Dissecting the Stereocontrol Elements of a Catalytic Asymmetric Chloroactonization: Syn Addition Obviates Bridging Chloronium.
By
Yousefi, Ashtekar, Whitehead, Jackson and Borhan
http://pubs.acs.org/doi/abs/10.1021/ja4072145
http://www.ncbi.nlm.nih.gov/pubmed/24025085
Funny story about this JACs communication (JACs 2013 135, 14524): I was reading this paper while riding a stationary bike at my campus gym, when a certain faculty member approached (name withheld to protect the guilty). He asked "What are you reading?". I showed him the paper and he said "That looks brutal!" I laughed. This science in this paper is excellent, but it was a poor choice by me for a blog that focuses on NMR. By the time I realized that the NMR methodology was not novel, I was too deep into the paper to pull back. Nevertheless, I think this publication is worth discussing, because it presents an interesting solution to a difficult diastereospecific assignment problem.
As an exercise for myself, I'll see if I can briefly describe the problem and why this paper is relevant to people interested in NMR. Then I'll show the author's data and interpretations.
Yousefi et al. are interested in the reaction below: an enantioselective halocyclizations of alkenes.
This type of chemistry is important as "a robust, versatile route a wide range of heterocycles." The specific question that the authors address is the following: Why is this reaction enantioselective? To address this question, the author use NMR spectroscopy of isotopically labeled precursors to assess the mechanism. Figure 1 describes the two proposed intermediates: path a - three-membered chlorenium ion intermediate; path b - carbocation intermediate. SPOILER ALERT (this part is in the title): It is path b.
These two mechanism offer some predicable consequence. If the reaction proceeds by path a, the "enantioselectivity would be controlled in parallel with the initial asymmetric chlorenium delivery, yielding anti addition". If the reaction proceeds by path b, "the reaction's enantioselectivity would be determined at the (presumably catalyst controlled) ring-closing step." If the author's can show syn addition, then path a can be ruled out. The problem demonstrating syn addition is that "the chlorine resides on a nonstereogenic carbon with no record of its attach path on the alkene." So it is not easy to determine the addition, unless you can somehow label the product!
The authors synthesize a E-deuterated analog of the alkene.
Then they perform the halocyclization reaction and analyze the products by NMR.
At this point I'll note that the publication itself has ZERO NMR spectra in any figure. So you'll have to dig through the SI to see any of their data. Here is the spectrum of their products.
No integrals or peaks picked, but I see 2 methylenes from the lactone at 2.5 and 2.8 ppm and the 5 phenyl protons at 7.4 ppm. At 3.75 ppm is the CH adjacent to the Cl. To remind you, below is the expected molecule for the protonated starting material:
One relevant factor to consider is that their deuterated analog is not perfect. They report 94:6 E:Z and 88% D-incorporation. So they have a bit of protonated product in with their deuterated product. Looking at this data I see a "roofed" non-first order CH2 from the protonated product (peaks at 3.815, 3.805 and 3.772 ppm with the final leg hidden under the big peak at 3.74 ppm) overlapping with two CHD diastereomers at 3.805 and 3.74 ppm.
The author's interpretation is explained in the following figure from the SI:
You may be asking how they know that c is the R,R or S,S diastereomer and f is the R,S or S,R diastereomer? This gets to the heart of the difficult problem in diastereospecific resonance assignment. Let me quote directly from the paper: "The absolute stereochemistry of the CHDCl group in the major isolate was straightforwardly established via NOE analysis of epoxide 3-D obtained from the chemically transformed chloroactone product 2-D"
To translate, the deuteratd epoxide (3-D) has a peak at 2.98 ppm in 1D 1H NMR spectrum. The protonated epoxide (3) has two peaks at 2.98 and 2.73 ppm. Using NOE, the peak at 2.98 is established as trans the phenyl group. (This data is nowhere to be found in the body of the paper or SI, by the way.) Hence the deuteron in 3-D must be cis. Retrosynthetic analysis can be used to establish the stereochemistry of the major product 2-D.
I'll leave it to the organic chemists to fight through their mechanistic arguments. Their NMR argument is interesting to me, though. Basically, the authors cannot complete diastereospecific assignment of 2-D using conventional approaches, so they modify the molecule in a stereochemically predictable manner to simplify the problem. I find this approach to be clever.
Like I said at the beginning, this article is not for the faint of heart. I don't know that I am really all that interested in mechanistic details of this reaction. My interest is in the NMR. Frankly, the authors do not wow me with their NMR, but I am intrigued by their solution to the diastereospecific assignment problem.
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