross-coupling reaction occurs. Upon the hydrolysis of the lactone moiety, the resultant carboxylate once again sets up the π-electron conjugation of the product, and fluorescene emission occurs. Another interesting aspect, for which cell biologists may be interested, is that the chemical product will localize to mitochondria, due to the presence of the lipophilic cationic triphenylphosphonium group on the structure of the product [2].


Figure 3. The concept of the Suzuki reaction. Taken from Ref. [1].

The confocal microscopy image nicely illustrates this observation. (Figure 4) For the controls, the red colour signifies the mitochondria and the blue signifies the cell nucleus. Upon the Suzuki reaction, the chemical compound is shown in green and it clearly localizes to the mitochondira.


Figure 4. The confocal images for the Suzuki reaction. The diagram on the left is the control, for which the nucleus is shown in blue and the mitochondria is red. For the diagram on the right, the Suzuki reaction has taken place and it is clear that the fluorescent chemical product (green) is localized in the mitochondria of the cell. Taken from Ref. [1].

This work means that further developments will lead to great applications in chemical biology and drug delivery. More importantly, this is a multidisciplinary research project, and is of interest to chemists enthusiastic about catalysis, cell biologists and materials scientists. A truly spectacular piece of work!

-Ed Law 11/02/2011

This work is covered in RSC Chemistry World Website. [3]
http://www.rsc.org/chemistryworld/News/2011/February/06021101.asp

References:

1. Palladium-mediated intracellular chemistry
Rahimi M. Yusop, Asier Unciti-Broceta, Emma M. V. Johansson, Rosario M. Sánchez-Martín & Mark Bradley
Nature Chemistry, 6 February 2011.
doi:10.1038/nchem.981

2. Delivery of bioactive molecules to mitochondria in vivo.
Smith, R. A., Porteous, C. M., Gane, A. M. & Murphy, M. P.
Proc. Natl Acad. Sci. USA 2003, 100, 5407–5412.

3. http://www.rsc.org/chemistryworld/News/2011/February/06021101.asp

Expand the Universe!

Figure 1. Diversity-Oriented Synthesis (DOS). Taken from Ref. [3].

The world of chemical compounds has a parallel to the field of astronomy. The curious ones are never happy about having one universe. The question they always ask is: are there any other universes out there?

The world of chemical compounds resembles that of a chemical ‘space’. Our universe is ‘Nature’. So we are living in a ‘chemical universe’ that includes all the natural products generated from Nature. We rely on these natural products to survive. Organic chemists undertake the challenges of synthesizing these complex molecules. We use these compounds as inspirations to make better drugs. But is that enough? Well, we have taken a step further – we develop analogues of these compounds to improve their biological activities. The next question would be: can we make compounds that are not present in the ‘Natural Product’ Space? Can we expand the ‘chemical space’ using chemistry?

The answer is a resounding ‘yes’, and the way we do it is through the strategy called ‘diversity-oriented synthesis’ (DOS), which is pioneered by Prof. Schreiber at Harvard [1,2]. This week, we have an article in NATURE by Spring et. al. [3]. In the article, they describe and emphasize the potential of using DOS to expand the chemical space. Figure 1 [3] illustrates the promise of DOS. From a common ‘intermediate’, which is densely functionalized, we can use a number of distinct strategies (chemical reactions) to arrive at a number of different ‘drug-like compounds’. The example shown in Figure 1 is indeed an exemplary one. As we will notice, the 3 ‘drug-like compounds’ that are generated from the common ‘intermediate’ have very distinct chemical structures (skeletons), which is exactly the promise DOS offers. Even in a non-DOS setting, it is still possible to generate chemical structures which are distinct to each other - if they are formed via mechanistically different reaction pathways. What DOS stresses about is the promise that chemical structures (skeletons) which are not present in the 'natural-product' world can be synthesized.

On the other hand, the Fragment-based screening (FBS) strategy in the diagram is not at all problematic – that is something that we have been adopting all the time when we are developing new reactions. The fact is just that when both strategies are placed side-by-side, DOS seems to offer a more diverse repertoire of chemical structures. While the retrosynthetic strategy is about a logical analysis of a synthetic problem towards a starting precursor, DOS is working in the opposite direction: we are working form the starting precursor to a diverse array of possible chemical structures.

Diversity-oriented synthesis (DOS) is an engagement in creativity and imagination, with the ultimate aim to explore and expand the ‘chemical space’ we are yet to discover. Expand your universe!

-by Ed Law 4/2/2011


To see an impressive example of DOS by Schreiber et. al., see the following Wikipedia page [4,5]:

http://en.wikipedia.org/wiki/Divergent_synthesis

Reference:

1. In this article I would like to focus on the potential of generating novel chemical structures by diversity-oriented synthesis (DOS). In the perspective of the pharmaceutical industry, DOS is not the most common way of generating lead compounds for screening. This is due to the vast variety of distinct chemical structures that will render the compound libraries less systematic and organized for screening studies. Nevertheless, DOS is a strategy that calls for further exploration in the industry, because we can generate compounds with novel biological properties not present in ‘natural product-like’ compounds.

2. (a)A Planning Strategy for Diversity-Oriented Synthesis. Martin D. Burke and Stuart L. Schreiber Angew. Chemie. Int. Ed. 2003, 43, 1, 46–58. (b) For some recent examples, see: (i)Expanding Stereochemical and Skeletal Diversity Using Petasis Reactions and 1,3-Dipolar Cycloadditions Giovanni Muncipinto, Taner Kaya, J. Anthony Wilson, Naoya Kumagai, Paul A. Clemons, and Stuart L. Schreiber. Org. Lett., 2010, 12 (22), P. 5230–5233; (ii) Gold(I)-Catalyzed Coupling Reactions for the Synthesis of Diverse Small Molecules Using the Build/Couple/Pair Strategy. Tuoping Luo and Stuart L. Schreiber. J. Am. Chem. Soc., 2009, 131 (15), P. 5667–5674

3. Drug discovery: A question of library design. Philip J. Hajduk, Warren R. J. D. Galloway & David R. Spring. Nature 2011, 470, 42–43.

4. http://en.wikipedia.org/wiki/Divergent_synthesis

5. The original reference: Short Synthesis of Skeletally and Stereochemically Diverse Small Molecules by Coupling Petasis Condensation Reactions to Cyclization Reactions Naoya Kumagai, Giovanni Muncipinto, Stuart L. Schreiber. Angew. Chemie. Int. Ed. 2006, 45, 22, 3635-3638.

Know Your Next Move

Figure 1. The scans that explain it all. (Taken from Ref. [1]).

The cognitive understanding of how someone solves a problem is a fascinating question. This SCIENCE paper serves as a nice example. The investigators used MRI to study the cognitive properties of Shogi players. [1] Shogi is a type of Japanese chess game. It was known that master chess players tend a have strong ‘pattern recognition’ ability in these games [2]. Since these expert players are very sensitive to the different patterns on the chess board, they have a better prospect of deciding the best ‘next move’.

The reason why I am interested is because there is often an analogy between playing chess and planning in organic synthesis. This is really the ‘problem-solving skill required by an organic chemist. Professor Corey’s ‘Retrosynthetic Analysis’ [3], for which he was awarded a Nobel Prize, represents an extremely logical way to look at a hard synthetic problem. In essence we start from the target molecule and ask the question, ‘how can we lead from a simpler X to this target molecule?’ When we have found out the identity of X, we repeat the question iteratively until it reaches a final X, for which the chemical structure is simple enough. Every time we ask the question, we are ‘deciding on our next move’ as in the game of chess. Indeed, there are good computer algorithms for retrosynthetic planning.

What intrigues me is the cognitive properties behind this engagement – why do certain ‘total synthesis gurus’ can devise neat and effective methods, or even ingenious cascade reactions to the seemingly insurmountable targets, while others struggle on pieces of papers and seems to get to nowhere?

As in the cases for chess and shogi, are some form of ‘pattern recognition’ mechanisms operating in those synthetic masterminds’ situations? To the best of my knowledge this sounds like a relatively unexplored area and the implications will be extremely interesting!

References:

1. The Neural Basis of Intuitive Best Next-Move Generation in Board Game Experts
Xiaohong Wan
Science Vol. 331 no. 6015 pp. 341-346
DOI: 10.1126/science.1194732

2. Instant Notes in Cognitive Psychology P.117
Jackie Andrade, Jon May
Taylor & Francis

3. The Logic of Chemical Synthesis
E. J. Corey, Xue-Min Cheng
Wiley-Blackwell

Iron Lady

Figure 1. The Iron Catalyst used in Ref. [4]. (Taken from Ref. [4])

I have a strong interest in Prof. M. Christina White’s work (University of Illinois) for quite some time. My very first fascination in her research originated from an impressive Science paper back in 2007[1]. What they have achieved in that investigation was that they enabled C-H oxidations of organic substrates using an iron catalyst. These represent examples of C-H activations, and are full of cytochrome P450 undertones. An ‘alter ego’ of her chemistry resides in the use of a Pd(II) system – with the theme of C-H activation intact. This catalyst leads to various useful reactions from allylic aminations {2} to oxidative Heck reaction [3].

On NATURE CHEMISTRY this week, the group has developed a nice iron hydroxylation catalyst to carry out useful organic transformations (Figure 2). The idea is biomimetic, which means that is inspired by Nature. [4]


Figure 2. Diversification with an Iron catalyst. (Taken from [4]).

The idea is as follows. One single ‘non-haem’ iron enzyme is capable of doing a number of diverse reactions. The rationale behind this versatility is that the enzyme can direct the ‘radical intermediates’ from the reactions towards different reaction pathways (i.e. different reaction outcomes) with active site control and substrate modifications. [4] Thus the group has ‘diverted ‘ their designed iron catalyst to 2 specific types of reactions – hydroxylase / desaturation reactions with aliphatic C-H bonds as substrates. This also operates via substrate control -the presence of a carboxylic acid functionality is required. Not only have they probed and gained insight about the inner mechanisms, they have also employed the iron catalyst to diversification of natural products.

On Thursday (27th Jan 2011) there was also an advance article of the group from Angew Chemie. Int. Ed. (Figure 3) [5] They have discovered that even without preorganizations, they use a macrocyclization reaction, either a Yamaguchi esterification or their Pd (II)-catalyzed C-H Oxidation strategy, towards the natural product erythromycin, a popular target in the synthetic community.


Figure 3. Macrocyclizations without biasing elements. (Taken from [5]).

References:

1. A Predictably Selective Aliphatic C–H Oxidation Reaction for Complex Molecule Synthesis
Mark S. Chen and M. Christina White
Science 318, 783 (2007)
DOI: 10.1126/science.1148597

2. For some recent examples, see:
(a) Diversification of a β-lactam pharmacophore via allylic C-H amination: accelerating effect of Lewis acid co-catalyst.
X. Qi, G. T. Rice, M. S. Lall, M. S. Plummer, M. C. White
Tetrahedron, 2010, 66, 4816

(b) Allylic C-H Amination for Preparation of syn-1,3-Amino Alcohol Motifs."
G.T. Rice and M.C. White
J. Am. Chem. Soc. 2009, 131, 11707
DOI: 10.1021/ja9054959

3. "A General and Highly Selective Chelate-Controlled Intermolecular Oxidative Heck Reaction."
J.H. Delcamp; A.P. Brucks; and M.C. White
J. Am. Chem. Soc. 2008
DOI: 10.1021/ja804120r

4. Diverting non-haem iron catalysed aliphatic C–H hydroxylations towards desaturations
Marinus A. Bigi, Sean A. Reed & M. Christina White
Nature Chemistry
doi:10.1038/nchem.967
Published online: 23 January 2011

5. On the Macrocyclization of the Erythromycin Core: Preorganization is Not Required
Erik M. Stang and M. Christina White
Angew. Chemie. Int. Ed.
DOI: 10.1002/anie.201007309
Article first published online: 27 Jan 2011

The Magnificent Six

Figure 1. 3 Numbers, 1 Reaction. (Taken from Ref. [1])

Publications about synthetic concepts are always good, and it is better if their uses can lead to useful, complex structures – a polycyclic system is a good contender. This from group China has demonstrated a nice strategy of making complex , polycyclic scaffolds with Tsuji-Trost style chemistry , catalyzed by Pd(0) catalyst [1]. Figure 1 nicely illustrates how synthons with 3, 4, or 6 carbon atoms can be achieved by Pd(0) catalysis [1]. Worthy of note is the 4-C Synthon scenario. The ‘TMM’ approach has proved to be a classic example for transition metal-catalyzed cycloaddition [2].


Figure 2. Linking 2 rings with a molecular bridge (Path b). (Taken from Ref. [1])

How the researchers use the 6-C synthon for synthesis is nicely shown in Figure 2 [1]. What it really does (path b) is making a fused bicyclic system by creating a ‘chemical link’, rather than stitching 2 rings together (path a).

Thus they allow Compound 3 to react in a double Tsuji-Trost manner to give Comoiund 16 (Figure 3). Compound 16 sets the stage for a double Diels-Alder Reaction with DMAD as the dienophile. The result is the beautiful, symmetric system 17. This double Tsuji-Trost approach should be further developed for synthetic uses.


Figure 3. The symmetric craft - the synthesis of a polycyclic system. (Taken from Ref. [1]).

References:

1. New strategy to construct fused/bridged/spiro carbocyclic scaffolds based on the design of novel 6-C synthon precursor Jia Liu, Xi Wang, Chang-Liang Sun, Bi-Jie Li, Zhang-Jie shi and Min Wang
Org. Biomol. Chem., 2011, Advance Article
DOI: 10.1039/C0OB00660B

2. Some examples:
(a) B. M. Trost and D. M. T. Chan, J. Am. Chem. Soc., 1979, 101, 6429; (b) B. M. Trost, T. N. Nanninga and T. Satoh, J. Am. Chem. Soc., 1985, 107, 721; (c) B. M. Trost and D. T. MacPherson, J. Am. Chem. Soc., 1987, 109, 3483; (d) B. M. Trost, Pure Appl. Chem., 1988, 60, 1615

A Tale of 2 Cycles

Figure 1. 2 catalytic cycles crossing path – the plan. (Taken from Ref. [2])

If you have read my article on ‘Atom Economy’ before [1], you should see why this publication by Professor Trost’s group is fascinating[2]. The article asks the question: what will happen when 2 useful catalytic cycles cross path (Figure 1) [2]?


Figure 2. Sum is greater than the parts – the work of 2 catalysts to provide useful structures. (Take from Ref. [2])

While one may speculate a myriad of products is the result, the group has shown us that by careful design the outcome can be extremely useful (Figure 2) [2]. By using a vanadium catalyst for the atom-economical Meyer-Schuster type reaction [3], and a Palladium catalyst for the Tsuji-Trost reaction. By combining the 2 catalytic cycles together, useful ‘allylated, α, β-unsaturated ketones’ can be achieved (Figure 2, 3) [2]. Figure 3 shows the 3 possible scenarios involving the 2 intriguing catalytic cycles [2]. This should serve as great inspirations for multi-catalytic reactions.


Figure 3. The products formed from using one / both of the catalysts. (Taken from Ref. [2])

Reference:

1. For my article ‘Atom Economy’ on 13th June 2010, please see:
http://emockscience.blogspot.com/2010/06/c-6-carbons-12-carbons-18-carbons-waste.html

2. Contemporaneous Dual Catalysis by Coupling Highly Transient Nucelophilic and Electrophilic Intermediates Generated in Situ
Barry M. Trost and Xinjun Luan
Journal of America Chemical Society
DOI: 10.1021/ja110501v

3. Victorio Cadierno, Pascale Crochet, Sergio E. García-Garrido, José Gimeno
Dalton Trans., 2010, (17),4015-4031

Aromatic String Pullers

Figure 1. The dehydrogenative rearrangement to give aromatic systems by the Shi group. Taken from Ref. [1].

This article from Professor Shi’s group shows a number of innovations. Firstly, it reiterates the synthetic potential of cyclopropene, not only as a 3-carbon building block but also as an allylic disguise , when interacting with a metal such as palladium. Secondly, the simple precursor is capable of a dehydrogenative arrangement under palladium catalyst, forming benzene derivatives as a result, and lose H2 gas as a side-product. Dehydrogenative reactions involving transition metal catalysis is a hot area in current organic synthesis. When the structure of the starting precursor is complex, interesting polycyclic compounds form as a result.

Reference:

1. Preparation of Di-μ-chlorobis[π-1-chloro-1-aryl-2-(2′,2′-diarylvinyl)allyl]palladium(II) Complexes and a Novel Dehydrogenative Rearrangement of Arylvinylcyclopropenes for the Synthesis of 7H-Benzo[c]fluorene Derivatives
Zhi-Bin Zhu, Kai Chen, Yin Wei, and Min Shi
Organometallics, DOI: 10.1021/om1009846

Bioinorganic Wonder

Figure 1. Oxidative coupling. Taken from Ref. [1].

This is a bioinorganic reaction, and this is potentially important even for synthetic chemistry. The oxidative coupling reaction catalyzed by the enzyme tyrosinase and the di-copper center is impressive (Figure 1) [1]. Given that cyclo-peptides are biologically important synthetic targets, further developments of these oxidative coupling strategies should be desirable. We can imagine the tyrosinase as some form of chiral ligands. Two possible questions to ask is : (1) Can we control the stserochemistry of α-carbon using a chiral catalyst and (2) Can we expand the scope of substrates, e.g. having a side-chain with an oxygen rather than a sulphur?

Reference:
1. Post-Translational His-Cys Cross-Linkage Formation in Tyrosinase Induced by Copper(II)−Peroxo Species
Nobutaka Fujieda, Takuya Ikeda, Michiaki Murata, Sachiko Yanagisawa, Shigetoshi Aono, Kei Ohkubo, Satoshi Nagao, Takashi Ogura, Shun Hirota, Shunichi Fukuzumi, Yukihiro Nakamura, Yoji Hata, and Shinobu Itoh
J. Am. Chem. Soc.
DOI: 10.1021/ja108280w

Photoredox Catalysis - The Wonder of Visible Light

Figure 1. Work from the Liu group. Taken from Ref. [1].

The first 2 articles we are looking at this week are published as advance articles in Nature Chemistry [1, 3]. Both are very innovative work and there is a link between them. We will first take a look at the investigations and then look into the link – namely Photoredox catalysis.


Figure 2. The new reaction discovery by the Liu group. Taken from Ref. [1].

The first one is chemical biology carried out by Prof. David Liu’s group at Harvard (Figure 1,2). The innovative strategy of discovering novel chemical reactions blends chemistry and biology strategies (PCR) together [1]. They have developed a ‘DNA-templated reaction discovery system’ [1]. If the 2 reactants have a bond-formation process taken place (there is a reaction), an ‘in vitro selection, PCR Amplification and DNA microarray analysis’ will that specific combinations [1]. In this attempt they have succeeded in identifying the Ru (II)-catalyzed azide reduction protocol to amine, which was catalyzed by visible light. This methodology has the added advantage it is compatible at physiological conditions, which means that it can serve as a useful tool for synthesis concerning macromolecules.

The second one is carried out by Prof. Corey Stephenson’s group [3]. The conversion of an alcohol into an alkyl halide with triphenylphosphine is known as an Appel reaction. The mechanistic minds should immediately notice the inevitable formation of triphenylphosphine oxide – remember this fella from my article ‘Atom Economy’ back in June 2010? [2]

Stephenson’s group counteracted against this issue by using a Ruthenium salt and visible light as the catalyst (Figure 3)[3]. In the presence of the halide source (e.g. iodoform), the alkyl halide can be made with inversion of stereochemistry. But without the infamous phosphine oxide fella this time! This work is covered in an article of RSC Chemistry World [4].


Figure 3. Stephenson's Appel reaction. Taken from Ref.[3].

The common link is the photoredox catalysis involved, with the use of an interesting Ruthenium salt (Figure 3). In the presence of visible light, the Ru (II) salt is sensitized to a Ru(II)* state. With the further loss of an electron, Ru (III) is formed and the whole process is known as an oxidative quenching cycle. When Ru (III) is reduced back to Ru (II), this will enable the organic substrate to carry out an oxidation reaction, and continues further into the mechanistic sequences [1, 3]. The advantage of using visible light as a catalyst means that it can be developed as a green method of synthesis.

Indeed, this type of photocatalysis has been a hot area in synthetic chemistry. A recent JACS advance articles illustrates this notion. The reaction represents a cycloaddition of a linear precursor into a fused cyclopentane system, under photoredox catalysis and the presence of a Lewis Acid. It also illustrates the use of a cyclopropane as a 3-carbon building block (Figure 4) [5].


Figure 4. Yoon's cyclopentane synthesis. Taken from Ref. [5].


Prof. David MacMillan has also done impressive work in cascade organocatalytic work with the involvement of photoredox catalysis, employing both Ruthenium and Iridium salts (Figure 5)[6].


Figure 5. A nice example of MacMillan's organocatalytic synthesis. Taken from [6a].

Reference:
1. A biomolecule-compatible visible-light-induced azide reduction from a DNA-encoded reaction-discovery system
Yiyun Chen,Adam S. Kamlet,Jonathan B. Steinman& David R. Liu
Nature Chemistry 2011
doi:10.1038/nchem.932

2. For my article on ‘Atom Economy’ on 13/6/2010 see:
http://emockscience.blogspot.com/2010/06/c-6-carbons-12-carbons-18-carbons-waste.html

3.Visible-light-mediated conversion of alcohols to halides
Chunhui Dai,Jagan M. R. Narayanam& Corey R. J. Stephenson
Nature Chemistry 2011
doi:10.1038/nchem.949

4. The coverage in RSC Chemistry World:
http://www.rsc.org/chemistryworld/News/2011/January/09011101.asp

5. [3+2] Cycloadditions of Aryl Cyclopropyl Ketones by Visible Light Photocatalysis
Zhan Lu, Meihua Shen, and Tehshik P. Yoon
J. Am. Chem. Soc.
DOI: 10.1021/ja107849y

6. (a) Enantioselective α-Benzylation of Aldehydes via Photoredox Organocatalysis
Hui-Wen Shih, Mark N. Vander Wal, Rebecca L. Grange, and David W. C. MacMillan
J. Am. Chem. Soc., 2010, 132 (39), pp 13600–13603
DOI: 10.1021/ja106593m

(b) Enantioselective α-Trifluoromethylation of Aldehydes via Photoredox Organocatalysis
David A. Nagib, Mark E. Scott and David W. C. MacMillan
J. Am. Chem. Soc., 2009, 131 (31), pp 10875–10877
DOI: 10.1021/ja9053338

(c) Merging Photoredox Catalysis with Organocatalysis: The Direct Asymmetric Alkylation of Aldehydes
David A. Nicewicz and David W. C. MacMillan
Science 3 October 2008: 77-80
DOI:10.1126/science.1161976