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

Biological Computing

Figure 1. Taken from Ref. [1].

2 latest NATURE papers on biological logic gates, or biological computing [2, 3]. The logics behind them look more sophisticated!

These works are covered in a NATURE coverage. [1]

References:

1. Synthetic biology: Division of logic labour
Bochong Li & Lingchong You
Nature 469, 171–172 (13 January 2011)
doi:10.1038/469171a

2. Distributed biological computation with multicellular engineered networks
Sergi Regot, Javier Macia, Núria Conde, Kentaro Furukawa, Jimmy Kjellén, Tom Peeters, Stefan Hohmann, Eulàlia de Nadal, Francesc Posas & Ricard Solé
Nature 469, 207–211 (13 January 2011)
doi:10.1038/nature09679

3. Robust multicellular computing using genetically encoded NOR gates and chemical ‘wires’
Alvin Tamsir, Jeffrey J. Tabor & Christopher A. Voigt
AffiliationsContributionsCorresponding author
Nature 469, 212–215 (13 January 2011)
doi:10.1038/nature09565

Brief Surveys

Figure 1. Taken from [1].

This article illustrates the synthetic uses of linear N-Chloramines (Figure 1) [1]. Upon the treatment of a suitable base, the resultant azaallyl ions are capable to carry out cycloadditions to give useful pyrrolidine scaffolds. The azaallyl ion is also a disguise for an imine, which has the potential to carry out useful allylation reactions. It is intriguing to note that certain bases do not work well for these N-chloramines, as suggested by the workers.

Another one on the same issue of Tetrahedron Letters. Ever think of using chiral azo compounds (yes – that azo dye you have encountered in A-Level) to synthesize enantiopure amino acids (Figure 2, 3) [2]?


Figure 2. Taken from [2].


Figure 3. Taken from [2].

Reference:
1. Preparation of 2-azaallyl anions and imines from N-chloroamines and their cycloaddition and allylation
Shveta Pandiancherri, David W. Lupton
Tetrahedron Letters 52 (2011) 671–674

2. Chiral azo compounds: enantioselective synthesis and transformations into
β-amino alcohols and α-amino acids with a quaternary stereocenter
Friedrich R. Dietz, Agnes Prechter, Harald Gröger, Markus R. Heinrich
Tetrahedron Letters 52 (2011) 655–657

Don’t do this at home!

A commentary for the Nature Journal Article
Legal highs: the dark side of medicinal chemistry
David Nichols
Published online 5 January 2011
Nature 469, 7 (2011)
doi:10.1038/469007a

http://www.nature.com/news/2011/110105/full/469007a.html

E : -
Ever wonder where that intense, sour smell comes from? Well, it can just be someone making drugs in the neighbourhood! You have definitely seen this in films, and the scenario is indeed true – some ‘undercover chemists’ do synthesize drugs for illegal purposes. Evert heard of the ‘red, white and blue processes? Governments have taken measures to counteract against these unspeakable ingenuities: that is why common people cannot buy some of the the possible chemical precursors (in the form of tablets) in the Pharmacy or they need strict prescription. Yet the irony is down to the fact the bad guys are often wise (and vice) and they can then come up with other different synthetic routes – that depends on whether they have the chemistry brain, or with a novel production method. This is going to be a long war.
So, even I can convince you that you can make barbiturate in your kitchen with the correct chemical starting materials, a saucepan, a sealed pack of ice and an edition of Vogel, this type of adventure is extremely dangerous and illegal. Just don’t do this at home!

P.S. Love the title ‘Legal HIGHS’.

Biological Logic Gate III: PCR

Figure 1. Taken from Ref. [1].

The passion of biological logic gates does not cease – at least that also catches NATURE’s attention [1]! Very creative work – a ‘PCR’ type logic gate triggered by the presence of metal ions [2]. The 2 inputs are the presence of 2 different metal ions (Hg2+ , Ag2+). If the metal ion triggers the respective polymerase action, PCR products will be formed and the output can be observed on the fluorescence intensity from gel electrophoresis. The group has achieved an ‘All-or-none’, an ‘AND’ and an ‘OR’ gate so far. This work and some previous ones should again stress the interesting concept of nucleic acid : metal ion interactions and its specificity issues. As suggested, this is ‘molecular computing’ [1] in action.

Reference:

1. Molecular computing: DNA as a logic operator
Thomas Carell
Nature 469, 45–46 (06 January 2011)
doi:10.1038/469045a
http://www.nature.com/nature/journal/v469/n7328/full/469045a.html#/references

2. “Illusionary” Polymerase Activity Triggered by Metal Ions: Use for Molecular Logic-Gate Operations
Ki Soo Park, Cheulhee Jung, and Hyun Gyu Park
Angew. Chem. Int. Ed. 2010, 49, 9757 –9760
DOI: 10.1002/anie.201004406

Supramolecular wonders

Figure 1. Taken from Ref. [1].

We can definitely not miss this supramolecular achievement of Prof. Anderson’s group [1, 2]. They have built up this wonderful molecular architecture by the strategy of template-directed synthesis, which is a common strategy in supramolecular synthesis (Figure 1, part a). The template used is a Vernier template.

The result of this strategy is elegant (Figure 1, part b). The inner core is a dendrimer, while the outer core is a circular chain, combined with alternating diynes and zinc porphyrins. The inner dendritic core is locked inside the the outer circle via the pyridine N – Zn interactions. The imaginative ones should surmise that the assembly resembles a Ferris wheel. Also worthy of note is the meticulous use of palladium-catalysed cross-coupling reaction in the synthesis, for which its pioneers take home the Chemistry Nobel Prizes in 2010. What a blend of molecular beauty and creativity.

Reference:

1. Vernier templating and synthesis of a 12-porphyrin nano-ring
Melanie C. O’Sullivan,Johannes K. Sprafke,Dmitry V. Kondratuk,Corentin Rinfray,Timothy D. W. Claridge,Alex Saywell,Matthew O. Blunt,James N. O’Shea,
Peter H. Beton,Marc Malfois& Harry L. Anderson
Nature 469, 72–75
doi:10.1038/nature09683

2. The work is also covered in an article:
Supramolecular chemistry: Bigger and better synthesis
Christopher Hunter
Nature 469, 39–41 (06 January 2011).
doi:10.1038/469039a
Read it online:
http://www.nature.com/nature/journal/v469/n7328/full/469039a.html

The Mask

Taken from Ref (1).

This is a brilliant achievement from Prof. Miyaura’s group. (1) The work represents his masterstroke – the use of Rhodium-catalyzed asymmetric conjugate additions in organic synthesis. While the group has always been using boronic acids as the substrates for their system (2), they also advocate for the use of lithium triolborate version for the substrates (3). The impressive enantiomeric excess (ee) serves as a testament to the sophistication of this methodology.
The real reason to share this article is because it also illustrates of good example of using heterocyclic systems in organic synthesis. The furan system is indeed a ‘disguise’ for the carboxylic acid – all we need to unmask it – is to treat furan with ozone. Thus what the group is really driving at is to install the carboxylic acid functionality in a conjugative manner, but then they achieve that via the intermediate furan. Given the readily availability of heterocyclic systems and a well-documented literature, this type of strategy is worthy of note. Indeed, this topic has been reviewed extensively (4,5) and Prof. Myers’ book on the topic is highly inspiring (6). Another great testament to the creativeness of organic chemists.

Reference:
(1) Rhodium-Catalyzed 1,4-Addition of Lithium 2-Furyltriolborates to Unsaturated Ketones and Esters for Enantioselective Synthesis of -Oxo-Carboxylic Acids By Oxidation of the Furyl Ring with Ozone
Xiao-Qiang Yu, Tomohiko Shirai, Yasunori Yamamoto and Norio Miyaura
Chemistry An Asian Journal - Article first published online: 4 JAN 2011
DOI: 10.1002/asia.201000589

(2) For recent works, see: (a) Journal of Organometallic Chemistry, Volume 692, Issues 1-3, 1 January 2007, Pages 428-435; (b) Tetrahedron, Volume 62, Issue 41, 9 October 2006, Pages 9610-9621; (c)J. Org. Chem., 2003, 68 (15), pp 6000–6004; (d) J. Org. Chem., 2001, 66 (26), pp 8944–8946; (e) J. Org. Chem., 2000, 65 (19), pp 5951–5955.

(3) Yu, Xiao-Qiang; Yamamoto, Yasunori; Miyaura, Norio:
Rhodium-Catalyzed Asymmetric 1,4-Addition of Heteroaryl Cyclic Triolborate to α,β-Unsaturated Carbonyl Compounds
Synlett 2009; 2009: 994-998

(4) Michael Shipman Aromatic heterocycles as intermediates in natural product synthesis. Contemp. Org. Synth., 1995, 2, 1-17

(5) Rafael Chinchilla Carmen Nájera, and Miguel Yus. Metalated heterocycles in organic synthesis: recent applications. ARKIVOC 2007 (x) 152-231.

(6) A.I. Meyers, Heterocycles in Organic Synthesis (General heterocyclic chemistry series) (1974) John Wiley & Sons Inc. ISBN-10: 0471600652, ISBN-13: 978-0471600657.

A useful synthetic sequence

Figure 1. From Ref [1].

This is a very useful synthetic sequence for partially saturated piperidines. The reactions can be done in a one-pot manner to furnish a nitrile group (TMSCN) or allyl functionality (Ally-TMS) on the piperidine system. Both of these functionalities have great synthetic potentials: the nitrile can be hydrolyzed to afford carboxylic acid derivatives and the allyl group can be seen as a handle for other transformations (e.g. extension).


Figure 2. From Ref [1].

Asymmetric version is also possible and the authors’ rationale is presented in Figure 2. Note the highly organized transition state to ensure good enantioselectivity.

Reference:
[1]. Synthesis of 1,2,4-trisubstituted-1,2,5,6-tetrahydropyridines
Meng-Yang Chang , Ming-Fang Lee, Nien-Chia Lee, Yu-Ping Huang, Chung-Han Lin
Tetrahedron Letters 52 (2011) 588–591

Caught Red-handed

http://www.economist.com/node/17843620

In order to diagnosize cancer at an earlier stage (benign tumors), a nice approach to 'track down' small tumors is highly sought after. This research group is able to make the tumors 'glow' with the help of a series of virus. The virus can infect the tumor cells and they also have the ability to cause the production of a fluorescent protein. When the virus replicates, more tumor cells will be infected. The result is that these tumor cells glows brighter and brighter, and they can thus be observed using a rather expensive camera (at this stage). While the normal biotechnology employs Green Fluorescent Protein (GFP), green light is not a good choice for the purpose because its frequency is too high for it to travel readily through human tissues. So red the fluorescent protein is chosen instead to carry out this mission (to rationalize, think about the relationship velocity of light = frequency x wavelength). This 'red shift' makes the strategy work - and the tumors are caught RED-handed.

Reference:

The Economist
Making cancer glow away
Jan 4th 2011

A Bio-organometallic Feat

Taken from Reference (1) - from the JACS Website.

What a fascinating bio-organometallic achievment. The star here is a Ruthenium complex, which is known as a Carbon monoxide releasing molecules (CORM) due to its ability to lose (thus deliver) a CO molecule (to set the record straight a glycinate ligand and a chloride ion are also liberated) and the result is a RuII(CO)2 intermediate. This will in turn react with the protein lyzozyme to form a complex, for which its structure was determined by crystallography and also with a number of cutting-edge spectroscopic techniques (including of course LC-MS). CORMs are interesting because they have demonstrated therapeutic potentials for future drugs.

Reference:

(1) CORM-3 Reactivity toward Proteins: The Crystal Structure of a Ru(II) Dicarbonyl−Lysozyme Complex
Teresa Santos-Silva, Abhik Mukhopadhyay, Joo D. Seixas, Gonalo J. L. Bernardes, Carlos C. Romo, and Maria J. Romo
J. Am. Chem. Soc., Article ASAP
Publication Date (Web): January 4, 2011
DOI: 10.1021/ja108820s

Biological Logic Gate II: Electronic GENOsensor

I am quite excited to see yet another biological logic gate article in ChemComm – this time a more biochemical favour. The system is also an AND gate. The inputs are contributed by 2 genes, gyrB and K-ras (this one is a famous oncogene), and the output is presented by the I/V characteristic.


Figure 1. The Basic Principle.

Here is how the system works (Figure 1). At the beginning, the two strands of DNA are restricted in closed loop structures, and they are known as ‘hairpins’. The 2 redox tags (MB and Fc) positioned on them can transfer 2 respective electrons to a proximal electrode (colored in yellow in the figure). If for some reason, the hairpin is released to become a straight strand, the redox tag is too far away to transmit the electron to the electrode, and a decrease in intensity of the I/V plot will be observed. This ‘proximity effect’ is indeed very common in molecular biology, and I believe my biological readers are definitely aware of something called ‘FRET’.

This is where the ‘logic’ comes into play: when the 2 corresponding single-stranded DNA comes to bind with each of this hairpin, the effect will the release of the hairpin and a decrease of I/V will be the output. For course, the output will be ‘1’ if both single-stranded DNAs (inputs) are present to release the two hairpins (outputs). The observed I/V characteristics on Figure 2 clearly illustrates the action of the genosensor. Impressive!


Figure 2. The work of the AND Genosensor.


Reference:

A reagentless and disposable electronic genosensor: from multiplexed analysis to molecular logic gates
Yun Xiang, Xiaoqing Qian, Ying Chen, Yuyong Zhang, Yaqin Chai and Ruo Yuan
Chem. Commun., 2011, Advance Article
DOI: 10.1039/C0CC04350H

Biological Logic Gates

As I have mentioned before, logic gates are not restricted to the textbooks of electronics, they are also exciting stuff for system biologists!

This group has constructed a bacterial 'AND' logic gate, and the Boolean logic behind its operation should be acceptable to any readers who has done Physics or Pascal Programming. The idea is to use 2 chemical molecules ('C12' and 'C4') as input signals and this leads to the biosynthesis of a molecule called phenazine. Phenazine provides an electron source and creates an electric current (in milliamperes). Thus the observable output is the generation of the electric current. This idea is indeed inspired by the biosynthetic route that takes place in the bacteria (see Figure 1).


Figure 1. The inspiration.


Figure 2. Some findings from the investigation.

We can all appreciate the outcome of the experiment - only when both input chemical signals are TRUE (when both C12 and C4 are present) will we have a TRUE output - electric current is generated. One intriguing aspect I will like to draw your attention to is the observation that when C4 is present alone in the medium, it generates a somewhat larger current than when C12 is present. (Figure 2) In theory, since both of these scenarios will contribute to a FALSE output, their result in the current reading should be similar. The explanation offered by the team is that as C4 comes later in the synthetic sequence, so its sole presence somehow contributes to a 'fake' signal to the system that the output should be TRUE. Obviously, since C12 is absent, it will not be possible to be assigned a TRUE value by Boolean Logic - therefore it is still FALSE. The conclusion: very impressive idea!

Reference:

Bacteria-based AND logic gate: a decision-making and self-powered biosensor Zhongjian Li, Miriam A. Rosenbaum, Arvind Venkataraman, Tsz Kin Tam, Evgeny Katz and Largus T. Angenent
Chem. Commun., 2011, Advance Article
DOI: 10.1039/C0CC05037G

Platinum wonders

This is impressive. Not only have they successfully made the fascinating (and elusive?) Pt (IV) complexes, their investigations also led us to a number of thought-provoking questions. First, can a Pd (II) / Pd (IV) parallel be drawn - this will definitely become useful insights to synthetic chemists. The system they have been using to achieve this is an interesting one - a pyridine linked to a fluorobenzene. The ortho hydrogen to the pyridine ring that has shown some intriguing interactions to the platinum centre. Thus if we modify the substituent group on the benzene to other types of functionality (e.g. EDG), the impact it will impart on this 'reactive hydrogen' is also worth looking at. This kind of makes sense because the authors have noted torsional effects on the phenyl-pyridine ring towards the energy profile. Of course, the alkyl group on the pyridine - which is where all the agostic interactions originate and the key to the formation of the Pt (IV) centre. It will also be great to see what will happen if we impart some form of restrictions to this side chains (e.g. installation of t-butyl group or a more complicated side chain) and probe the differences it will cause to the formation of the Pt(IV) centres. Overall, a very useful investigation.


Reference:
Platinum(IV) centres with agostic interactions from either sp2 or sp3 C–H bonds Sarah H. Crosby, Robert J. Deeth, Guy J. Clarkson and Jonathan P. Rourke
Dalton Trans., 2011, Advance Article
DOI: 10.1039/C0DT01428A

Textbook reaction with a twist

A nice demonstration of the classic 'synthetic logic' of heterocycles. This author makes useful imidazole derivatives with Zinc Triflate as the catalyst.

Reference:
A novel Zn-catalyzed hydroamination of propargylamides: a general synthesis of di- and tri-substituted imidazoles

Anahit Pews-Davtyan and Matthias Beller
Chem. Commun., 2011, Advance Article

DOI: 10.1039/C0CC04625F