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.